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compounds directly activate the apoptosis pathway


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ATLANTA, June 4 — With a new class of drugs, researchers are on the trail of killer receptors on the surface of cancer cells.

Two novel compounds directly activate the apoptosis pathway and trigger suicide in tumor cells, according to data from phase I trials.

Standard chemotherapy drugs and other targeted agents may ultimately induce cell death via this pathway, but the novel agents represent the first successful effort to directly activate apoptosis.

"This is a very rapid and efficient method of activating apoptosis," said Stan Lipkowitz, M.D., Ph.D., principal investigator of cell and molecular biology at the National Cancer Institute in Bethesda, Md., who was not involved in the research but discussed the trials during a scientific session.

One of the drugs, Apo2L/TRAIL, is a recombinant human protein that binds to two cell surface receptors - death receptor 4 and 5. Binding to the receptors initiates an intracellular signaling cascade that leads to cell death. The second drug, YM155, is a small molecule that lifts a blockade of this same pro-death pathway by inactivating a protein called Survivin, which is commonly overexpressed in cancer cells but is rarely found in healthy cells.

Significantly, Apo2L/TRAIL or YM155 work independently of the p53 protein, which controls another branch of the apoptosis pathway. "As many tumors have aberrations in the p53 gene, this will be very useful," said Dr. Lipkowitz. Drugs like Apo2L/TRAIL or YM155 that work around p53 may enable clinicians to kill tumor cells that would be resistant to standard chemotherapy agents.

Of 37 patients with colorectal, melanoma, lung, or ovarian tumors, among others, treated in a phase I trial with Apo2L/TRAIL, one (3%) achieved a partial response and 21 (56%) had stable disease, said Roy S. Herbst, M.D., Ph.D., chief of thoracic medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston, and lead investigator on the study. Patients in the study had had a median of four prior therapies (range 0 to 14).

A maximally tolerated dose has not been determined yet, and the study is continuing to accrue patients at increasing dose levels at all five study centers. Two patients (4%) had grade 3 or 4 fatigue and one patient (2%) had grade 3 or 4 anorexia. The most common low grade toxicities were fatigue (30%), nausea (21%), vomiting (17%), anemia (16%), pyrexia (16%), headache (12%), diarrhea (10%) and anorexia (10%).

"Ultimately this drug will require randomized trials, but my feeling is that we now have a drug that is safe and has some early efficacy," said Dr. Herbst. "We can combine it with chemotherapy, radiation, or other targeted therapies."

Forty-one patients have enrolled in the YM155 phase I trial, all of whom have advanced solid tumors or refractory non-Hodgkin's lymphoma and have been treated previously with a median of five therapies (range 2 to 17), said Anthony W. Tolcher, M.D., of the Institute for Drug Development at the Cancer Therapy and Research Center in San Antonio, who led the study.

Of those 41 patients, six showed some evidence of response. Three patients with non-Hodgkin's lymphoma had partial responses, one patient with non-small cell lung cancer had a minor response, and two patients with hormone refractory prostate cancer had a PSA response, the magnitude of which was not specified.

"This drug showed very impressive activity for a phase I study," said Dr. Tolcher.

The maximally tolerated dose for YM155 is 4.8 mg/m2/day continuous IV for seven days given every three weeks. At that dose, five patients had grade 3 stomatitis, eight had grade 1 or 2 arthralgia, and one had grade 4 neutropenia. Low-grade fever was also common, but specific numbers were not provided. The dose limiting toxicity was transient renal dysfunction, which occurred at 6.0 mg/m2/day.

Both compounds are expected to be used in combination with other anti-cancer regimens. Chemotherapy agents and other targeted agents can bring cells to the edge of the cliff. "These agents can push them over the edge." said Dr. Herbst.

The Apo2L/TRAIL study was sponsored by Genentech and Amgen. The YM155 trial was supported by Astellas Pharma US.

Primary source: ASCO Annual Meeting

Source reference:

AW Tolcher, et al. "A phase I study of YM155, a novel survivin suppressant, administered by 168 hour continuous infusion to patients with advanced solid tumors." ASCO annual meeting 2006. Abstract 3104.

Additional source: ASCO Annual Meeting

Source reference:

RS Herbst, et al. "A phase I safety and pharmacokinetic (PK) study of recombinant Apo2L/TRAIL, an apoptosis-inducing protein in patients with advanced cancer." ASCO annual meeting 2006. Abstract 3103.

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