Articles about new Colorectal Cancer drugs, treatment methods, research etc.

RNA Interference Stops Colon Cancer Spread In Mice

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24 May 2006

Using one of the newest and most powerful tools of biomedical science, University of Texas Medical Branch at Galveston (UTMB) researchers have scored a dramatic success in the battle against colorectal cancer.

The scientists were the first to use what are known as "small interfering RNAs" to block the spread of human colorectal cancer cells implanted in laboratory mice. Small interfering RNAs (siRNAs), first described in 2001, are tiny bits of genetic material that can prevent the translation of genes into proteins -- including specific proteins involved in biochemical reactions that promote cancer and other diseases.

According to the federal Centers for Disease Control and Prevention, colorectal cancer is the country's second leading cancer killer. In 2002,
04 Apr 2006the most recent year for which statistics are available, 70,651 men and 68,883 women were diagnosed with the colorectal cancer in the United States; 28,471 men and 28,132 women died from the disease.

"What's exciting about this is that by using siRNAs we were able to selectively block components of the PI3K pathway, a biochemical pathway that is activated in a number of cancers, and suppress the spread of colon cancer in experimental animals," said UTMB professor of surgery B. Mark Evers, senior author of a paper on the research published in the June issue of Annals of Surgery. "Over the last couple of years people have talked a lot about cell-culture studies of siRNAs, but only a handful of labs have pushed it to animal models, which we need to do before going on to clinical trials."

To study the effects of siRNAs targeted against the PI3K pathway in mice, the researchers used a well-established technique in which human colorectal cancer cells were implanted into the spleens of genetically engineered immune-deficient "nude" mice. They then injected siRNAs designed to prevent the production of two specific PI3K proteins into the mice. The result was a major reduction in the spread of colorectal cancer to the liver.

Evers and the paper's other authors -- UTMB research fellows Piotr Rychahou and Lindsey Jackson and pathology professor Srinivasan Rajaraman -- also conducted a detailed analysis of the PI3K pathway's components and did experiments to determine how their siRNAs would affect colorectal cancer cell cultures. Scientists have already developed chemical inhibitors to attack the pathway (some of which are now in clinical trials), but toxic side effects limit their use.

"When we treat with siRNA and then follow the treatment with standard chemotherapeutic agents, we can markedly increase the rate at which cancer cells are killed," Evers said. "Since we have not seen any toxicity with these siRNAs in our mice, we think we can potentially also use them as a way to sensitize tumors and launch a combined attack that will allow us to achieve much better results with reduced side effects."

Jim Kelly
jpkelly@utmb.edu∞
University of Texas Medical Branch at Galveston
http://www.utmb.edu/∞
http://www.medilexicon.com/medicalnews.php?newsid=43954∞

Alcohol Consumption Habits May Threaten GI Health

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23 May 2006

Many studies have evaluated the risks and benefits of alcohol intake, with some concentrating on potential benefits while others focus on the risks of abuse. According to new research presented at Digestive Disease Week? 2006 (DDW), the volume of alcohol ingested and how it is mixed with other beverages can affect the health of the gastrointestinal (GI) system. DDW is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

"Many factors come into play when managing a healthy lifestyle. In this case, patterns of alcohol consumption may significantly affect digestive health," said Lee Kaplan, M.D., Ph.D., associate professor of medicine, Harvard Medical School and director of the Massachusetts General Hospital Weight Center. "Researchers explore a variety of drinking methods to differentiate which patterns are most harmful and which may have some beneficial protective effects."

Artificially Sweetened, Compared to Regular Mixers, Accelerate Gastric Emptying and the Rate of Alcohol Absorption [Abstract M2198]

When alcohol is mixed with beverages such as orange juice or soda, the rate of alcohol absorption into the blood stream depends not only on the individual, but also the "mixer." Researchers at the Royal Adelaide Hospital in Australia analyzed alcoholic beverages mixed with diet or regular soda (with sucrose) to determine the rate of gastric emptying and blood alcohol response. They found that alcohol combined with sugar-free mixers were processed through the stomach and entered the blood stream much more quickly than alcohol with regular mixers.

Researchers analyzed eight male volunteers who consumed orange-flavored vodka beverages with both a diet mixer and regular mixer. Participants were monitored to track the rate at which the mixer was emptied from the stomach and their subsequent blood alcohol concentration (BAC) levels.

From this study, the team discovered that the substitution of artificial sweeteners for sucrose in mixed alcoholic beverages may have a substantial effect on the rate of gastric emptying and the blood alcohol response. The time to empty half of the diet drink from the stomach was 21 minutes, compared to regular drinks which took 36 minutes for the same degree of emptying. Peak blood alcohol concentrations were substantially greater with diet drinks at an average of 0.05 percent, while regular drinks measured at 0.03 percent BAC.

"Today, more and more people are shifting personal preferences by choosing 'diet' drinks as a healthier alternative," said Chris Rayner, M.D., of Royal Adelaide Hospital and lead author of the study. "What people do not understand is the potential side effects that diet mixed alcoholic drinks may have on their body's response to alcohol."

Moderate Alcohol Consumption Protects Against Colorectal Adenomas [Abstract M2263]

In illnesses from cardiovascular disease to cancer, studies on alcohol consumption have revealed a wide spectrum of risks and benefits. Researchers from the University of North Carolina took a closer look at the effects of alcohol consumption on the risk of colorectal adenomas (polyps) and found that, surprisingly, moderate amounts of alcohol may have a protective effect against colorectal adenomas, a potential precursor to colorectal cancer.

Although previous analyses have identified an increased risk of colon cancer in conjunction with excessive alcohol consumption, only a few have examined in-depth the relationship between the amount of alcohol intake and the corresponding risk of colorectal adenomas and cancers.

To evaluate risk factors for colorectal adenomas, researchers implemented a case-control study of 725 eligible patients - 203 case and 522 controls. After undergoing a colonoscopy, participants were divided into five groups based on the average number of alcoholic drinks consumed per week: 1) 0 drinks per week; 2) >0 and <2 drinks per week; 3) 2 to <7 drinks per week (moderate drinkers); 4) 7 to <14 drinks per week; and 5) =14 drinks per week. The results were adjusted for the effects age, gender, body mass index (BMI), use of non-steroidal anti-inflammatory medications, race, and smoking status. When compared to non-drinkers and heavy drinkers, moderate drinkers (between >0 and <2 and 2 to<7 drinks per week) had the lowest adjusted probability of having an adenoma. Using moderate drinkers (>0 and <2 drinks per week) as the reference group, researchers found that non-drinkers were 41 percent more likely to have a colorectal adenoma. Patients consuming 7 to 14 drinks per week were 65 percent more likely to have an adenoma, and those consuming more than 14 drinks per week were two and a half times more likely to have an adenoma.

"Consuming alcohol within a moderate limit may be beneficial to the colon, but we cannot assume that the rate of alcohol consumption is the only factor," said Gregory Austin, M.D., of the University of North Carolina and lead study author. "It is vital that researchers take a broader approach into understanding the development of colorectal adenomas and the range of effects that various lifestyle choices or habits may have."
http://www.medilexicon.com/medicalnews.php?newsid=43870∞

EntreMed Initiates Combination Phase 2 Clinical Trial With Panzem(R) NCD In Carcinoid Cancer

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16 May 2006

EntreMed, Inc. (Nasdaq: ENMD), a clinical-stage pharmaceutical company developing therapeutics for the treatment of cancer and inflammatory diseases, today announced that it has commenced a Phase 2 clinical trial to evaluate the safety and efficacy of its lead clinical-stage drug candidate, Panzem(R) NCD, in combination with Avastin(R) (bevacizumab) in patients with locally advanced or metastatic carcinoid tumors. The study will be coordinated by Boston's Dana-Farber/Partners Cancer Care (DFPCC), a collaboration among The Brigham and Women's Hospital, Inc., Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Beth Israel Deaconess Medical Center (BIDMC). The study sites include the Dana-Farber Cancer Institute, Massachusetts General Hospital, and Beth Israel Deaconess Medical Center and will be conducted under the direction of Matthew Kulke, M.D. as principal investigator.

Panzem(R) (2ME2) is an orally-active small molecule that attacks tumor cells through multiple mechanisms of action and has antiangiogenic activity. Panzem(R) NCD, a liquid nanocrystal formulation of 2ME2, can attack tumors on multiple fronts -- directly by disrupting microtubules, an intracellular matrix necessary for the rapid division of cancer cells (mitosis), by inducing programmed cell death (apoptosis), and by blocking blood vessels that feed tumors (angiogenesis inhibition). Recent Phase 1bstudies with Panzem(R) NCD have shown that the pharmacokinetic target forantitumor activity was achieved and, additionally, that Panzem(R) NCD has an acceptable toxicity profile at the therapeutic dose. Panzem(R) NCD is currently in a Phase 2 clinical trial for brain cancer and a clinical trial in combination with Taxol(R) in metastatic breast cancer, both being conducted at the Duke University Medical Center.

"Patients with metastatic carcinoid tumors have very few effective treatment options. Combination chemotherapy, when used, generally results in a response rate of 10-15%. We believe that combining two agents with antiangiogenic activity represents a unique approach to treatment, and may produce higher response rates than combination chemotherapy or either antiangiogenic agent alone. Novel, effective therapies are needed to improve the outcomes for these patients," said Carolyn F. Sidor, M.D., M.B.A., EntreMed's Vice President and Chief Medical Officer.

Dr. Sidor further commented, "This clinical trial represents our second Phase 2 study for Panzem(R) NCD, and our first Phase 2 clinical trial in combination with an approved antiangiogenic agent. We look forward to working with the Dana-Farber/Partners Cancer Care team on this important study."
http://www.medilexicon.com/medicalnews.php?newsid=43485∞

Celecoxib May Help Prevent Colorectal Cancer In High Risk Patients, Studies Confirm

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04 Apr 2006

During the past year, the study of the potential use of COX-2 (cyclooxygenase-2) inhibitors to prevent Colorectal Cancer and breast cancer has come under intense scrutiny. Recent research questioned the safety of these medicines as pain relievers, which was the initial indication, as well as for chemoprevention of cancer. Now, the latest data show that COX-2 inhibitors are highly effective in preventing pre-malignant tumors of the colon, and therefore may be useful in preventing colorectal cancer among high-risk patients.

According to two studies presented today at the 97th Annual Meeting of the American Association for Cancer Research, the over-expression of the COX-2 enzyme is related to the growth and spread of colorectal tumors. COX-2 inhibitors may reduce the occurrence of the precursor,colorectal adenomas(benign tumors) in patients with a family history of the disease, as well as the development of sporadic colorectal tumors.

Celecoxib reduces sporadic colorectal adenomas: Results from the Adenoma Prevention with Celecoxib (APC) trial.: Abstract No. CP-3 Investigators from the Adenoma Prevention with Celecoxib Study (APC) enrolled 2,035 patients to a randomized, double-blind trial of the COX-2 inhibitor, celecoxib (Celebrex?), to prevent colorectal adenomas. Results of the study revealed that celecoxib significantly reduced the formation of large intestinal adenomas during a 3-year period after removal of polyps in patients at high risk of developing colorectal cancer.

Of the participants, 679 patients received a placebo, 685 patients received 200 mg of celecoxib and 671 patients received 400 mg of celecoxib, administered twice daily. The randomization of this trial took into consideration the use of low dose aspirin in 31 percent of participants. A follow-up colonoscopy was conducted in 89 percent of participants after one year and 76 percent received a follow-up colonoscopy at three years.

The incidence of one or more benign tumors during colonoscopy was 61 percent in those taking placebo; in patients taking celecoxib this percentage was reduced by 45 percent (p<0.0001). The relative risk of advanced neoplasms (tumor) with adenomas more than one centimeter in diameter or with tubulovillous or villous features (premalignant rectal polyps), severe dysplasia (abnormal growth) or invasive cancer were also drastically reduced in patients using celecoxib, with 66 percent fewer tumors in these patients (p<0.0001).

"The results of this study show that patients at risk for developing colorectal cancer have dramatically fewer pre-malignant tumors when they take celecoxib," said Monica Bertagnolli, M.D., associate professor of surgery, Harvard University, Boston, Mass.

"This work shows that drugs that inhibit COX-2 activity are important tools in developing effective preventive therapies for colorectal cancer," she said.

Chemoprevention of Colorectal Adenomas With Celecoxib in an International Randomized, Placebo-Controlled, Double-Blind Trial: Abstract No. CP-3

A prior study has shown that administration of the COX-2 inhibitor, celecoxib, is associated with a reduction in colorectal adenoma size and number in familial adenomatous polyposis (FAP). Therefore, researchers in the Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP) with Celecoxib Trial tested the effectiveness of celecoxib in reducing the incidence of sporadic colorectal adenomas.

The PreSAP study was a randomized, double-blind, placebo-controlled study enrolling 1,561 patients at 107 sites in 32 countries. PreSAP researchers hoped to determine the effectiveness of taking 400 mg celecoxib once daily to reduce the number of patients with new adenomas and the grade, size and number of new adenomas.

The trial started in March 2001 with patients who had undergone removal of all colorectal polyps, known as a polypectomy. Patients were excluded if they had FAP, hereditary nonpolyposis colorectal cancer (with an absence of polyps) or a history of inflammatory bowel disease. During the trial, patients did not take nonsteroidal anti-inflammatory drugs (NSAIDs) except cardioprotective doses of aspirin.

"Results of our study showed that celecoxib holds great promise for the prevention of cancer," said Nadir Arber, M.D., M.Sc., Head, Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Israel. "For patients at high-risk of developing colorectal cancer, celecoxib may be considered while weighing the risk of potential cardiovascular events."

Patients were split into a 3:2 ratio of celecoxib and placebo and divided by baseline aspirin use (17 percent, placebo; 16.6 percent celecoxib) or non-use(83 percent placebo; 83.4 percent celecoxib); 933 patients received celecoxib and 628 received placebo. Of the total patients, 88.7 percent underwent a colonoscopy with or without removal of polyps at one year and 79.2 percent at year three.

The administration of celecoxib was stopped after the Adenoma Prevention with Celecoxib (APC) study found at 33 months a two-to-three-fold increase in serious adverse cardiovascular events. PreSAP data at the time of the APC announcement indicated a hazard ratio of 1.2 for those taking celecoxib compared with placebo for death from cardiovascular events and nonfatal heart attack or stroke.

The incidence of adenomas at year three was 49.3 percent in the placebo group, but significantly lower in the group taking celecoxib (p<0.0001). In high-risk patients, the recurrence was also greatly reduced (p=0.0002). The prevalence of adverse events was similar in both the placebo (74 percent) and celecoxib groups (76.8 percent), although patients taking celecoxib had a higher risk of cardiovascular events than those taking placebo (7.5 percent versus 4.6 percent).

Said Dr. Arber, "Research has shown that in order to reduce incidence of cancer, we need to develop better prevention methods for those at highest risk of developing the disease.

"We are encouraged by these results and hope the data from both the APC and PreSAP trials lead to the continuation and implementation of additional clinical trials with COX-2 inhibitors for the prevention of colorectal and other cancers, such as breast. Understanding the molecular mechanisms by which these compounds work is another important scientific goal."
http://www.medilexicon.com/medicalnews.php?newsid=40841∞

Celebrex May Have Colon Cancer Protecting Qualities

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04 Apr 2006

New research indicates that controversial Cox-2 inhibitors may protect patients from developing colon cancer, especially in high-risk individuals. Celebrex is a Cox-2 inhibitor.

There has been a great deal of controversy surrounding Cox-2 inhibitors because of their cardiovascular risks. Cox-2 inhibitors are anti-inflammatory drugs (used for pain relief). They are safer for the stomach than most other pain relievers. Vioxx and Bextra were withdrawn from the market. The only Cox-2 inhibitor still available is Celebrex.

Two studies presented at the American Association for Cancer Research, Washington D.C., USA, indicate that these types of drugs may protect people from colon cancer.

APC Study

One study, called APC (Adenoma Prevention with Celecoxib), included 2,000 patients who were high-risk (for developing colon cancer) - some of them were given either 200 or 400 milligrams of Celebrex, twice a day. Others were given a placebo.

One year and three years later the 2,000 patients underwent colonoscopies.

The scientists found that among the patients given Celebrex, the incidence of at least one benign tumor was 45% lower (than the placebo group). Also, the Celebrex group had a 65% lower chance of developing more serious conditions, such as invasive cancer. As the patients had a 100% to 200% higher chance of developing serious cardiovascular problems the study was stopped early.

PreSAP Study

This study, called Prevention of Colorectal Sporadic Adenomatous Polyps (PreSAP), examined how effective Celebrex might be in protecting patients from sporadic colorectal adenomas.

1,561 patients, selected randomly, were either given 400 milligrams of Celebrex, once a day, or a placebo. All the patients had undergone colorectal polyps removal (all of them). After a follow-up three years later, the Celebrex group had a significantly lower incidence of polyps when compared to the placebo group.

In both trials all participants were given aspirin.
http://www.medilexicon.com/medicalnews.php?newsid=40963∞

Blood Pressure Drugs Associated With Reduced Risk Of Esophageal, Pancreatic And Colon Cancers

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24 May 2006

Thousands of individuals currently taking angiotension converting enzyme (ACE) inhibitors, a type of medication commonly used to lower blood pressure, may be doing more than treating their hypertension. According to research presented today at Digestive Disease Week? 2006 (DDW), ACE inhibitors not only effectively lower blood pressure, but they are also associated with a significant decrease in risk of developing three types of cancers: esophageal, pancreatic and colon. DDW is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.

Using a study population of nearly 500,000 U.S. veterans, researchers from the Overton Brooks VA Medical Center in Shreveport, LA, completed three case-controlled studies examining the correlation between ACE inhibitor use and esophageal, pancreatic and colon cancer incidence. The team analyzed statistics from the Veterans' Integrated Service Network (VISN 16) database, a resource tool containing information about every veteran that has received care from the South Central VA Health Care Network from October 1998 to June 2004. Among the 483,733 patients in the study, 659 had esophageal cancer, 475 had pancreatic cancer, and 6,697 had colon and rectal cancer; approximately 38 percent were taking ACE inhibitors.

While ACE inhibitors were associated with a reduction in risk for all three cancer types, it was most effective in lowering the risk of developing esophageal cancer, with a 55 percent risk reduction as compared to the controls. Results from the second study showed that ACE inhibitor use offered a 48 percent reduced risk of pancreatic cancer. And in the third study, investigators found that ACE inhibitor use was associated with a 47 percent reduced risk of colon cancer.

The studies were controlled for age, race, gender, body mass index, smoking, alcohol use, reflux, non-steroidal anti-inflammatory (NSAID) use, diabetes and statin use. However, dosage, duration and type of ACE inhibitor used were not factored into the analyses.

"Our results call for further studies to investigate the promising benefits of ACE Inhibitors in cancer prevention," said Vikas Khurana, M.D., lead study author from the Overton Brooks VA Medical Center in Shreveport, LA. "Through confirmatory research we hope to shed light on the valuable role ACE inhibitors may play in advancing current treatment options for multiple cancers." Researchers believe the potential benefit of ACE Inhibitors against cancer may be due to the suppression of tumor angiogenesis by blocking a growth protein called VEGF (Vascular Endothelial Growth Factor), which is believed to play a significant role in the growth and reproduction of tumors.

Digestive Disease Week? (DDW) is the largest international gathering of physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery. Jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE) and the Society for Surgery of the Alimentary Tract (SSAT), DDW takes place May 20-25, 2006 in Los Angeles, California. The meeting showcases more than 5,000 abstracts and hundreds of lectures on the latest advances in GI research, medicine and technology.
http://www.medilexicon.com/medicalnews.php?newsid=43960∞

Callisto Announces Plan To Initiate A Single Agent Phase II Clinical Trial Of Atiprimod In Advanced Carcinoid Cancer Patients

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28 Jun 2006

Callisto Pharmaceuticals, Inc. (Amex: KAL)(FWB:CA4), a developer of new drug treatments in the fight against cancer and other major health threats, announced today the decision to initiate a single-agent Phase II clinical trial of Atiprimod in advanced carcinoid cancer patients. Originally planned as a Phase I/IIa trial, the decision to proceed directly to Phase II was based on a careful review of the Atiprimod safety and toxicity data obtained from the two ongoing trials of Atiprimod in advanced cancer and multiple myeloma patients, respectively. Based on these data, a fixed dosing regimen has been finalized for the planned single-agent Phase II trial in advanced carcinoid cancer patients. The finalized protocol is being submitted to the Institutional Review Boards of the 3 key sites planned for the carcinoid cancer trial with the hope of having this trial underway in the next few months.

"The decision to alter the next Atiprimod trial in carcinoid patients from a Phase I/IIa to a Phase II trial is an extremely important step for Callisto," said Gary S. Jacob, Ph.D., Chief Executive Officer of Callisto. "It will considerably speed up the rate at which we can get to a determination of the potential of Atiprimod to treat advanced carcinoid patients. Close to 100 patients have now been treated with this drug in Phase I clinical trials in rheumatoid arthritis, multiple myeloma and advanced cancer patients and we are very comfortable with the safety profile of this drug."

"We are very excited to be able to go directly into a pilot phase II clinical trial planned to involve approximately 30 patients to determine this drug's efficacy in a tumor where patients have very few treatment options," said Dr. Arthur Sytkowski, Consulting CMO and Medical Monitor of Callisto Pharmaceuticals. "The tumor regression and reduction in symptoms seen in the carcinoid patients from the earlier advanced cancer trial is very encouraging and indicates that a Phase II trial of Atiprimod specifically to treat advanced carcinoid patients is clearly warranted."

Atiprimod is an orally bio-available small molecule drug that displays multiple mechanisms of action. The drug has been shown to be antiangiogenic, inhibit secretion of VEGF and IL-6, elicit an apoptotic response (programmed cellular death), and inhibit phosphorylation of key kinases involved in tumor progression and survival including Akt and STAT3. Callisto earlier announced on June 2, 2006 interim data from a Phase I trial of Atiprimod in advanced cancer patients. The patients who were entered into this Phase I trial had growing tumors and symptoms that were no longer controlled by the standard therapies utilized. During treatment, three of the five advanced carcinoid patients had measurable tumor regressions and loss of many of the debilitating symptoms of this disease. Importantly, one patient remained on drug through 7 cycles (seven months), exhibiting significant tumor regression.
http://www.medilexicon.com/medicalnews.php?newsid=46049∞

Metastatic Colorectal Cancer In Patients Who Have Failed Prior Chemotherapy - License Application For FDA Approval Of Panitumumab

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03 Apr 2006

Amgen (Nasdaq: AMGN) and Abgenix, Inc. (Nasdaq: ABGX) today announced that Amgen has completed the Biologic License Application (BLA) submission with the U.S. Food and Drug Administration (FDA) for panitumumab. The potential indication is for the treatment of metastatic colorectal cancer in patients who have failed prior chemotherapy, including oxaliplatin and/or irinotecan containing regimens. The rolling BLA submission was initiated in December 2005.

"The pivotal Phase 3 study of panitumumab not only met the primary endpoint of improving progression-free survival in patients with metastatic colorectal cancer, but the results surpassed our expectations based on preset measurement criteria in the protocol," said Willard Dere, M.D., chief medical officer and senior vice president of Global Development at Amgen. "Completing the BLA brings us one step closer to realizing our goal of making panitumumab accessible to patients with metastatic colorectal cancer who have failed available treatment options."

Amgen and Abgenix previously announced that data from a randomized Phase 3 trial involving 463 patients showed that those who received panitumumab every two weeks showed a 46 percent decrease in tumor progression rate versus those who received best supportive care alone (p less than 0.000 000 001). The most common side effect was acneiform rash. Other side effects less commonly observed were fatigue, nausea and mild diarrhea.

Results from this pivotal Phase 3 study will be presented in a Clinical Plenary Session at the 97th Annual Meeting of the American Association for Cancer Research on April 3, 2006. Amgen will host a webcast with the investment community to discuss the results on Monday, April 3, 2006, at 12:30 P.M. EDT. Open to members of the news media, investors and the general public, the webcast can be found on Amgen's Web site, www.amgen.com, under Investors. It will be archived and available for replay at least 72 hours after the event.
http://www.medilexicon.com/medicalnews.php?newsid=40763∞

Targeted Therapies Showing Great Promise Against Colorectal Cancer

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04 Apr 2006

Results from a Phase III study of a new drug show promise for patients with colorectal cancer that has spread to other parts of the body, according to a study presented today during the 97th Annual Meeting of the American Association for Cancer Research.

Investigators have shown that panitumumab improves progression-free survival in patients with metastatic colorectal cancer (mCRC) who had failed standard chemotherapy. In the randomized trial of 463 patients, those who received panitumumab with best supportive care every two weeks (231 pts) showed a 46 percent decrease in the rate of tumor progression or death versus those who received only best supportive care (232 pts). At week 24, approximately four times as many pantimumab patients were alive and progression-free versus those on best-supportive care (18 percent versus five percent). Twice as many panitumumab patients were alive and progression-free at week 32 (10 percent versus four percent).

Study investigators also reported that panitumumab significantly improved disease control. In patients who responded, the median duration of response was 17 weeks. Extended follow-up also revealed that even after 32 weeks, a larger percentage of patients in the panitumumab with best supportive care group were alive without progression than in the group assigned to best supportive care alone.

"We are encouraged by these results, particularly that panitumumab was well- tolerated in patients with metastatic colorectal cancer, with very few major adverse reactions," said Marc Peeters, M.D., Ph.D., coordinator of the Digestive Oncology Unit, from Ghent University Hospital in Belgium.

Recently, researchers have begun to focus their efforts on developing cancer therapies that are not only effective, but also are easier on the body than current therapies. Using newer therapies that are derived from human protein sequences, investigators are finding that the body is less likely to develop side effects from these drug,s such as allergic reactions.

Panitumumab is the first fully human monoclonal antibody that targets the epidermal growth factor receptor (EGFr), a protein that plays an important role in cancer cell signaling. EGFr activates when naturally occurring proteins in the body, such as epidermal growth factor (EGF), bind to it and trigger signals to encourage cell growth. Panitumumab binds to EGFr, preventing the natural protein from binding to it and interfering with the signals that would otherwise stimulate growth of the cancer cell and allow it to survive.

"Studies involving the use of panitumumab alone and in combination with other therapies for various cancers may confirm that the use of human monoclonal antibodies is a great step forward to effectively treat cancer," said Dr. Peeters.

The most common side effect was rash, and other lesser side effects included fatigue, nausea and diarrhea. No anti-drug antibody formation was observed.
http://www.medilexicon.com/medicalnews.php?newsid=40840∞

Stool Testing Novel Technique For Detecting Colon Cancer

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29 May 2006

Researchers at Mount Sinai School of Medicine have found that an improved version of the non-invasive fecal DNA (fDNA) test to screen for colon cancer (CRC) demonstrates a higher sensitivity for detecting cancers of the colon. This data will be presented at the Digestive Disease Week (DDW) conference on May 21, 2006 in Los Angeles.

Previous studies have shown that a first generation fDNA test (PV1) was effective in the detection of colon cancer but partial degradation of DNA was a limitation. Using a second-generation test, the research team, led by Dr. Steven Itzkowitz, primary goal was to determine the sensitivity (SENS) and specificity (SPEC) of the new test in patients with known CRC and those with normal colonoscopies (NL). Compared to PV1 data, the addition of buffer and gel-capture technology, as well as new markers of colon cancer, increased test sensitivity for cancer detection to 88%.

?This is an exciting achievement for this technology. Fecal DNA testing has already shown promise for non-invasive tool for colon cancer detection. But, we can now say this test is more sensitive which ultimately means better results for the clinician and the patient. Better tests mean greater detection and less loss of life,? said Steven Itzkowitz, M.D., Professor and Associate Director of Gastroenterology at The Mount Sinai Medical Center. ?The fact that the new version of the test includes fewer markers makes the new test even easier to perform.?

Patients in this prospective multi-center study were enrolled and consented after colonoscopic findings of either a normal colon (n=122) or CRC (n=40). Patients had no personal or family history of CRC or polyps. Approximately 6-14 days after colonoscopy (prior to surgery for the CRC group), patients submitted a single stool sample to which they had immediately added buffer and then shipped the specimen by express courier to the clinical lab. Stools were homogenized and DNA was extracted using sequence-specific gel-capture.
http://www.medilexicon.com/medicalnews.php?newsid=44231∞

3-D Imaging That Flies "through" And "around" Lung And Colon Cancer: Coming Soon

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16 Jul 2006

Stanford University researchers demonstrated for the first time the ability to create 3-D positron emission tomography (PET)/computed tomography (CT) images for "fly-through" and "fly-around viewing" of cancer in the lungs and colon, according to a study in the July issue of the Journal of Nuclear Medicine.

This powerful ability to meld functional data with accurate anatomical information of possible cancerous tumors--from inside the body--provides a visual navigation of organs oftentimes portrayed on television crime shows like "CSI." Such visualization "may be used to detect and characterize cancer, spare someone from more invasive medical procedures, lead to better disease detection rates of colon cancer, provide surgical guidance and detect which tumors may be easier to biopsy," detailed Andrew Quon, clinical assistant professor of radiology/diagnostic radiology at California's Stanford University.

"Three-dimensional fusion provides unique views of the body that internal organs typically impede," said Quon. "Our new imaging and processing protocol can peel away the organs, highlight tumors and detect cancerous 'hot spots'--providing an omnipotent perspective of the body," he indicated. Stanford's 3-D fusion imaging "appears to have potential for presurgical visualization, particularly in guiding biopsies," explained the co-author of "'Flying Through'" and 'Flying Around' a PET/CT Scan: Pilot Study and Development of 3-D Integrated 18F-FDG PET/CT for Virtual Bronchoscopy and Colonoscopy." This imaging technique "may add important diagnostic information that may herald new applications for the use of PET/CT," he noted. In addition, its diagnostic value was demonstrated in one case in which it revealed a cancer lesion that had not been detected by PET, CT or PET/CT imaging. "This one case shows the potential synergistic enhancement of both PET and CT when rendered into three dimensions," said Quon.

PET and CT are standard imaging tools that can be used to pinpoint the location of cancer within the body. When PET is used to image cancer, a radiopharmaceutical (such as fluorodeoxyglucose or FDG, which includes both a sugar and a radionuclide) is injected into a patient. Cancer cells metabolize sugar at higher rates than normal cells, and the radiopharmaceutical is drawn in higher concentrations to cancerous areas. The highly sensitive PET scan picks up the metabolic signal of actively growing cancer cells. The CT scan generates a detailed picture of internal anatomy, locating and revealing the size and shape of abnormal cancer growths. When these two results are fused together, the functional data from the PET imaging is correlated with anatomy on the CT images to provide a single detailed and informative image.

Standard 2-D PET and PET/CT images (with FDG) are accurate for evaluating lung and colorectal cancer; however, they lack the anatomic information that can be provided by 3-D images from a multidetector CT scan. Even so, with 3-D CT scans, small and flat lesions in the lungs and colon are difficult to see or characterize, said Quon. "Our study takes this to another level," he noted, indicating that fused PET/CT images with 3-D volume rendering may provide additional beneficial information for image interpretation and create new areas of clinical application. While this technology may become standard over the next three to five years, "it could have exciting applications in cardiovascular imaging, providing 3-D views of blood vessels and possibly identifying individuals at risk for heart disease," he predicted.

In the case of a patient with colorectal cancer--a term used to refer to cancer that develops in the colon or rectum and is the second leading cause of cancer-related deaths in the United States--the current standard of care is a colonoscopy, a procedure where a long, flexible, lighted tube is inserted into the rectum and guided slowly into the colon. The tube or scope transmits an image of the inside of the colon onto a video screen so its lining can be examined.
While the initial findings are exciting, the researchers proved the concept rather than validated the technique. Future validation studies will be conducted and software tools need additional development, said Quon, who indicated that the technique might be expanded to include other tracers and anatomic regions besides the chest and colon.

"'Flying Through'" and 'Flying Around' a PET/CT Scan: Pilot Study and Development of 3-D Integrated 18F-FDG PET/CT for Virtual Bronchoscopy and Colonoscopy," appears in the July issue of the Journal of Nuclear Medicine, which is published by SNM. Besides Quon, co-authors include Sandy Napel, Christopher F. Beaulieu and Sanjiv Sam Gambhir, all with the radiology and bioengineering departments, Molecular Imaging Program, Stanford, University, Stanford, Calif.
http://www.medilexicon.com/medicalnews.php?newsid=47184∞

Aspirin And Other NSAIDs May Not Reduce The Risk Of Colorectal Cancer In Long-term Smokers

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05 Jul 2006

It is widely known that the use of aspirin and other nonsteroidal anti-inflammatory drugs, or NSAIDS, may reduce the risk of colorectal cancer by up to 40 percent, but this protective effect may not extend to long-term smokers, who already face an increased risk of the disease, according to a study led by researchers at Fred Hutchinson Cancer Research Center.

In a large, population-based study comparing risk factors in people with and without colorectal cancer, the researchers found the highest risk of colon cancer to be among long-term smokers of 20 or more years who had never used NSAIDs. The researchers also found that smokers who used NSAIDs were still at an approximate 30 percent higher risk of colon cancer than nonsmokers.

The findings, which appeared in the July 1 issue of Cancer Research, arise from the first study of its kind to examine the effects of NSAID use on colorectal-cancer risk among smokers, said first author Victoria Chia, a research associate in the Hutchinson Center's Cancer Prevention Program.

"Smoking has been linked to a modestly increased risk of colorectal cancer, and use of NSAIDs has been shown to significantly decrease the risk of colorectal cancer. We wanted to see if NSAIDs could counteract the adverse effects of smoking with regard to colorectal-cancer risk, and whether these associations differed by tumor characteristics," she said.

In particular, Chia and colleagues were interested in examining the impact of NSAIDs on a certain type of colorectal tumor that may be associated with smoking. Such tumors display microsatellite instability, an acquired genetic characteristic that indicates defects in DNA-repair machinery. Microsatellite instability, or MSI, occurs in approximately 15 percent to 20 percent of colon cancers.

The researchers found a two-fold increased risk of microsatellite-unstable colorectal tumors among long-term smokers who took NSAIDs -- about the same risk as smokers who had not used NSAIDs.

"Given the damage that smokers receive over their lifetime, even strong anti-progression agents, like NSAIDs, may be ineffective," the authors wrote. "NSAIDs may not be able to counteract the long-term effects of smoking, as evidenced by our observation that long-term smokers are at increased risk of colorectal cancer, despite current NSAID use."

The link between smoking and cancer stems from the fact that cigarette smoke contains hundreds of carcinogenic metabolic products that may damage DNA. "This accumulated damage might not be reversible," Chia said. "NSAIDs act to suppress inflammatory processes and may help limit the progression toward cancer. However, people who have microsatellite-unstable tumors may be even more susceptible to the effects of smoking because they already have a reduced capacity to repair DNA, even in the presence of strong anti-inflammatory agents."

Funded by the National Cancer Institute and the National Institutes of Health, the study involved 3,299 Seattle-area residents between the ages of 20 and 74 (mean age 60), approximately half with a history of colon cancer and approximately half without, who served as a control, or comparison group. Cancer cases were identified through the Puget Sound Surveillance, Epidemiology and End Results Program, a population-based registry. Controls were randomly selected to match the distribution of the cases regarding age and sex. Participants were interviewed by telephone about their smoking history and use of aspirin and other NSAID use, among other risk factors. Microsatellite instability was assessed in tumors from 1,202 cases.

Smoking was more common in cancer cases than controls, and NSAID use was more common among controls than cases.

Researchers from the Mayo Clinic College of Medicine collaborated on the study.
http://www.medilexicon.com/medicalnews.php?newsid=46451∞

Large International Phase III Trial In Metastatic Colorectal Cancer Meets Primary Endpoints For XELOX (Xeloda(R) + Oxaliplatin) And For Avastin

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01 Aug 2006

Roche announced today that a large, international Phase III study (NO16966) enrolling 2,035 previously untreated metastatic colorectal cancer patients met both primary endpoints. Results of the study showed that:

-- The chemotherapy combination Xeloda plus oxaliplatin, called XELOX, is as effective in terms of progression-free survival (PFS) -- a measure of the time patients live without their disease progressing -- as infused 5-FU/LV (5-fluorouracil/leucovorin) plus oxaliplatin, called FOLFOX;

-- The addition of Avastin to chemotherapy (FOLFOX and XELOX) significantly improved progression-free survival compared to chemotherapy alone.

Some variability in subgroup analyses for efficacy was observed. No new safety signals related to Avastin were observed in the trial.

"This is the first time we have significant data showing that oral Xeloda in combination with oxaliplatin is as effective as FOLFOX," said Lars E. Birgerson, Vice President, Medical Affairs, Roche. "This study demonstrates that oral Xeloda plus oxaliplatin (XELOX) provides a new treatment option for colorectal patients. These data again show the benefits of adding Avastin to chemotherapy. In this trial, Avastin combined with XELOX and FOLFOX improved the chance of delaying progression of the disease by 20% in patients with advanced colorectal cancer. Furthermore, the results of this study underscore the tremendous potential of combinations using cornerstone therapies such as Xeloda."
http://www.medilexicon.com/medicalnews.php?newsid=48399∞

Soy And Fish Have Cancer Preventing Qualities

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19 Nov 2006

If you give your child soy and soy products regularly, the chances of developing breast cancer later on in life is reduced. If you are a man and each fish regularly, your risk of developing colon cancer is lower than a man who does not eat fish regularly. This is according to two studies, the first carried out by researchers at the National Cancer Institute (USA) and the University of Hawaii, and the second at the Harvard School of Public Health.
Both studies were presented at an American Association for Cancer Research meeting, Boston, USA.

In this first study, the researchers looked at data on 1563 Asian/American women, of whom 597 had breast cancer and 966 did not. They found that the women who had eaten (aged 5-11) large quantities of tofu, miso and other soy products were 58% less likely to develop breast cancer as adults, compared to those who had eaten very little soy products. Even adolescent women/girls and adult women who regularly consumed soy products had a 25% lower chance of developing breast cancer.

The researchers suspect isoflavones, which are present in soy and have a similar effect to estrogens, may be the ingredients that offer the cancer protection.

The other study found that men who ate fish at least five times a week were 40% less likely to develop colon cancer compared to men who consumed fish once a week or less.

"Diet Can Provide Protection against Development of Certain Cancers, New Studies Show"
American Association for Cancer Research
http://www.medilexicon.com/medicalnews.php?newsid=57080∞

Statin Use Not Associated With Colorectal Cancer Risk

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05 Jan 2007

Regular use of cholesterol-lowering drugs called statins is not associated with a reduced risk of colorectal cancer, according to a population-based case-control study.

Laboratory tests of statins have found anticancer effects on colon cancer cells. One case-control study of people found that use of statins for at least 5 years reduced the risk of colorectal cancer by 50 percent. To further understand the possible association between statin use and colorectal cancer risk, Patricia F. Coogan, Sc.D., and colleagues at the Boston University School of Medicine used the Massachusetts Cancer Registry and hospital tumor registries to identify 1809 patients with colorectal cancer. They interviewed each patient, gathering data on medical history and medication use, including statins and non-steroidal anti-inflammatory drugs (NSAIDs), such as asprin. The researchers also used town registries to identify 1809 people without colorectal cancer who were similar in age, sex, and town precinct.

The researchers initially found a modest association between statin use and decreased colorectal cancer risk. However, after they took into account how often people took NSAIDs, the association between statin use and colorectal cancer risk disappeared. No association was found among recent, continuing, or discontinued users of statins, nor was there an association at various doses of statins. The researchers did find that use of NSAIDs alone was associated with a 21 percent decreased risk of colorectal cancer. They also found an association between statin use and reduced risk of stage IV colorectal cancer, a finding, the authors say, requires further confirmation.

Contact: Gina Digravio, Media Relations Manager, Boston University Medical School
http://www.medilexicon.com/medicalnews.php?newsid=60060∞

AstraZeneca Announces Recentin(R) As Global Trademark For Novel Cancer Treatment, AZD2171

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10 Jan 2007

AstraZeneca today announced RECENTIN? as the global trademark for AZD2171, its oral, highly potent and selective vascular endothelial growth factor (VEGF) signalling inhibitor. AZD2171 is currently in Phase II/III development for advanced non-small cell lung cancer (NSCLC) and advanced colorectal cancer (CRC) - as well as a wide-ranging signal search programme in other tumours.

Ian Triggs, Global Brand Strategy Director for AZD2171 commented:
"The announcement of a brand name represents a key milestone in the development of AZD2171"

Dr Nick Botwood, Global Medical Director for AZD2171, added:
"Pre-clinical data shows this compound is a potent suppressor of angiogenesis - an established approach in anti-cancer treatment. More importantly, early clinical trial data has also shown encouraging anti-tumour activity with AZD2171 and a side effect profile that appears to be predictable and manageable. The ongoing trial programme will be important to establish how AZD2171 may add to the treatment options currently available to patients."

VEGF is a key driver of angiogenesis - the formation of new blood vessels. By inhibiting VEGF receptors, AZD2171 hinders angiogenesis, thus preventing the blood supply that tumours need to grow and spread. There are three VEGF receptors involved in tumour angiogenesis, (VEGFR-1, VEGFR-2, VEGFR-3).

AZD2171 inhibits all three,1 in particular VEGFR-2, the predominant receptor through which VEGF exerts its effect on angiogenesis.

RECENTIN? is a trademark of the AstraZeneca group of Companies.
http://www.medilexicon.com/medicalnews.php?newsid=60506∞

MClone Systems Incorporated And Bristol-Myers Squibb Announce Application In Japan For Use Of ERBITUX In Metastatic Colorectal Cancer

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11 Feb 2007

ImClone Systems (NASDAQ: IMCL) and Bristol-Myers Squibb Company (NYSE: BMY) announced today that an application has been submitted with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) for the use of ERBITUX? (Cetuximab) in treating patients with advanced colorectal cancer. ERBITUX is the first IgG1 monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR) to be submitted for marketing authorization in Japan.

The Japanese submission was based on results from studies conducted in Europe and Japan which confirm the activity of ERBITUX in patients with metastatic colorectal cancer.

In Japan, the incidence of colorectal cancer has increased markedly during the last 50 years(1). Among men and women in Japan, the incidence is higher than for lung cancer (95,651 per year vs 66,453) and second to stomach cancer (95,651 per year vs 109,779). In terms of mortality, the ranking is slightly different: Colorectal cancer is now the third biggest cancer threat in Japan after lung and stomach cancer (38,206, 56,367 and 54,423 people per year, respectively)(2). Approximately 25 percent of colorectal cancer patients present with metastatic disease(3).

The filing in Japan is a result of a development collaboration between ImClone Systems, Bristol-Myers Squibb, and Merck 22KGaA"" of Darmstadt, Germany.
http://www.medilexicon.com/medicalnews.php?newsid=62804∞

The Multi-Tasking Reovirus Kills Cancer Cells And Primes The Immune System

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09 Feb 2007

In the past couple of years, researchers at Oncolytics Biotech have been developing a harmless virus as a potent cancer killer, but they have also been accumulating data that suggests in addition to directly killing tumor cells, the reovirus may prime the immune system to mount a separate, powerful and long lasting defence against cancer.

Evidence for this theory has been mounting for the past year. On January 10, 2007, Dr. Sheila Fraser of St. James's University Hospital in Leeds, U.K. delivered a paper at the Society of Academic & Research Surgery Conference in Cambridge, U.K., in which she described a test tube experiment further supporting this claim. Fraser's presentation, titled "Reovirus as a Potentially Immunogenic as well as Cytotoxic Therapy for Metastatic Colorectal Cancer," reported how cells taken from a colorectal cancer liver metastases were more susceptible to death many weeks after treatment with reovirus, and long after the virus had cleared the patient's system. These cells, when cultured in the laboratory, also appeared to be vulnerable to re-infection with reovirus. Moreover, Dr. Fraser noted that dendritic cells, which prime the immune system against cancer, were activated by exposure to the reovirus.

"We understand how the reovirus replicates within and kills cancer cells," explains Dr. Matt Coffey, Chief Scientific Officer at Oncolytics, "but we also observed that tumors sometimes continue to shrink long after the virus is gone." Immunologic work now suggests that reovirus exposure is "educating" the immune system to recognize and kill the same cancer cells that were attacked by reovirus. "If you can teach the immune system to recognize cancer cells," says Coffey, "it may be possible to fight off the disease for much longer than we originally anticipated."

Late in 2006, another collaborator, Dr. Alan Melcher of the Cancer Research UK Clinical Centre in Leeds, hypothesized that reovirus activation of dendritic cells, which are key to early detection of infection (through the innate immune response), may "instruct" cells belonging to the adaptive immune response, namely natural killer cells and T cells, to attack the tumor even after the virus no longer remains in the body. That poster was presented at the European National Societies of Immunology Meeting in Paris.

Interestingly, another study conducted in 2006 at the Mayo Clinic suggested that momentarily suppressing the immune system allows the virus to continue replicating, leading to increased cancer cell killing. This in turn leads to the creation of more tumor antigens (the elements that educate the immune system), thereby increasing the vaccinating effect of the virus and perhaps improving the efficacy of oncolytic virus therapy.

"The apparent dual mechanism of action for oncolytic viruses will need to be tested further, both in patients and in the laboratory. If the effects turn out to be genuine, the implications for long-term survival from many types of cancer could be significant," says Coffey. Researchers believe that therapies working simultaneously, but through different mechanisms, may overcome the resistance to treatment that is typically seen in cancer. In addition, this double attack on cancer could point to new treatment regimens based on conventional therapies like radiation and chemotherapy with biological agents.
http://www.medilexicon.com/medicalnews.php?newsid=62587∞

Tequila raw ingredient being developed into drug-carrier that targets colon diseases

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CHICAGO, March 27

Compounds derived from the blue agave, a fruit used to make tequila, shows promise in early laboratory studies as a natural, more effective way to deliver drugs to the colon than conventional drug-carriers, according to chemists at the University of Guadalajara in Mexico. The development could lead to improved treatments for ulcerative colitis, irritable bowel syndrome, cancer, Crohn?s disease and other colon diseases, they say.

Drug delivery to the colon is an ongoing challenge to physicians. Many drugs are destroyed by stomach acids before they?ve had a chance to reach the intestine, where they usually are absorbed. Researchers have tried to circumvent this problem by inserting the drugs into carrier molecules that resist breakdown in the stomach but have had difficulty finding a suitable carrier compound.

The tequila compounds, a class of polysaccharides known as fructans, were developed by the scientists in Mexico into tiny microspheres that are capable of carrying existing drugs that are used to treat colon diseases. Because the compounds resist destruction in the stomach, they could allow more of the drugs to reach the colon intact and improve their effectiveness, the researchers say. Their study was presented today at the 233rd national meeting of the American Chemical Society.

?This study shows that the agave fruit is good for more than just tequila. It also has medicinal value,? says study leader Guillermo Toriz, Ph.D., an assistant professor at the university. ?Agave fructan is the ideal natural carrier of drugs for the colon.?

Researchers have known for some time that fructans, which are polymers of fructose, are resistant to acid degradation and theorized that they might be a useful drug delivery vehicle. But only a few plant sources, such as agave, contain fructans in large amounts. The agave fruit is 80 percent fructans by weight when ripe, the researchers say.

Toriz and his associates extracted fructans from the blue agave, the base ingredient of tequila. They chemically modified the fructan compound to allow drugs to be encapsulated, making the drugs resistant to degradation in the digestive system.

The researchers then prepared microspheres of the compounds and filled them with ibuprofen as a model of drug delivery to the colon. In laboratory tests, the ibuprofen-filled microspheres were exposed to hydrochloric acid for an hour and appeared physically intact upon subsequent microscopic examination, the scientists say.

Topiz and his research group currently are working on improving the durability of the fructans and plan animal studies in the future. If further studies show promise, human studies of the agave microspheres are anticipated. Funding for the study was provided by the Mexican National Science and Technology Council.
http://www.eurekalert.org/pub_releases/2007-03/acs-tri031207.php∞

Tequila Raw Ingredient Being Developed Into Drug-carrier That Targets Colon Diseases

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31 Mar 2007

Compounds derived from the blue agave, a fruit used to make tequila, shows promise in early laboratory studies as a natural, more effective way to deliver drugs to the colon than conventional drug-carriers, according to chemists at the University of Guadalajara in Mexico. The development could lead to improved treatments for ulcerative colitis, irritable bowel syndrome, cancer, Crohn's disease and other colon diseases, they say.

Drug delivery to the colon is an ongoing challenge to physicians. Many drugs are destroyed by stomach acids before they've had a chance to reach the intestine, where they usually are absorbed. Researchers have tried to circumvent this problem by inserting the drugs into carrier molecules that resist breakdown in the stomach but have had difficulty finding a suitable carrier compound.

The tequila compounds, a class of polysaccharides known as fructans, were developed by the scientists in Mexico into tiny microspheres that are capable of carrying existing drugs that are used to treat colon diseases. Because the compounds resist destruction in the stomach, they could allow more of the drugs to reach the colon intact and improve their effectiveness, the researchers say. Their study was presented today at the 233rd national meeting of the American Chemical Society.

"This study shows that the agave fruit is good for more than just tequila. It also has medicinal value," says study leader Guillermo Toriz, Ph.D., an assistant professor at the university. "Agave fructan is the ideal natural carrier of drugs for the colon."

Researchers have known for some time that fructans, which are polymers of fructose, are resistant to acid degradation and theorized that they might be a useful drug delivery vehicle. But only a few plant sources, such as agave, contain fructans in large amounts. The agave fruit is 80 percent fructans by weight when ripe, the researchers say.

Toriz and his associates extracted fructans from the blue agave, the base ingredient of tequila. They chemically modified the fructan compound to allow drugs to be encapsulated, making the drugs resistant to degradation in the digestive system.

The researchers then prepared microspheres of the compounds and filled them with ibuprofen as a model of drug delivery to the colon. In laboratory tests, the ibuprofen-filled microspheres were exposed to hydrochloric acid for an hour and appeared physically intact upon subsequent microscopic examination, the scientists say.

Topiz and his research group currently are working on improving the durability of the fructans and plan animal studies in the future. If further studies show promise, human studies of the agave microspheres are anticipated. Funding for the study was provided by the Mexican National Science and Technology Council.
http://www.medilexicon.com/medicalnews.php?newsid=66392∞

Nuvelo Receives FDA Fast Track Status For rNAPc2 In Both First- And Second-Line Treatment Of Metastatic Colorectal Cancer

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29 Mar 2007

Nuvelo, Inc. (Nasdaq: NUVO) today announced that it has been granted two separate fast track designations by the U.S. Food and Drug Administration (FDA) for its product candidate, rNAPc2. The first fast track designation is for first-line treatment of metastatic colorectal cancer (mCRC) to improve progression-free survival and overall survival when added to Avastin(R)-containing 5- flurourocil (5-FU)-based chemotherapy regimens. The other is for second-line treatment of mCRC to improve progression-free survival and overall survival when added to 5-FU-based chemotherapy regimens. Fast track designation, which was mandated by the FDA Modernization Act of 1997, can potentially facilitate development and expedited review of Biologics License Applications (BLA). Fast track designation is reserved for new drugs that demonstrate the potential to address an unmet medical need and are intended for the treatment of a serious or life-threatening condition.

rNAPc2 is currently being studied in a Phase 2 clinical trial in subjects with mCRC, which accounted for approximately 55,000 colorectal cancer deaths in 2006. The primary objectives of this trial are to determine the safety and efficacy of twice-weekly, subcutaneous rNAPc2 for the second-line treatment of mCRC in combination with select 5-FU-based chemotherapy regimens.

"Given the magnitude of mCRC related deaths, there is a need for additional safe and effective treatments that prevent metastasis and prolong survival," said Michael Levy, M.D., executive vice president of research and development for Nuvelo. "We are pleased that the FDA has granted us fast track designation and are committed to developing rNAPc2 to further understand its potential to help this underserved patient population."
http://www.medilexicon.com/medicalnews.php?newsid=66347∞

Suicide Gene Therapy Kills Bowel Cancer Cells

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25 May 2007

An innovative type of gene therapy has for the first time succeeded in making bowel cancer cells commit suicide, according to a report in Cancer Research* this week.

The therapy, developed by Cancer Research UK-funded scientists at The Institute of Cancer Research, combines cutting-edge techniques to target tumour cells. Known as GDEPT (Gene-Directed Enzyme Prodrug Therapy), the treatment uses a virus to attack cancer cells.

But the researchers have added an extra gene to the virus. The virus is programmed to switch on the gene only if it reaches a tumour. When the gene is switched on, the virus produces a protein that activates an otherwise harmless 'prodrug', given separately.

Because this drug is only activated in tumours, it selectively kills only cancer cells. In normal tissue, the drug remains inactive, so healthy cells are not affected.

This is the first time such a therapy has proved successful at killing bowel cancer cells, albeit only in the laboratory. Cancer Research UK and The Institute of Cancer Research are supporting the development of the therapy, and hope to take it into early clinical trials in the future.

Lead researcher, Professor Caroline Springer of The Institute's Cancer Research UK Centre for Cancer Therapeutics, said: "We have developed a smart method to selectively target cancer cells. Normal cells are spared because the virus doesn't produce the protein that activates the drug unless it is inside a tumour.

"The beauty of our approach is that the cancer cells are made to commit suicide both by the virus and the activated drug �" the two work in tandem. And once activated, the drug has the added bonus of causing the virus to produce more of the activating protein, which activates more of the drug, and so on. It's the first time we've seen a 'positive feedback loop' like this in a GDEPT therapy."

The drug damages DNA inside the cancer cells to the point where the cells stop functioning. They have no choice but to shut down and die.

Another benefit of the therapy is that it doesn't just kill only the cancer cells infected by the virus.

"We also see a significant 'bystander effect'," added Prof Springer. "This means the cells killed by the virus or the drug release signals into the tumour that tell neighbouring cancer cells to die too."

In lab experiments, mice with bowel tumours that received the therapy lived twice as long as those that did not. The researchers suggest their technique could one day be used as a treatment for advanced bowel cancer that doesn't respond to standard chemotherapy.

Professor John Toy, medical director of Cancer Research UK, said: "GDEPT therapy has been in development for several years. But this study shows the technique - always a smart therapy - is becoming ever more sophisticated. For the first time it has been shown to be effective at killing bowel cancer cells in a laboratory model of human colon cancer. This is another stride towards the possible use of GDEPT for cancer patients."

* Cancer Research, Vol 67 Issue 10

GDEPT: an oncolytic adenovirus is injected into the bloodstream. The virus's DNA contains an added gene for CPG2 (Carboxypeptidase G2) but the gene is controlled so that it is only translated in the presence of telomerase, an enzyme found in many cancers but much less so in normal tissue. When the virus reaches a tumour that is producing telomerase, the gene is translated and the virus produces the protein CPG2.

Meanwhile a "prodrug" is injected. A prodrug is an inactive form of a drug. In this case the prodrug, called ZD2767P, is activated by CPG2 - hence it is only activated in regions of the body where the virus is producing CPG2, i.e. in tumours.
http://www.medilexicon.com/medicalnews.php?newsid=72020∞

Poniard Pharmaceuticals Announces Promising Data From Interim Safety Analysis Of Phase 1 Trials Of Picoplatin In Colorectal And Prostate Cancers

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02 Jun 2007

Poniard Pharmaceuticals, Inc. (Nasdaq: PARD), a biopharmaceutical company focused on oncology, today announced promising results from an interim safety analysis of two Phase 1 dose-escalating trials of picoplatin, a new generation platinum for the potential first-line treatment of metastatic colorectal cancer (CRC) and metastatic hormone-refractory prostate cancer (HRPC). Initial safety data from the Phase 1 trial in CRC demonstrated that picoplatin can be safely administered with fluorouracil and leucovorin, and initial safety data from the Phase 1 trial in HRPC demonstrated that picoplatin can be safely combined with the dose of docetaxel (Taxotere(R)) used in current practice for HRPC.

The data were included in abstracts published in the 2007 American Society of Clinical Oncology (ASCO) Annual Meeting Proceedings.

-- Abstract #14510. Gladkov Jr O, Manikhas G, Biakhov M, Tjulandin S, Karlin D. Phase 1 study of picoplatin in combination with 5- fluorouracil and leucovorin as initial therapy in subjects with metastatic colorectal cancer.

-- Abstract #15546. Roman L, Karlov P, Kaprin A, Gladkov Jr O, Breitz H. Phase 1 study of picoplatin and docetaxel with prednisone in patients with chemotherapy-na?ve metastatic hormone refractory prostate cancer.

"Our new data indicate that picoplatin can be safely combined with established cancer therapeutics. In 66 patients treated up to 10 months, we have observed reversible myelosuppression that is non-cumulative and has not led to any treatment-related mortality," said Jerry McMahon, Ph.D., chairman and CEO of Poniard. "These Phase 1 studies have explored different doses of picoplatin and different dosing schedules either in combination with docetaxel for prostate cancer or with 5-fluorouracil and leucovorin for colorectal cancer. We anticipate that the Phase 2 trials for both indications will begin in the third quarter of 2007, shortly after the maximum tolerated doses have been defined."

He added, "In the Phase 1 colorectal cancer study, only three patients have experienced grade 1 neuropathy to date. There has been no neuropathy greater than grade 1 in all patients treated, including four patients who have received a cumulative picoplatin dose of greater than 900 mg/m2. The objective of our planned Phase 2 trial is to confirm the neuropathy-sparing properties of picoplatin given once every two weeks in a randomized trial compared to oxaliplatin and to enable a Phase 3 clinical trial to show superior safety and efficacy of FOLPI (picoplatin combined with fluorouracil and leucovorin) compared to FOLFOX (oxaliplatin combined with fluorouracil and leucovorin). The goal of our planned Phase 2 study in prostate cancer is to generate proof-of-concept data demonstrating that picoplatin has improved efficacy with docetaxel and to enable future picoplatin combination studies with taxanes for prostate and other cancer indications."
http://www.medilexicon.com/medicalnews.php?newsid=72878∞

Scientists Develop New Drugs To Fight Colon And Breast Cancer More Effectively

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04 Jun 2007

The doctoral thesis 'Potencial terapeutico de nuevos farmacos antitumorales. Estudio sobre lineas celulares epiteliales' (Therapeutic Potential of New Antitumor Drugs. A Study on Epithelial Cell Lines) has allowed for the development of six new drugs to fight colon and breast cancer more effectively than other currently used drugs. The study was conducted at the Department of Human Anatomy and Embryology at the University of Granada (Universidad de Granada [http://www.ugr.es]∞) by Octavio Caba P?rez, member of the research group "Avances en Biomedicina" (Progress in Biomedicine), under the direction of professors Antonia Ar?nega, Juan Antonio Marchal and Fernando Rodr?guez.

The importance of this study, in which researchers from the Department of Pharmaceutical and Organic Chemistry have also collaborated, is that it enabled the identification of a total of six antitumor compounds similar to 5-fluorouracil (5-FU), one of the most widely-used drugs nowadays to fight colon and breast cancer. These compounds are more effective against malignant cells (those which are cancerous) and less toxic against benign cells (those which are unnecessarily destroyed or harmed with treatments such as chemotherapy).

As Caba P?rez points out, the current method used to fight tumors "produces several 'collateral damages'. A drug can be very effective against breast cancer, but it can also affect the rest of the benign epithelial tissue. As everybody knows, current treatments for cancer destroy a large number of unaffected cells in addition to affected cells," says Caba P?rez.

In this study researchers analyzed more than 150 drugs aimed at reducing the toxicity of the 5-FU against the benign cells, thus avoiding the reproduction of new carcinomas or other side effects. "We discarded compounds until we finally found six which have shown to be better than currently used drugs," says Caba P?rez.

Research on cell lines

So far, the study has been conducted on cell lines, and not on patients, using a new technique called "Microarrays" or "DNA Chips", which enables the identification of the effects produced by drugs on each gene the lowest and most specific level that Medicine can deal with.

"Our research," says Caba P?rez, "has been conducted with absolute precision with the aim of obtaining the lowest possible concentration of drug producing the most significant effect on cancerous cells". Therefore, this study has shown the importance of the presence of some toxic compounds like chlorine, flourine or uracil in drugs. This presence is one of the variables used to develop new antitumor drugs.

Part of the results of this study (which has been possible thanks to cooperation between the UGR [http://www.ugr.es∞] and the company VILPOMAS) have been published in the January 1 issue of the international journal "Tetrahedron". The remainder of the results will be published in various international journals on Biomedicine.

UNIVERSITY OF GRANADA - COMMUNICATIONS DEPARTMENT
Secretariado de Comunicaci?n - Universidad de Granada
Hospital Real - Cuesta del Hospicio s/n
http://www.ugr.es∞
http://www.medilexicon.com/medicalnews.php?newsid=72984∞

Colon Cancer Proteins Show Promise For Blood Test

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Article Date: 16 Jun 2007 - 1:00 PDT

Searching for less invasive screening tests for cancer, Johns Hopkins scientists have discovered proteins present in blood that accurately identify colon cancer and precancerous polyps.

Initial studies of the proteins, CCSA-3 and CCSA-4, suggest they could be used to develop a blood test to identify at-risk individuals.

"The reality is that many people are not getting regular screening colonoscopies," says cancer researcher Robert Getzenberg, Ph.D. "So, ideally we'd like to identify those with some molecular for the disease and really need them."

Current screening guidelines for healthy people call for a baseline colonoscopy - colonic cleansing, fasting and heavy sedation followed by the insertion of a flexible, optical-scanning scope through the rectum into the colon -- at age 50, followed by re-screening at least every five to 10 years. Colonoscopy is not foolproof; cancers can develop between screenings.

First discovered by Getzenberg and colleagues at the University of Pittsburgh through a protein scan, the two blood-dwelling proteins are thought to be remnants of cellular debris castoff from dead cancer cells. Although the proteins' roles are not entirely clear, the Johns Hopkins scientists say they are part of the scaffolding that supports structures within a cell's control center, the nucleus.

Alteration of such nuclear scaffolding is a hallmark of cancer cells that is easily detectable under the microscope as a misshapen and discolored nucleus. That led Getzenberg to the notion that "there must be something at the molecular level that would form a molecular flag for cancer via a blood test."

To find the flag, Getzenberg's team drew blood samples from 107 apparently healthy individuals the day before their scheduled colonoscopies, and from 28 colorectal cancer patients.

Using a particular concentration of scaffold-proteins as a marker for disease, the Johns Hopkins team - which did not know the colonoscopy results in advance -- were 100 percent accurate in identifying the 28 existing cancers. Using the same protein markers, investigators also correctly identified 51 of 53 individuals (96.2 percent) with normal colons and 14 of 18 (77.8 percent) people with advanced precancerous polyps, which Getzenberg says are the most important to detect through routine screening.

When researchers combined samples, they correctly identified 42 of 46 (91.3 percent) containing both cancers and advanced precancerous polyps. Protein levels were accurate in correctly assessing additional blood samples from 125 people with benign conditions and other cancers.

"These proteins seem very good at separating normal samples from cancerous ones and identifying other groups with pre-cancers at high risk for disease as well," says Getzenberg, who is a professor of urology and director of research at Johns Hopkins' Brady Urological Institute. Results are published in the June 15 issue of Cancer Research.

The researchers are planning larger studies at several hospitals over the next several months. It may take several years to complete the full range of testing.

Getzenberg says that storing and processing the samples are among the major hurdles in biomarker development, a field that spans ongoing research on many cancers and various body fluids. "It is difficult to get many facilities to adhere to precise storage and processing conditions important for keeping proteins stable," he says. "Different conditions could create incorrect results." Researchers also differ in the type of biomarkers they seek, with some looking for proteins, like Getzenberg, and others searching for DNA components.

Getzenberg and the University of Pittsburgh hold a patent for the technology described above, which is licensed to Onconome Inc. Funding for the study described in this article was provided by Onconome Inc. and the National Cancer Institute. Under a licensing agreement between Onconome Inc. and University of Pittsburgh, Getzenberg is entitled to a share of royalty received by the University on sales of products described in this article. Getzenberg also is a paid consultant to Onconome Inc. which has a licensing agreement with The Johns Hopkins University covering CCSA-3 and -4 related technologies. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.

Additional authors are Eddy S. Leman, Grant W. Cannon, Lori J. Sokoll, and Daniel W. Chan at Johns Hopkins; and Robert E. Schoen and Joel L. Weissfeld at the University of Pittsburgh Cancer Institute.

http://www.hopkinskimmelcancercenter.org∞
http://www.urology.jhu.edu/∞
http://www.jhmi.edu∞
http://www.medicalnewstoday.com/articles/74295.php∞

Pfizer Initiates Phase 3 Trial To Study Sunitinib Malate In Patients With Metastatic Colorectal Cancer

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Article Date: 06 Jul 2007 - 1:00 PDT

Pfizer announced recently the initiation of a Phase III clinical trial to evaluate the safety and efficacy of sunitinib malate, in combination with a standard chemotherapy regimen, in patients with metastatic colorectal cancer (mCRC) - cancer originating in the colon that has spread to other parts of the body. In addition, new data from a Phase I study being presented this week at the World Congress on Gastrointestinal Cancer (WCGC) in Barcelona showed that sunitinib malate is active and generally well-tolerated in combination with a standard chemotherapy regimen, FOLFIRI, in previously untreated patients with mCRC. These data support further evaluation of sunitinib malate in mCRC in a Phase III program.

"We are encouraged by these data which add to a growing body of research demonstrating the activity and tolerability of sunitinib malate in numerous cancers," said Charles Baum, MD PhD, head of oncology development at Pfizer. "Based on these early findings presented this week, Pfizer is committed to continued exploration of sunitinib malate in the treatment of advanced colorectal cancer through a global Phase III program."

Sunitinib Malate Phase III Trial in Colorectal Cancer

A multi-national Phase III study is currently open and enrolling in Europe, Canada, Asia and South America and will include more than 700 patients to evaluate the safety and efficacy of sunitinib malate combined with FOLFIRI, a standard chemotherapy regimen used in mCRC comprised of fluorouracil (5-FU), folinic acid (leucovorin), and irinotecan, compared with FOLFIRI plus placebo, in the first-line treatment of patients with mCRC.

Sunitinib malate is a multi-kinase inhibitor which works by inhibiting angiogenesis, the process by which tumors acquire blood vessels bringing oxygen and nutrients needed for growth, and proliferation, the process by which cells multiply.
http://www.medicalnewstoday.com/articles/76036.php∞

Treatment Developed Which Slows The Growth Of Colon And Liver Cancers

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Article Date: 24 Jun 2007 - 15:00 PDT

Leire Garc?a Navarro, a researcher at the School of Pharmacy of the University of Navarra, has developed a new treatment which slows the growth of colon and liver cancers.

This discovery is the principal result of her doctoral dissertation, entitled "Lipo-Polymeric Vectors for the Transfer of DNA in Cancer Cells of the Colon", which was subsidized by the Basque Government. In order to carry out the study, this scientist of the Department of Pharmacy and Pharmaceutical Technology used genetic therapy with non-viral vectors for transferring genetic material to the cancerous cells. With this technique, we can assure the therapeutic function of the drug in a wide variety of tissues. In addition, we can apply the treatment repeatedly, since it does not generate immunity, as occurs with viral vectors.

With the objective of improving the effectiveness of this methodology, the specialist worked on designing non-viral systems which act directly upon the liver and the colon. In this manner, she prepared, optimized and evaluated, in vitro and in vivo, a new pharmaceutical format called 'lipopolyplex.' This compound aids the genetic material in penetrating into the damaged cells, and allows drug release in tumorous organs. 500,000 deaths per year

Experimentation with the new drug in mice has shown that it slows tumor growth with respect to those animals subjected to other procedures. This diminishing of the cancerogenous area is possible, according to the scientist, thanks to the stimulation of the immune system, since the introduction of the correct gene in the diseased body can cause it to repair itself and destroy the tumor.

In addition, the researcher of the University of Navarra noted that colon cancer alone causes more than 500,000 deaths per year in the West, and currently the only effective treatment is surgery. Despite this treatment, noted the researcher, between 40 and 60% of colon cancer patients die, and for this reason it is important that we seek out treatment based on genetic therapy.
http://www.medicalnewstoday.com/articles/74904.php∞

Improving Colorectal Cancer Treatment

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Article Date: 29 Jun 2007 - 1:00 PDT

Researchers have provided new information about a protein responsible for colorectal cancer and the target of a potential drug against this cancer.

Called clusterin, this protein has been linked to the development of tumor cells and resistance to cancer therapy, but how it works is not well understood. Pending questions include how this protein is expressed in normal and cancer cells, how it helps cancer cells escape ionizing radiation and chemotherapy, and which patients will benefit from treatment with a drug targeting clusterin.

Claus Lindbjerg Andersen, Torben Falck Orntoft, and colleagues discovered that clusterin is not expressed in normal cells, while in 25 percent of colorectal tumors, the cancer cells contained clusterin. They also showed that the protein is actually made by the cancer cells themselves. These new findings should help improve current therapies against colorectal cancer, especially for patients with tumors producing clusterin, the scientists concluded.
http://www.medicalnewstoday.com/articles/75500.php∞

In First Line Treatment Of Metastatic Colorectal Cancer Erbitux Demonstrates Consistent Efficacy

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Article Date: 03 Jul 2007 - 1:00 PDT

The first European presentation of key Erbitux? (cetuximab) data at the 9th World Congress of Gastrointestinal Cancers (WCGIC) reinforces the consistent efficacy of Erbitux in the first-line treatment of metastatic colorectal cancer (mCRC). The key Erbitux studies presented - involving more than 70 centres across Europe - represent best practice in clinical trials management and collaboration.

Two key studies presented at the meeting, validate the role of Erbitux as an effective first-line treatment in mCRC patients, when used in conjunction with two different types of chemotherapy treatment. The CRYSTALa trial, a phase III study of Erbitux plus FOLFIRI (irinotecan-based therapy) compared with FOLFIRI alone, met the primary endpoint of significantly increasing median duration of progression-free survival in patients with previously untreated mCRC. This randomized, controlled trial studied almost 1,200 patients and demonstrated a 15% reduction (hazard ratio: 0.085) in the risk of metastatic colorectal cancer growing or spreading compared to the control arm, which was statistically significant (p=0.0479). In addition, one year after trial therapy initiation, 34% of patients in the Erbitux arm had not progressed vs 23% of patients in the control arm.

The study also achieved its secondary endpoint of significantly increasing response rate (tumor shrinkage by 50% or more) (47% in the Erbitux plus FOLFIRI group compared to 39% in the FOLFIRI alone group). Furthermore, in a subgroup analysis of patients who had liver limited disease (patients who had liver metastases only), the positive effect of the addition of Erbitux was even more pronounced, resulting in a PFS of 11.4 months with Erbitux vs. 9.2 months in the control arm and a 36% reduction in the risk of metastatic colorectal cancer growing or spreading. The number of complete resections of the metastases in the subgroup who had liver metastases only was more than double with Erbitux plus FOLFIRI vs. control arm (9.8% versus 4.5%). The number of complete resections in the overall population was three times higher in the Erbitux plus FOLFIRI arm.

"These results indicate that we have a new first-line treatment option for metastatic colorectal cancer," said Eric Van Cutsem, MD, PhD, a professor at University Hospital Gasthuisberg in Leuven, Belgium, and lead author of the study. "These findings are remarkable because they point towards the potential for this combination to provide a cure for those patients who were able to undergo a complete resection."

The CRYSTAL results were supported by the findings of the OPUSb study. Erbitux plus FOLFOX (oxaliplatin-based therapy) was compared with FOLFOX alone to measure overall response rate (tumor shrinkage by 50% or more). Response rate was found to be 46% in the Erbitux arm compared with 36% in the oxaliplatin-only arm. The safety profile of Erbitux in combination with chemotherapy was manageable and consistent with the current safety information.

Commenting on the studies, Carsten Bokemeyer, MD, PhD and lead author for the OPUS study from the University Hospital Hamburg, Germany, says: "Overall, these first-line studies demonstrate that, when added to current standard chemotherapy, Erbitux significantly increases response and resection rates, which in turn, significantly increases the chance of cure for mCRC patients."

As well as first-line use, a number of studies presented at WCGIC reinforce the versatility of Erbitux in treating a broad range of patients with mCRC. Data from the phase III EPICc study, which compared Erbitux plus irinotecan with irinotecan alone in mCRC patients who had failed first-line treatment with oxaliplatin-based chemotherapy, showed that progression-free survival, response rate and health-related quality of life was significantly improved in the Erbitux arm. A new retrospective European study (Bouchahda et al) on the use of Erbitux in elderly patients with extensively pre-treated mCRC demonstrated that the combination of Erbitux with irinotecan-based therapy resulted in good activity and acceptable tolerability comparable to that of the non-elderly population.

Commenting on the data for an important subgroup of the CRYSTAL trial, which had liver limited disease, Dr Wolfgang Wein, Senior Executive Vice President, Oncology, Merck Serono - a division of Merck KGaA, Darmstadt, Germany said "We are delighted with the results presented at WCGIC. Besides the significant outcomes for the overall population in the CRYSTAL trial we were able to define the patients with the greatest benefit. In patients with metastases limited to the liver 10% of patients had a complete resection of the tumor, which means hope for cure. This was possible because Erbitux significantly increased the tumor response rate".

More than 370,000 people develop colorectal cancer in Europe every year, accounting for 13% of the total cancer burden and around 200,000 deaths.1 Approximately 25% of patients present with metastatic disease.2 Five-year survival rates for patients with mCRC are as low as 5%.3
http://www.medicalnewstoday.com/articles/75760.php∞

Pfizer Initiates Phase 3 Trial To Study Sunitinib Malate In Patients With Metastatic Colorectal Cancer

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Article Date: 06 Jul 2007 - 1:00 PDT

Pfizer announced recently the initiation of a Phase III clinical trial to evaluate the safety and efficacy of sunitinib malate, in combination with a standard chemotherapy regimen, in patients with metastatic colorectal cancer (mCRC) - cancer originating in the colon that has spread to other parts of the body. In addition, new data from a Phase I study being presented this week at the World Congress on Gastrointestinal Cancer (WCGC) in Barcelona showed that sunitinib malate is active and generally well-tolerated in combination with a standard chemotherapy regimen, FOLFIRI, in previously untreated patients with mCRC. These data support further evaluation of sunitinib malate in mCRC in a Phase III program.

"We are encouraged by these data which add to a growing body of research demonstrating the activity and tolerability of sunitinib malate in numerous cancers," said Charles Baum, MD PhD, head of oncology development at Pfizer. "Based on these early findings presented this week, Pfizer is committed to continued exploration of sunitinib malate in the treatment of advanced colorectal cancer through a global Phase III program."

Sunitinib Malate Phase III Trial in Colorectal Cancer

A multi-national Phase III study is currently open and enrolling in Europe, Canada, Asia and South America and will include more than 700 patients to evaluate the safety and efficacy of sunitinib malate combined with FOLFIRI, a standard chemotherapy regimen used in mCRC comprised of fluorouracil (5-FU), folinic acid (leucovorin), and irinotecan, compared with FOLFIRI plus placebo, in the first-line treatment of patients with mCRC.

Sunitinib malate is a multi-kinase inhibitor which works by inhibiting angiogenesis, the process by which tumors acquire blood vessels bringing oxygen and nutrients needed for growth, and proliferation, the process by which cells multiply.

Phase I Study in Metastatic Colorectal Cancer

New data presented this week from an ongoing, open-label Phase I trial of 16 previously untreated mCRC patients randomized to three distinct dosing regimens, determined the maximum tolerated dose (MTD) for sunitinib malate of four weeks on treatment followed by two weeks off (4/2) in combination with FOLFIRI was 37.5 mg/day. This regimen appeared to be active and generally well-tolerated in patients who have received no prior treatment for metastatic disease. Of the 10 patients who received this dosing regimen, four patients experienced partial response to date and stable disease has been observed in six patients. Treatment emergent grade 3 adverse events for patients on the sunitinib malate 37.5 mg/day 4/2 regimen were one case of respiratory tract infection and two cases of neutropenia without fever.

"Despite progress in recent years, colorectal cancer remains a hard-to-treat cancer for which new options are sorely needed," said Alfredo Carrato MD, PhD, Elche University Hospital and lead investigator on the sunitinib malate multi-national Phase III trial in mCRC. "These data support further research of sunitinib malate in metastatic colorectal cancer, in an effort to potentially expand the range of therapies available to physicians and patients."

For more information about sunitinib malate trials currently open and enrolling, please visit http://www.ClinicalTrials.gov∞ or http://www.suntrials.com∞ or call Pfizer Oncology's toll-free number at 001-646-277-4066.

Disclosure Notice: The information contained in this release is as of June 27, 2007. Pfizer assumes no obligation to update any forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about various products in development, including their potential benefits, that involves substantial risks and uncertainties. Such risks and uncertainties include, among other things, the uncertainties inherent in research and development; decisions by regulatory authorities regarding whether and when to approve any drug applications that may be filed for any such products in development as well as their decisions regarding labeling and other matters that could affect their availability or commercial potential; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer's Annual Report on Form 10-K for the fiscal year ended December 31, 2006 and in its reports on Form 10-Q and Form 8-K.

http://www.pfizer.com∞
http://www.medicalnewstoday.com/articles/76036.php∞

Phase II Study Of Therapeutic Vaccine Shows Efficacy In Patients With Metastatic Colorectal Cancer

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Article Date: 03 Aug 2007 - 1:00 PDT

A therapeutic cancer vaccine has shown effectiveness when given alongside chemotherapy to patients with metastatic colorectal cancer in a phase II trial, according to researchers at Oxford BioMedica (UK) Ltd. The study found that six of the 17 metastatic colorectal cancer patients in the study showed tumor shrinkage, classified as complete or partial responses following independent expert review.

The study, reported in the August 1 issue of Clinical Cancer Research, a journal of the American Association for Cancer Research, was designed to demonstrate the safety and immunogenicity of the vaccine, called modified vaccinia Ankara-encoding 5T4 (TroVax?), when used alongside standard chemotherapy. The research was funded by Oxford BioMedica which is developing the vaccine in partnership with Sanofi-Aventis.

Unlike preventative vaccines, such as the human papillomavirus vaccine to prevent cervical cancer, TroVax is a therapeutic vaccine, designed to stimulate the immune systems of patients who already have cancer. The vaccine consists of an attenuated (non-disease causing) version of the vaccinia virus modified to deliver the gene for 5T4, a protein found in many tumors.

"The idea is that the modified virus enters cells, produces the tumor protein and stimulates the immune system," said lead study author Richard Harrop, Ph.D., vice president of clinical immunology at Oxford BioMedica. "To give a vaccine alongside chemotherapy might seem counterintuitive, since chemotherapy can weaken the immune system, but our study shows that TroVax could be complementary to standard chemotherapy, enhancing the immune response to tumors."

The target of this immuno-therapy approach is a tumor antigen called 5T4, a protein embedded within the membrane of cancer cells. The protein is rarely found in normal tissues, but is produced at high levels by a wide range of human cancers, including colorectal, renal, gastric and ovarian. The production of 5T4 has been associated with cancer metastasis and poor prognosis for patients.

"Typically, the immune system doesn't pay attention to this molecule, so by producing 5T4 artificially in combination with the 'danger signals' associated with a viral infection, we are demanding that the immune system take notice," Harrop said. "TroVax causes cells at the injection site to produce 5T4 in a way which agitates the immune system into producing antibodies and killer T cells. It is hoped that these two components of the immune system then migrate to tumors and kill them without harming any normal tissues."

"In essence, it's like turning up your stereo in the hopes that it will attract the police to your neighbor's rowdy party," Harrop said.

Harrop and his colleagues administered the vaccine to 17 patients with metastatic colorectal cancer just before, during and after the patients were treated with the standard chemotherapy regimen FOLFOX which consists of the agents: 5-fluorouracil, folinic acid and oxaliplatin.

Through the course of the study, the researchers monitored the patients for an immune response to 5T4. Eleven of the 17 patients who received the complete course of vaccinations (six injections) mounted strong immune responses to the 5T4 tumor protein. Of these 11 patients, six exhibited significant shrinkage of their tumors and one patient no longer had any detectable tumors. Researchers noted no complications stemming from TroVax vaccination or any other evidence that would call into question the safety of the vaccine.

While the study was not designed to prove that patients survived longer than would normally be expected, the researchers noted that, on average, the overall median survival was 68 weeks in all 17 vaccinated patients and 118 weeks in the 11 patients who received all six vaccinations.

According to Harrop, the researchers are currently testing the vaccine in a phase III trial in renal cancer patients in the U.S. and Europe and Sanofi Aventis is planning a phase III study in colorectal cancer.

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes nearly 26,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 70 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment, and patient care. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship, and advocacy.

http://www.aacr.org∞
http://www.medicalnewstoday.com/articles/78551.php∞

Fighting Colorectal And Breast Cancer With Newly Identified Enzyme

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Article Date: 02 Nov 2007 - 3:00 PDT

Researchers at the Virginia Commonwealth University Massey Cancer Center have identified the enzyme sphingosine kinase 2 as a possible new therapeutic target to improve the efficacy of chemotherapy for colon and breast cancer.

In the Nov. 1 issue of the journal Cancer Research, researchers examined human colon and breast cancer cells and established a role of sphingosine kinase 2 (SphK2), an enzyme that forms the potent lipid mediator sphingosine-1-phosphate in the death of cancer cells mediated by the chemotherapeutic drug, doxorubicin.

Doxorubicin is able to kill cancer cells by working with p53, one of the most protective anti-cancer proteins in the human body. However, doxorubicin also relies on p53- independent mechanisms to induce death in colon and breast cancer cells.

"Understanding how doxorubicin kills in a p53-independent manner is a major goal of cancer researchers because most cancer cells have mutated p53," said lead author Sarah Spiegel, Ph.D., chair and professor in the VCU Department of Biochemistry and Molecular Biology and co-leader of the cancer center's cancer cell biology program.

According to Spiegel, the study demonstrated that SphK2 is important for p53-independent induction of expression of p21, a cyclin-dependent kinase inhibitor. This p21 regulates the cell cycle, and apoptosis or programmed cell suicide, mediated by doxorubicin. Human colon and breast cancer cells were killed more efficiently by doxorubicin when SphK2 was removed from the cells.

"Therefore, the findings suggest that SphK2 influences the balance between cytostasis, and apoptosis of human cancer cells," Spiegel said. Cytostasis refers to the stoppage of cellular growth and multiplication.

Spiegel said that cell death was induced by doxorubicin and decreased p21.

Spiegel, who is internationally recognized for her pioneering work on new lipid mediators that regulate cell growth and cell death, and her colleagues, first discovered the role of sphingosine-1-phosphate in cell growth regulation nearly a decade ago. Spiegel and her team are continuing this work to better understand the functions of these enzymes.
http://www.medicalnewstoday.com/articles/87494.php∞

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