Human reovirus-based drug Reolysin has potential to tackle Kras mutant colorectal cancer: Oncolytics

Reolysin, an experimental human reovirus-based drug therapy could be an effective tool in dealing with drug resistant form of colorectal-cancer.

Reolysin in combination with FOLFIRI (Folinic Acid (leucovorin) + Fluorouracil (5-FU) + Irinotecan) in patients with oxaliplatin refractory/intolerant Kras mutant colorectal cancer has been initiated in US, according to Oncolytics Biotech.

Oncolytics Biotech Inc has already submitted Reolysin data to the U.S. Food and Drug Administration  for review.

The trial is a Phase I dose escalation study with three dose levels and cohorts of three to six patients to determine a maximum tolerated dose and dose-limiting toxicities with the combination of Reolysin and FOLFIRI.

FOLFIRI will be administered on the first day of a two week (14 day) cycle, while Reolysin will be administered on days one through five of a four week (28 day) cycle.

Oncolytics made the decision to conduct a trial in this indication following observed activity in colorectal cancers with Reolysin in both the clinical and preclinical settings, stated Dr. Brad Thompson, president and CEO of Oncolytics.

This includes a National Cancer Institute screen of seven colorectal cancer cell lines (four with ras mutations), all of which were susceptible to Reolysin; preclinical research into the efficacy of Reolysin in combination with various chemotherapeutic agents in colorectal cancer cell lines; observation of CEA responses and stable disease in colorectal patients in a Phase I study of Reolysin as a monotherapy; and evidence of viral replication of reovirus in liver metastases in patients with metastatic colorectal cancer in a translational study with REOLYSIN as a monotherapy that is currently ongoing.

Up to 45% of second line colorectal cancer patients have Kras mutations. This makes this an attractive target for Reolysin which appears to be active in tumors with this mutation, he added.

Eligible patients include those with histologically confirmed cancer of the colon or rectum with Kras mutation and measurable disease. They must have progressed on or within 190 days after last dose of oxaliplatin regimen as front-line therapy in the metastatic setting or be intolerant to oxaliplatin.

The American Cancer Society estimates that nearly 147,000 Americans were diagnosed with colorectal cancer and an estimated 49,920 were expected to die from the disease in 2009.

The prognosis for patients diagnosed with colorectal cancer at the localized stage is good with a five-year survival rate of 90%, however only about 40% of cases are diagnosed at this stage; five-year survival rates drop to 68% with the spread to adjacent organs or lymphnodes and 11% for distant metastases.

Colorectal cancer is the third leading cause of cancer death among both men and women in the United States.

Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics.

Oncolytics’ clinical program includes a variety of human trials including a Phase III trial in head and neck cancers using Reolysin, its proprietary formulation of the human reovirus.

Reolysin preferentially replicates in cancer cells that have an activated RAS pathway. Approximately two thirds of all cancers have an activated RAS pathway, including most metastatic disease.

A large number of mutations, including mutations in EGFR, Her2 or Kras along the RAS pathway lead to RAS pathway activation.

Reovirus, an acronym for Respiratory Enteric Orphan virus, is generally believed to inhabit the respiratory and bowel systems in humans.

Reovirus is found naturally in sewage and water supplies. By age 12, half of all children show evidence of reovirus exposure and by adulthood, most people have been exposed.

However, the disease is non-pathogenic, meaning there are typically no symptoms from infections. The link to its cancer-killing ability was established after the reovirus was discovered to reproduce well in various cancer cell lines.

Tumours bearing an activated Ras pathway are deficient in their ability to activate the anti-viral response mediated by the host cellular protein, PKR. Since PKR is responsible for preventing reovirus replication, tumour cells lacking the activity of PKR are susceptible to reovirus replication.

As normal cells do not possess Ras activations, these cells are able to stop reovirus infection through normal PKR activity. In tumour cells with an activated Ras pathway, reovirus is able to freely replicate and eventually kill the host tumour cells.

As cell death occurs, progeny virus particles are then free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until there are no longer any tumour cells carrying an activated Ras pathway available.

More recently, Oncolytics has discovered that tumour antigens generated by this viral oncolysis may educate the immune system to recognize and kill tumour cells.

The activation of the Ras pathway can be mimicked in non-cancerous cells by treating these cells with the chemical 2-aminopurine (2-AP) which prevents the activation of PKR.

Oncolytics’ clinical program includes human trials using Reolysin alone and in combination with radiation and chemotherapy.

Oncolytics Biotech Inc has announced that the Cancer Therapy & Research Center at the University of Texas Health Science Center (CTRC) has started patient enrolment in a U.S. Phase 2 clinical trial using intravenous administration of Reolysin in lung cancer patients.