Novel Apoptosis-Inducing Agents Entering Phase I Trials

VANCOUVER, Canada-Novel apoptosis-inducing agents, which have entered phase I clinical trials, represent new avenues for therapeutic intervention and are expected to enhance current treatment strategies, said Anthony Tolcher, MD, director of clinical research at the Institute for Drug Development, San Antonio, Texas. "It's been a lonely world for those of us who have been pursuing drugs that target apoptosis, compared to those that target pathways of proliferation, such as the epidermal growth factor receptor, which has been a main focus at this entire meeting," Dr. Tolcher commented at the 10th World Conference on Lung Cancer. At a session on targeted therapy for lung cancer, Dr. Tolcher predicted that although apoptosis-inducing agents are still in early clinical development, "they may have a role in 3 to 5 years in the clinical setting." Apoptosis is critical for normal physiologic processes. Elimination of certain cells (eg, viral-infected cells or self-reactive T cells that are involved in autoimmunity) is important to health. Aberrant and diminished apoptosis is common to many types of malignancies and takes many forms, including altered expression of the tumor necrosis factor receptor family, overexpression of bcl-2, altered expression of DR4 (death receptor 4) and DR5 (death receptor 5), diminished Bax expression, PTEN mutations, and more. Both extrinsic and intrinsic pathways govern cell death. "The reduction in cell death goes hand in hand with mechanisms that increase cell proliferation," Dr. Tolcher said. Drugs targeting programmed cell death, said Dr. Tolcher, are currently directed primarily at bcl-2 inhibitors and the TRAIL (tumor necrosis factor receptor apoptosis-inducing ligand) receptor family, "a large family of death receptors" that initiates the external apoptotic pathway. Subtypes TRAILR1 and TRAIL R2 are considered the targets for cancer therapies. They are highly expressed in many tumor cells and their activation kills tumor cells directly. Several strategies have been proposed for TRAIL-receptor activation, including use of small peptides or recombinant monoclonal antibody agonists that bind to the external domain. Monoclonal antibodies, which have a long elimination half-life, are ideal when long exposure to a drug is desired, therefore this avenue is encouraging, he said. In experimental studies, agents targeting DR4 and DR5 have been shown to induce tumor regression and possibly yield a long-term "cure" in non- small-cell lung cancer xenografts. The drug is given as a single intravenous dose every 28 days, and no dose-limiting toxicity has yet been noted in early clinical trials. These agents are now under clinical investigation. DR4 is being studied in the US and Canada, and DR5 is in clinical trials in Europe. Bcl-2 as a Target In the intrinsic pathway, bcl-2 is a promising target. The bcl-2 protein is overexpressed in many solid tumors. Bcl-2 is overexpressed in more than 50% of small-cell lung cancer tumors, and in 30% of non-small-cell lung cancers. Overexpression shuts down the apoptotic pathway, making bcl-2 a negative prognostic factor, despite current therapy, clinical studies have shown. One way to target bcl-2 is with antisense oligonucleotides, which are small strands of nucleotides that bind to messenger RNA. The first-generation antisense oligonucleotides did not work because they were unstable in normal plasma, but newer agents are stable. The drug at the forefront of this class is oblimersen (G3139), which shows dose-dependent reductions in mRNA and has synergy with a broad array of chemotherapy agents. "What led to Aventis licensing this drug was its effect in non-small cell lung cancer xenograft H460. There was modest log cell kill and small change in tumor growth over controls, but when given with docetaxel(Drug information on docetaxel) there was significant tumor control, tumor growth delay, a greater log cell kill, and complete responses in 4 out of 7 animals and long-term survival," he said. "Bcl-2 may be associated with resistance to current chemotherapy, but with an agent such as docetaxel we see true synergy," Dr. Tolcher said. The most dramatic performance of oblimersen has been with chronic lymphocytic leukemia (CLL). Pivotal studies with this agent have been completed in CLL, multiple myeloma, and melanoma. In non-small-cell lung cancer, a randomized phase II study is now comparing docetaxel versus docetaxel plus oblimersen. "For our patients, apoptotic-inducing agents represent a whole new avenue that has not been explored-cell death-by targeting bcl-2 and TRAIL," Dr. Tolcher said. "These agents may also enhance our current forms of therapy."