Abstract IA16: Targeting molecular chaperone and stress pathways to hit multiple hallmarks and overcome resistance

Abstract

Abstract It is interesting and informative to review how the ‘Hallmarks' or Phenotypic Traits of cancers became codified and evolved over time. The original and now seminal ‘Hallmarks of Cancer' article by Hanahan and Weinberg (Cell 100 646-74 2000) codified the six classic—and now very well-known—Hallmark features. Next, Kroemer and Pouyssegur reassessed Tumor Cell Metabolism and discussed how alterations in this proposed seventh Hallmark are intertwined with cancer, either as cause or consequence (Cancer Cell 13 472-82 2008). Kroemer and Pouyssegur also highlighted Avoidance of Immunosurveillance as an additional element which would subsequently be incorporated as an eighth Hallmark. In 2011, a decade after their seminal article, Hanahan and Weinberg revisited their original Hallmarks, highlighting Genomic Instability and also the Inflammatory State that is driven by cells of the immune system as additional Hallmarks (Cell 144 646-74 2011). In addition, they emphasized the importance of the tumor microenvironment in cancer progression. In the intervening period, meanwhile, Luo, Solimini and Elledge provided their own view of the expanded classic Hallmarks to include the Stress Phenotypes of Tumorigenesis. Moreover, they also set out their personal version of a revised conceptual framework for a combination of Oncogene and Non-Oncogene Addictions—with former concept having been promoted by Weinstein (Science 297 63-64 2002) and the latter by Luo et al themselves—and proposed how these contribute to the Cancer State. Of note they codified Metabolic Stress, Proteotoxic Stress, Mitototic Stress, Oxidative Stress and DNA Damage Stress into their overall model. Running throughout the evolution of thinking about the Hallmarks of Cancer, captured and signposted by the above articles, is the concept that modern cancer therapies should be directed towards intervening with these key Phenotypic Traits. Luo et al emphasized that both Oncogene and Non-Oncogene Addictions could be exploited by either sensitizing cancer cells to stress or overloading stress-management pathways to selectively kill cancer cells. Of course the activity of bortezomib and other proteasome inhibitors in multiple myeloma—which is especially sensitive to proteotoxic stress overload owing to massive immunoglobin synthesis—is a poster child for this approach. Over the last several years our lab and Unit have pursued various Non-Oncogene Addiction targets that could be classified as exploiting Proteotoxic Stress as a key feature of the Cancer State. In this talk, I will review and update our experience with inhibitors of the molecular chaperone HSP90, including discovery and clinical evaluation of luminespib or AUY 922 (Eccles et al Cancer Res 68 2850-60 2008; Polier et al Nat Chem Biol 9 307-312 2013; Samant et al PNAS 111 6834-9 2014; Smith et al Oncogene 34 15-26 2015; Ferraldeschi et al Cancer Res in press) and targeting HSP70 family members (Powers et al Cancer Cell 14 250-62 2008; Zhang et al Cancer Lett 339 49-59 2013; unpublished data). A particular current interest is in targeting the HSF1 pathway which, as with HSP90 inhibition, provides opportunities for hitting multiple Hallmarks and Vulnerabilities of the Cancer State and providing the potential to overcome cancer evolution and drug resistance (Workman et al Oncotarget 7 3658-61 2016). The challenge, however, is to find a way to drug this intractable ligand-less transcription factor (de Billy et al Cancer Cell 8 3806-8 2009). New unpublished data will be shown to illustrate targeting molecular chaperone and stress pathways to hit multiple Hallmarks of Cancer and overcome resistance, as part of a combinatorial approach to extend cancer survival and increase cure rates. Citation Format: Paul Workman. Targeting molecular chaperone and stress pathways to hit multiple hallmarks and overcome resistance. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA16.