Early results find activity in drug that turns on tumor 'death' receptorsATLANTA - The first clinical trial to evaluate a new type of drug that activates "death" receptors on cancer cells has found it to be both safe and suggestive of potential benefit, say researchers from The University of Texas M. D. Anderson Cancer Center.
The drug, human Apo2L/TRAIL (Apo2L), produced only minimal side effects in the 58 patients being tested in the ongoing Phase I study, reports Roy Herbst, M.D., Ph.D., professor and chief, Section of Thoracic Medical Oncology.
Herbst also says that the agent shrunk tumors in one patient with sarcoma, and seemed to stabilize cancer growth in about 56 percent of the 58 patients, but added that it is too early to adequately assess the benefit of Apo2L, especially since the maximum dose that can treat patients and still be well tolerated has not yet been reached.
"This is an interesting new class of targeted agents, and Apo2L may well prove to be promising as we study it further," says Herbst, who presented safety data on the Phase I clinical trial at the 42nd annual meeting of the American Society of Clinical Oncology.
Patients with a variety of advanced cancers are participating in the clinical trial, which is being conducted at five centers around the country. In preclinical studies, Apo2L selectively induced programmed cell death (also known as apoptosis, or cell suicide) in cancer cells while sparing normal cells. It showed activity in animal models of leukemia, non-small cell lung cancer, melanoma and cancers of the colon, prostate and breast.
The drug is designed to activate pathways inside tumor cells that lead to destruction of these cells.
"Normally, the p53 gene regulates cell suicide in the presence of cell damage, such as that induced by chemotherapy and radiotherapy, but this gene is mutated - and therefore inactivated - in more than half of all cancers. We expect this agent to work even in those patients with mutated p53," Herbst says.
Herbst and his team have been trying to exploit a different and natural way to induce cell suicide, through so-called death receptors that are located on the outside of all cells.
These receptors, which are believed to be especially numerous on cancer cells, work in tandem with the tumor-necrosis factor receptor (TNFR) super-family, which can signal cell destruction from outside the cell (unlike p53, which activates suicide from inside the cell.) Drugs aimed at treating autoimmune disease have been developed that block specific death receptors; now oncology researchers have designed agents that will selectively activate death receptors 4 and 5 (DR4, DR5) known to be present on cancer cells.
The first TNFR agents developed to induce apoptosis resulted in liver toxicity, so researchers looked for the natural "ligand," or protein, that bound on to DR4 and DR5. The biotechnology firms Genentech and Amgen found and cloned the Apo2L/TRAIL gene, and used its protein product to create a recombinant protein that closely resembles this natural ligand. According to Herbst, Apo2L is the only agent of its kind that can directly activate both DR4 and DR5, which then mounts an immune response that can attack the tumor cells.
Herbst suspects that Apo2L and other death receptor agents being developed for cancer treatment will work best when used with chemotherapy and/or radiation, and says Apo2L will be tested in combination therapy after this dose escalation study ends.
The study was funded by Genentech. Herbst has received research support, and is a consultant for, both Amgen and Genentech.
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