What did Pope John Paul II, Ronald Reagan and Robin Gibb of the Bee Gees have in common? Each was diagnosed with colorectal cancer, the third most commonly diagnosed cancer in the world and the fourth most common cause of cancer death.
Now Calgary-based Oncolytics Biotech Inc. has reported interesting new findings at the American Society of Clinical Oncology's 2013 Gastrointestinal Cancers Symposium (ASCO GI), held January 24-26 in San Francisco. The meeting attracted a diverse group of individuals involved in the prevention, detection and treatment of gastrointestinal cancers.
Oncolytics presented a poster reporting results from a phase 1 study in patients with colorectal cancer. In the study, REOLYSIN, a biologic agent developed by Oncolytics, was administered (along with a standard chemotherapy regimen called FOLFIRI, composed of folinic acid, fluorouracil and irinotecan) to 18 patients with colorectal cancer. The primary objectives were dose-limiting toxicity to determine maximum tolerated dose and pharmacokinetics; secondary endpoints were antitumor activity, response rate, progression-free and overall survival. The combination of REOLYSIN and FOLFIRI was found to be safe, well-tolerated and resulted in disease control in the majority of the patients. The researchers were encouraged by this activity and safety trial, and are planning advanced-phase studies.
The lead author of the study was Allyson Ocean, M.D., a medical oncologist and attending physician in gastrointestinal oncology, Solid Tumor Division, at New York Presbyterian Hospital/Weill Cornell Medical Center; assistant professor of medicine at the Weill Medical College of Cornell University; and medical oncologist at The Jay Monahan Center for Gastrointestinal Health.
The results will come as encouraging news to those who have been diagnosed with colorectal cancer, who face some stark statistics: According to the U.S. National Cancer Institute (a division of NIH), more than 140,000 Americans were diagnosed with this cancer in 2012, while nearly 52,000 died of it the same year. Globally, more than one million people get colorectal cancer annually, resulting in the deaths of about half a million.
Triggered by uncontrolled cell growth in the colon or rectum, colorectal cancer is often curable when confined to these areas, but the prognosis is much bleaker when it has spread, with management focusing on surgery, chemotherapy and radiation, with all of the attendant risks of these procedures. For example, while chemotherapy can shrink tumors, they often grow back and become resistant, or refractory to the treatment.
Oncolytics' approach to treatment comes from an area called oncolytic virotherapeutics. Here, viruses are harnessed to infect, multiply within and subsequently lyse cancer cells; the virus targets tumors without affecting normal tissue. Oncolytics developed REOLYSIN from naturally occurring reovirus. The virus has demonstrated impressive results in clinical trials on its own, but particularly in combination with certain chemotherapeutics. In preclinical studies in a wide variety of cancer cell lines, investigators found that when used together, reovirus and chemotherapy resulted in more efficient and synergistic anti-cancer activity than when each agent was used on its own.
Many consider reovirus, from which REOLYSIN is derived, to be the most promising form of oncolytic virus. This virus preferentially replicates in cancer cells that feature a common mutation known as an "activated Ras pathway," while sparing normal cells. This makes it intrinsically tumor selective without the need for any genetic manipulation.
Reovirus is a virus with no known associated disease. It replicates in the cytoplasm and therefore does not integrate into the cell's DNA. Reovirus is found everywhere in nature and has been isolated from untreated sewage, river and stagnant waters. Exposure to reovirus is common in humans, with half of all children by the age of 12 having been exposed and up to 100 percent testing positive by adulthood.
Tumors bearing an activated Ras pathway cannot activate the antiviral response mediated by the host cellular protein, PKR. Studies have shown that reovirus actively replicates in transformed cell lines with an active Ras signaling pathway, eventually killing the host cell and freeing the viral progeny that go on to infect and kill more Ras-activated tumor cells. When normal cells are infected with reovirus, the immune system can neutralize the virus. Approximately one-third of human cancers have activating mutations in the Ras gene itself, and it is possible that more than two-thirds of cancer cells have an activated Ras signaling pathway because of activating mutations in genes upstream or downstream of Ras.
Future studies will provide an even clearer perspective on whether REOLYSIN offers an effective route toward a reliable and commercially viable complement to chemotherapy for oncologists and their colorectal cancer patients. There may be new hope on the horizon for these patients—a hope coming from within the human body itself.