Novel Apoptosis-Inducing Agents Entering Phase I Trials

VANCOUVER, Canada-Novelapoptosis-inducing agents, which haveentered phase I clinical trials, representnew avenues for therapeutic interventionand are expected to enhancecurrent treatment strategies, said AnthonyTolcher, MD, director of clinicalresearch at the Institute for DrugDevelopment, San Antonio, Texas."It's been a lonely world for thoseof us who have been pursuing drugsthat target apoptosis, compared tothose that target pathways of proliferation,such as the epidermal growthfactor receptor, which has been a mainfocus at this entire meeting," Dr.Tolcher commented at the 10th WorldConference on Lung Cancer.At a session on targeted therapy forlung cancer, Dr. Tolcher predicted thatalthough apoptosis-inducing agentsare still in early clinical development,"they may have a role in 3 to 5 years inthe clinical setting."Apoptosis is critical for normalphysiologic processes. Elimination ofcertain cells (eg, viral-infected cells orself-reactive T cells that are involved inautoimmunity) is important to health.Aberrant and diminished apoptosis iscommon to many types of malignanciesand takes many forms, includingaltered expression of the tumor necrosisfactor receptor family, overexpressionof bcl-2, altered expression ofDR4 (death receptor 4) and DR5 (deathreceptor 5), diminished Bax expression,PTEN mutations, and more.Both extrinsic and intrinsic pathwaysgovern cell death."The reduction in cell death goes handin hand with mechanisms that increasecell proliferation," Dr. Tolcher said.Drugs targeting programmed celldeath, said Dr. Tolcher, are currentlydirected primarily at bcl-2 inhibitorsand the TRAIL (tumor necrosis factorreceptor apoptosis-inducing ligand)receptor family, "a large family of deathreceptors" that initiates the externalapoptotic pathway. Subtypes TRAILR1and TRAIL R2 are considered thetargets for cancer therapies. They arehighly expressed in many tumor cellsand their activation kills tumor cellsdirectly.Several strategies have been proposedfor TRAIL-receptor activation,including use of small peptides or recombinantmonoclonal antibody agoniststhat bind to the external domain.Monoclonal antibodies, which have along elimination half-life, are idealwhen long exposure to a drug is desired,therefore this avenue is encouraging,he said.In experimental studies, agents targetingDR4 and DR5 have been shownto induce tumor regression and possiblyyield a long-term "cure" in non-small-cell lung cancer xenografts. Thedrug is given as a single intravenousdose every 28 days, and no dose-limitingtoxicity has yet been noted in earlyclinical trials.These agents are now under clinicalinvestigation. DR4 is being studied inthe US and Canada, and DR5 is inclinical trials in Europe.Bcl-2 as a TargetIn the intrinsic pathway, bcl-2 is apromising target. The bcl-2 protein isoverexpressed in many solid tumors.Bcl-2 is overexpressed in more than50% of small-cell lung cancer tumors,and in 30% of non-small-cell lungcancers. Overexpression shuts downthe apoptotic pathway, making bcl-2 anegative prognostic factor, despite currenttherapy, clinical studies haveshown.One way to target bcl-2 is with antisenseoligonucleotides, which aresmall strands of nucleotides that bindto messenger RNA. The first-generationantisense oligonucleotides did notwork because they were unstable innormal plasma, but newer agents arestable. The drug at the forefront of thisclass is oblimersen (G3139), whichshows dose-dependent reductions inmRNA and has synergy with a broadarray of chemotherapy agents."What led to Aventis licensing thisdrug was its effect in non-small celllung cancer xenograft H460. There wasmodest log cell kill and small change intumor growth over controls, but whengiven with docetaxel there was significanttumor control, tumor growthdelay, a greater log cell kill, and completeresponses in 4 out of 7 animalsand long-term survival," he said."Bcl-2 may be associated with resistanceto current chemotherapy, butwith an agent such as docetaxel we seetrue synergy," Dr. Tolcher said.The most dramatic performance ofoblimersen has been with chronic lymphocyticleukemia (CLL). Pivotal studieswith this agent have been completedin CLL, multiple myeloma, andmelanoma. In non-small-cell lungcancer, a randomized phase II study isnow comparing docetaxel versusdocetaxel plus oblimersen."For our patients, apoptotic-inducingagents represent a whole new avenuethat has not been explored-celldeath-by targeting bcl-2 and TRAIL,"Dr. Tolcher said. "These agents mayalso enhance our current forms oftherapy."