Tuesday, May 7, 2024
5/7/2024
Summary Small cell lung cancer (SCLC) is a highly aggressive and lethal disease, accounting for about 15% of all lung cancers. SCLC patients often initially respond to chemotherapy; however, their tumors invariably recur within 6 to 12 months. Treatment regimens for SCLC have remained largely unchanged for the past decades. Nonetheless, the addition of immunotherapy (such as anti-PD-L1 therapy) to chemotherapy was recently approved for the first-line treatment of adult patients with extensive-stage SCLC (ES-SCLC). Although the clinical benefit of adding anti-PD-L1 has been modest with an increase in median overall survival (OS) of approximately 2 months, these results have suggested that anti-tumor immunity can play a role in SCLC treatment. Notably, there are limited options for treating SCLC with targeted agents, emphasizing the critical need for identifying new targets and treatment paradigms. Our proposed studies address these unmet needs. SCLC has been increasingly recognized as a highly heterogeneous disease, which is largely regulated by four transcription factors (TFs). Neuroendocrine (NE) SCLC subtypes have been characterized by differential expression of the ASCL1 and NEUROD1 TFs and non-NE SCLCs by POU2F3 and YAP1. A recent study demonstrated an essential role of master regulator MYC in driving the evolution dynamics of these subtypes of SCLC, postulating their dependence on mutual transcriptional and epigenetic programs for tumor initiation and survival. We aim to leverage our recent discoveries for targeted therapy and state-of-the-art preclinical platform to identify novel strategies that mitigate the common dependencies in heterogenous SCLC. We previously demonstrated that SCLC cells are addicted to a CDK7-regulated gene expression program mediated, in part, by oncogenic members of the MYC family of TFs and proto-oncogenic NE lineage TFs. Furthermore, our recent data has uncovered a previously unrecognized role of MUC1-C in regulating common oncogenic transcriptomes in both NE and non-NE SCLC. In addition, we have successfully established multiple orthotopic murine SCLC models, which represent the four SCLC subtypes that include SCLC-ASCL1, -NEUROD1, -YAP1 and -POU2F3. Importantly, these murine models have an intact lung immune system making them a powerful resource for immune-oncology studies. Utilizing this preclinical platform, we will 1). evaluate the efficacy of MUC1-C inhibitor alone and in combination with CDK7 inhibitor in NE and non-NE SCLC in vitro and in vivo; 2). define the TME alterations induced by MUC1-C inhibition alone and in combination with CDK7 inhibition; and 3). define the cancer intrinsic and extrinsic mechanisms by which MUC1-C and CDK7 inhibition alone and in combination contribute to antitumor immunity. Ultimately, characterizing the underlying mechanisms associated with responses to our targeted therapies will help develop tailored treatment for SCLC patients.
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