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CCR Focus |
Authors' Affiliations: 1 Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts and 2 Abramson Cancer Center at the University of Pennsylvania, Philadelphia, Pennsylvania
Requests for reprints: Edward J. Benz, Jr., Dana-Farber Cancer Institute, Harvard University, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4266; Fax: 617-632-2161; E-mail: edward_benz{at}dfci.harvard.edu.
This issue of CCR Focus comprises four representative articles that closely fit the research interests of Stanley J. Korsmeyer, to whom this volume is dedicated. The first article, and perhaps the most related to Korsmeyer's work, is a review by Nika Danial of the structure and function of the ever growing BCL-2 family of proteins and their potential role in disorders as apparently disparate as cancer and diabetes (1). The second article by Amaravadi and Thompson broadens the discussion of cell death to include a penetrating analysis of the roles of necrosis and autophagy in cancer treatment (2). Our current understanding of autophagy and necrosis could not have been as adequately characterized without the generation of cells deficient in proapoptotic Bcl-2 family members (3, 4). This is followed by a third article by Rixe and Fojo, who emphasize that effective cancer treatment can occur by inducing cytostasis rather than cytotoxicity, because cytostasis is often poorly tolerated in tumor cells and, in fact, if sustained, should lead to cell death (5). They point out that we must be careful not to attribute to cytostasis what is merely insufficiently effective therapy. Finally, Verdine and Walensky return to apoptosis and show that the alpha helices of BH3 death domains can be made into drugs by means of peptide stapling and actually induce apoptosis in cancer cells (6).
Each of these four reviews make several cogent shared points, even though each deals with substantively different aspects of the process by which cell death is governed in nature.
First, the processes governing cell death involve complex interlaced metabolic pathways that form an intricate system of checks and balances. It follows that these systems present many opportunities for therapeutic intervention, but many distinct challenges as well. The cell protects itself from dying. If one wishes to promote the death of unwanted cells, one must develop agents that can defeat multiple pathways of cellular self-preservation, in addition to stimulating the prodeath pathways.
Second, we know relatively less about the factors ensuring the proper balance of prodeath and antideath pathway activities in many normal tissues. Some of these can be inferred by the incidental effects of other cytotoxic and noncytotoxic drugs on cell death pathways. We have considerably less information about what kinds of toxicities to anticipate with agents capable of altering the death/survival balance in a direct and potent way. Thus, any effort involving experimental therapeutics targeting these pathways will require a considerable amount of basic cellular and physiologic research directed at anticipating and controlling unforeseen toxicities.
Third, the complex pathways described in each of the four reviews are particularly heavily dependent on protein-protein interactions, the formation of multiprotein complexes, alterations in transmembrane transport, and perturbation of core metabolic pathways involved in basic cell maintenance. The complex interactions currently understood for intrinsic and extrinsic apoptotic pathways are shown in Fig. 1 . As noted in the article by Walensky and Verdine, making these pathways druggable may well require a different kind of medicinal chemistry, one focused on agents that directly perturb protein-protein or protein-organelle interactions, rather than inhibiting or stimulating enzymatic activities (6).
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These considerations suggest that demonstrating efficacy in single agent trials may be difficult, making the introduction of the drug into a practical setting more daunting. A good example of this challenge is the excitement generated by early phase clinical trials of the antisense Bcl-2 molecule oblimersen. Although promising phase I/II results prompted multiple randomized phase III clinical trials in chronic lymphocytic leukemia, metastatic melanoma, multiple myeloma, and acute myelogenous leukemia, oblimersen as a single agent did not improve survival in any randomized phase III trial (8). A randomized trial with oblimersen in combination with dacarbazine in melanoma also failed to improve survival (9), but in recently reported results, oblimersen, in combination with cyclophosphamide and fludarabine, met its primary efficacy end point of improving complete response (10). Seven years after its entry into human trials, trials of oblimersen are ongoing and this experience underscores the difficulty in establishing clinical roles for agents that target cell death pathways. Finally, because these agents will likely be incorporated quickly into multiagent regimens, an additional challenge is assigning praise and blame to the novel prodeath agent or the existing cancer therapy for antitumor benefits and toxicities observed in the patient.
To overcome some of these challenges, it will be important to incorporate biomarker studies into clinical trials to determine why this promising new class of drugs does not reproduce the results obtained in laboratory studies. Is the target present in the patient's tumor? Is the drug hitting its target? Is there measurable cell death? Is there evidence of activated resistance mechanisms? Should the primary efficacy end point of early trials be response rate or progression-free survival? Unless these questions are tackled head-on in the clinic, we risk rejecting life-saving therapeutics and turning our backs on the promising preclinical research that supports these agents.
Each of these reviews also makes it clear that a far more detailed understanding of the derangements of the cell survival/death balance will be critical if we are to understand the clinical behavior of individual forms of cancer in patients. The notion that the most important difference between tumor cells and their normal counterparts is their accelerated rate of cell division has long since been discarded in favor of more sophisticated notions of malregulation of cell growth and proliferation. Nonetheless, despite the knowledge gained by studies of the specific abnormalities in tumor cell genomes, much of our therapeutic approach to individual forms of cancer is still focused around the issue of cell proliferation. It is true that we now target specific steps in cell cycle regulation, signal transduction, receptor-mediated signaling, and hormone-driven proliferation, more precisely and selectively than in the past. Even in the advanced era of targeted drug development, many of the targets we select for drug development continue to be those that, directly or indirectly, are thought to drive inappropriate proliferation or to fail to stop it.
It is very clear, as pointed out in these reviews, that the efficacy of many existing drugs is at least partly dependent on the cooperation of the targeted cell. If cell death pathways remain sufficiently intact or unblocked, the stimulus for apoptosis caused by drug-induced damage will lead to the death of the tumor cell. If not, the drugs are largely or completely ineffective. To improve the efficacy of targeted agents, it might be necessary to match the choice of a proliferation target with agents that target the specific aberrancy in the cell survival equation within the targeted cancer cells.
Another strategy that might identify the patient population that could most benefit from cell death modulators is to test these agents in molecularly defined tumors rather than traditional disease-specific clinical trials. In 1985, in the same year that the discovery of the association between B cell lymphomas and chronically overexpressed Bcl2 was reported (11), lymphomas were generated in transgenic mice chronically expressing the c-Myc oncogene (12). It was quickly appreciated that acute expression of Myc is a powerful stimulus for apoptosis (13) yet Myc is one of the most widely dysregulated oncogenes in cancer (14). Cancer cells that express Myc must have simultaneous defects in the pathways that control apoptosis to survive the Myc-induced oncogenic stress. Since then, nearly 18,000 articles have been published about Myc, but therapeutics have not yet been successfully developed to exploit the fact that unopposed Myc may be one of the most powerful anticancer therapies nature will create. A central role for dysregulated Bcl-2 family proteins (15–17) has been established in allowing tumor cells to escape Myc-induced apoptosis. With the novel strategies to target apoptosis described in this issue of CCR Focus, a new light could be shed on exploiting the double-edged sword of oncogenesis for the benefit of our patients (18).
Taken together, all of these considerations make it clear that Korsmeyer's insight into the role played by impaired apoptosis has uncovered a complexity that we must understand and deal with if we are to develop effective and safe therapies. The work inspired by Korsmeyer and his contemporaries has shown the extraordinary intricacy of the governing biochemical pathways. To date, most of what we have learned has been instructive but daunting. Finding ways to manipulate these pathways will not be a simple task. It is thus somewhat surprising and heartening that a number of agents have been identified and are advancing to clinical trials (Table 1 ). Remarkably, these agents have shown considerable promise in preclinical studies. We can only hope that at least a few of them will be chaperoned effectively through clinical trials and eventually promote a step change for cancer treatment.
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References
This article has been cited by other articles:
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  G. L. Verdine and L. D. Walensky The Challenge of Drugging Undruggable Targets in Cancer: Lessons Learned from Targeting BCL-2 Family Members Clin. Cancer Res., December 15, 2007; 13(24): 7264 - 7270. [Abstract] [Full Text] [PDF]
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R. K. Amaravadi and C. B. Thompson The Roles of Therapy-Induced Autophagy and Necrosis in Cancer Treatment Clin. Cancer Res., December 15, 2007; 13(24): 7271 - 7279. [Abstract] [Full Text] [PDF]
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