Detection and elimination of drug tolerant persister cells in small cell lung cancer

Project Summary Small cell lung cancer (SCLC) is a highly aggressive, neuroendocrine malignancy that follows predictable and dispiriting clinical course. Initially, SCLC patients are uniformly treated with combination chemo-immunotherapy and, for most patients, this approach initially appears successful with dramatic improvement in clinical symptoms and tumor burden. However, just as rapidly as the tumor recedes, it invariably recurs and, upon recurrence, exhibits more molecularly heterogeneous and drug-resistant biology. This narrowly missed opportunity in which SCLC is nearly vanquished only to re-emerge even stronger highlights the urgent, unmet need to identify and target those drug tolerant persister cells (DTPCs) responsible for this malignant sleight of hand. This need is explicitly articulated by the National Cancer Institute’s Scientific Framework for Small Cell Lung Cancer as one of five initiatives within the Recalcitrant Cancer Act - “investigate the mechanisms underlying both the high initial rate of response to primary SCLC therapy and the rapid emergence of drug and radiation resistance following completion of treatment”. To address this need, we have assembled an unparalleled repository of SCLC patient samples and patient-derived models from all relevant clinical timepoints, as well as a multi-disciplinary team with scientific, clinical, translational, and computational expertise in SCLC. Our preliminary data in SCLC models validate not only the existence of these long-hypothesized DTPCs, but also the feasibility of their procurement for molecular and therapeutic analyses. Further, we have demonstrated the relapsed SCLC state is enriched for, though not solely composed of, putative DTPCs with unique therapeutic vulnerabilities. Based on these data, we hypothesize that we can technically enrich for and select DTPCs from SCLC genetically-engineered and patient- derived models, as well as patient samples, and that their cell surface proteome represents an actionable vulnerability for their elimination. To address these hypotheses, we propose the following Aims: in Aim 1, we will collect DTPCs and molecularly characterize DTPCs in SCLC models treated with standard platinum-based chemotherapy to then track their emergence and trajectory in models and patient samples. In Aim 2, we will characterize the ability of the newest class of just-approved SCLC agents – a bi-specific T-cell engager (BiTE) against Delta-like ligand 3 (DLL3) – to shape, or even eliminate, the post-platinum DTPC population. Lastly, in Aim 3, we will develop preclinical antibody-based therapeutics, like antibody-drug conjugates (ADCs) or chimeric antigen receptor (CAR) T-cells that specifically target surface proteins enriched in those DTPCs that survive both platinum-based chemotherapy and DLL3 BiTEs. Together, these aims will comprehensively characterize and validate the DTPC landscape following state-of-the-art SCLC treatments and offer clear candidates for their elimination in future clinical trials.