Abstract IA01: The discovery of next-generation cancer targets and therapeutics

Abstract

Abstract Cancer is driven by the accumulation of somatic genetic alterations that alter the activity of tumor suppressor and oncogenes. Together these activities lead to the dysregulation of cell proliferation, cell survival and metabolic pathways, among many others, that culminate in the acquisition of the transformed phenotype characteristic of malignant tumors. Reversing the consequences of oncogenic mutations through therapeutic intervention has been repeatedly demonstrated to bring significant patient benefit across a spectrum of oncogenes including BCR-ABL, BRAF, EGFR, cKIT, HER2, RET, ROS and ALK among others. Exemplary of both this paradigm is the longstanding experience of treating BCR-ABL+ chronic myelogenous leukemia (CML) patients with inhibitors of the Abelson kinase (ABL). Small clinical studies have recently shown that drug withdrawal can be associated with treatment free remission in a subset of patients achieving deep molecular responses. Towards the goal of eradicating CML, we have developed a novel potent and selective allosteric inhibitor of ABL, known as ABL001. ABL001 binds at a regulatory site typically occupied by a myristoyl group in wild-type ABL and inhibits ABL kinase activity through a mechanism distinct from catalytic site inhibitors. As a result, mutagenesis and genetic bar-coding experiments revealed a spectrum of resistance highly distinct from that seen with catalytic site inhibitors suggesting the possibility that co-administration of CML tumor cells with both types of inhibitors might act to block the development of therapeutic resistance. In vivo experiments showed that combination but not the single agent ABL001 and nilotinib could eradicate CML xenografts with sustained responses after treatment cessation. ABL001 is now in phase I clinical testing. Advances in next-generation sequencing and projects including the Cancer Genome Anatomy project and the International Cancer Genome Consortium have given us a detailed description of the genetic alterations across a broad spectrum of cancer. This however, does not immediately lead to a detailed functional understanding of those genes whose protein products are necessary for the maintenance of cancer viability. In order to more deeply understand the genes and pathways critical to the survival of cancer cells we have taken on the functional annotation of the Cancer Cell Line Encyclopedia (Nature 2012;483:603-7) through the use of deep pooled shRNA libraries. The resulting effort termed Project DRIVE (Deep RNAi-screening for Viablity Effects in cancer) has led to the generation of drop-out shRNA data for 7,500 genes targeted by 20 shRNAs per gene across 390 cancer cell lines. The data from this effort are highly robust identifying all known oncogenes mutated in the set of interrogated cell lines, along with multiple new cancer dependent features not previously described. Most recently, this project led to the discovery of PRMT5 as a novel dependency in cancers harboring co-deletion of MTAP and CDKN2A (Science 2016 351:1208-1) a finding that will be further described in the lecture. Citation Format: William Sellers. The discovery of next-generation cancer targets and therapeutics. [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 IA01.