EXPLOITING THE CANCER GENOME: Strategies for the Discovery and Clinical Development of Targeted Molecular Therapeutics

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1 EXPLOITING THE CANCER GENOME: Strategies for the Discovery and Clinical Development of Targeted Molecular Therapeutics Timothy A. Yap and Paul Workman Supplemental Material Section 9 of this review discusses various strategies for drugging the cancer genome, focusing on blocking oncogene addiction, drugging the oncogenic lipid kinome, addressing nononcogene addiction, exploiting synthetic lethality, and overcoming apoptotic resistance with small molecules. The latter is covered here Overcoming Apoptotic Resistance Cancer cells evade apoptosis through numerous mechanisms, including inactivation of p53 gene mutations that are present in more than 50% of cancers and HDM2 gene amplification, which promotes the ubiquitination and degradation of p53 (1). Somatic inactivation of BAX mutations in cancers with DNA mismatch repair, as well as rare DR5 genetic mutations or caspase 8 epigenetic silencing along the extrinsic apoptotic pathway, may also lead to the evasion of cellular apoptosis (2-- 4). Genetic aberrations of components of other key signaling networks, such as the PI3K/AKT pathway discussed above, may also abrogate cellular apoptosis (5). With an improved knowledge of the mechanisms underlying the evasion of apoptosis in cancer, several antitumor therapeutic strategies have been pursued, including those targeting the BCL-2 protein family, proapoptotic receptor agonists, and inhibitor of apoptosis proteins (IAPs).

2 BCL-2 PROTEIN FAMILY. This heterogeneous group includes the prosurvival proteins (e.g., BCL-2 and BCL-X L ) and the proapoptotic proteins (e.g., BAX, BAK, and BH3-domain-only proteins) (6). A fine balance exists between these two sets of proteins, which have opposing functions. Thus, a rational therapeutic strategy for targeting the deregulation of apoptotic signaling pathways in cancer is to tip the balance between the prosurvival and proapoptotic proteins toward programmed cell death. The BCL-2 protein is a rational antitumor target because it is often overexpressed in cancer and is also involved in the development of resistance to both chemotherapy and radiotherapy. In view of this, numerous drug development programs have focused on the development of antitumor therapeutics against BCL-2. The clinical candidate furthest along in development is the antisense oligonucleotide oblimersen (Genasense ; Genta, Inc.), which binds to the first six codons of human BCL-2 mrna, suppressing BCL-2 expression (7). Oblimersen has completed Phase III clinical trials in melanoma and chronic lymphocytic leukemia but has yet to obtain approval from the U.S. Food and Drug Administration (FDA) or European Medicines Agency (EMEA) (8--10). Other proposed anti-bcl-2 agents in clinical trials include the oral small-molecule pan-bcl-2 inhibitor AT-101 [R-(-)- gossypol; Ascenta Therapeutics], which is in Phase I/II studies in a range of cancers, such as lung cancer, castration-resistant prostate cancer, and glioblastoma multiforme, in combination with different chemotherapies (11; see also Another pan-bcl2 small-molecule inhibitor is obatoclax (GX15-070; Gemin X Biotechnologies), which inhibits the association between the prosurvival proteins MCL-1 and BAK in cells and overcomes MCL-1- mediated resistance to cellular apoptosis (12, 13). Obatoclax is being assessed as a single agent and in combination with chemotherapies in Phase I/II clinical trials in patients with advanced tumors (14; see also Other BCL-2 inhibitors in Phase I/II trials include SPC2992 (Santaris Pharma) and ABT- 263 (Abbott/Genentech) ( Recent preclinical evidence has provided new potential strategies for targeting BCL-2. Kolluri and colleagues (15) demonstrated that the nuclear receptor NUR77

3 may covert BCL-2 from a prosurvival protein to a proapoptotic one through the binding of a loop found between the BCL-2 BH3 and BH4 domains. This leads to the inhibition of BCL-X L and induction of BAX/BAK-dependent apoptosis. Another therapeutic approach is to directly activate the proapoptotic proteins, for example, by targeting BAX and BAK. Walensky and colleagues (16) recently discovered a novel activation site that may represent a rational target for activating BAX PROAPOPTOTIC RECEPTOR AGONISTS. The proapoptotic receptors DR4 and DR5 may lead to the activation of apoptotic caspases independent of p53 and are frequently overexpressed in cancers, making them attractive targets in novel drug development (1). Proapoptotic receptor agonists (PARAs) may have added advantages over agents that target the intrinsic apoptotic pathway as they do not depend on p53 for effective tumor apoptosis and may potentially circumvent p53-mediated drug resistance (17). Dulanermin (rhapo2l/trail) is a recombinant human protein that activates both DR4 and DR5 and is being assessed in Phase II oncology trials in combination with established agents. Preclinical data have also shown that PARAs such as dulanermin may result in highly selective tumor induction of apoptosis (18). In view of this, a growing body of research has focused on the identification of predictive biomarkers aimed at enhancing responses to these agents. Potential biomarkers include O-glycosylation enzymes and mutations in caspase 8 and Bax genes (1, 19). Other PARAs in clinical trials include anti-dr5 monoclonal antibodies such as Apomab (Genentech), AMG-655 (Amgen) and lexatumumab (Human Genome Sciences/Kirin), and the anti-dr4 monoclonal antibody mapatumumab (Human Genome Sciences/GlaxoSmithKline/Takeda) ( INHIBITOR OF APOPTOSIS PROTEINS. Inhibitor of apoptosis proteins (IAPs), which include cellular IAP1 (ciap1), ciap2, XIAP, and survivin, regulate apoptotic caspases and other processes pivotal to cellular survival, such as the ubiquitin-dependent activation of nuclear factor (NF)-κB (20). IAP abnormalities are a frequent finding in multiple malignancies and are implicated in tumor progression, chemoresistance, and a poor prognosis. Targeting these IAPs is thus an attractive anticancer strategy, and current approaches include the use of antisense molecules and small-molecule inhibitors of these

4 IAPs and mimetics of the IAP antagonist Diablo. These agents, which are in Phase I/II clinical trials, include the survivin antisense compound LY (Eli Lilly/Isis Pharmaceuticals), the XIAP antisense compound AEG35156 (Aegera Therapeutics), the small-molecule survivin antagonist YM-155 (Astellas Pharma), and the IAP inhibitor HGS1029 (Human Genome Sciences) ( FUTURE DIRECTIONS FOR APOPTOSIS-TARGETING AGENTS. Despite the promise of these apoptosis-targeting agents over the past decade, late-phase clinical trials have been disappointing, and none of the agents has been approved by the FDA or EMEA for the treatment of solid tumors. The reasons for this will need to be dissected, and key issues will need to be addressed in the future. An important consideration is that the majority of apoptotic targets involve intracellular protein-protein interactions, which may be difficult to modulate with the range of compounds and molecular tools currently available. Future potential targets may include endoplasmic reticulum stress proteins and protective unfolded protein response proteins, which are upregulated in cancer cells for multiple reasons, including aneuploidy, oncogenic stress, and hypoxia (21). The dual targeting of both p53 and NF-κB may be necessary for antitumor efficacy, but further studies are necessary to develop this as a therapeutic strategy (22). Finally, as with other drug programs discussed above, the optimal combinations and scheduling of therapeutic regimens will need to be established through the use of intelligent adaptive clinical trial designs, and the development of predictive biomarkers for the enrichment of antitumor responses to these agents will be imperative (23). Supplemental References 1. Ashkenazi A Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat. Rev. Drug Discov. 7: Rampino N, Yamamoto H, Ionov Y, Li Y, Sawai H, et al Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science 275:

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