Jumonji KDM4A drives targetable oncogenic programs in small cell lung cancer

Ut Southwestern Medical Center, Dallas TX

Investigators

Abstract

Abstract Small cell lung cancer (SCLC) is a recalcitrant disease that rapidly acquires drug resistance and for which no mechanistically novel drug therapies have been developed over the last several decades. SCLC responds poorly to second line therapy or immunotherapy. There is therefore a challenging yet impactful opportunity to discover new therapeutic strategies against this recalcitrant tumor type. A major obstacle to accomplishing this goal is that over 500 drugs under clinical development have shown no benefit over current first line etoposide treatment. We have highly promising preliminary data in cell culture and in vivo models that strongly support that epigenetic enzymes of the Jumonji lysine demethylase family (Jumonji KDMs) constitute viable druggable targets in SCLC, and even in disease that has acquired chemotherapy resistance. Here we therefore propose a new idea: that Jumonji demethylases are key contributors to SCLC and to its fast-acquired resistance to therapy. We have novel tools to probe this idea pharmacologically: namely, enzyme inhibitors developed by us with proven in vivo efficacy. Thus, we propose an innovative three-pronged therapeutic paradigm: treating SCLC with Jumonji inhibitors as first line therapy, treating SCLC resistant to etoposide with second line Jumonji inhibitors alone or in combination with other agents for which we have a biological rationale (including mTOR inhibitors because of the gene expression profiles we observe in treated cells), and combining Jumonji inhibitors with standard first line therapy upfront to prevent therapeutic resistance in the first place. Mechanistically, the impact of pharmacological or genetic inhibition of Jumonji KDM4A on the SCLC epigenome and transcriptome will be defined. Our preliminary data demonstrates that SCLC cell lines and xenografts, including etoposide resistant SCLC cells, are sensitive to the pan-Jumonji inhibitor JIB-04 and to the Jumonji KDM4 subfamily inhibitor SD-70, through on-target activity. Furthermore, we show that Jumonji inhibition alters levels of the neuroendocrine transcription factors that drive SCLC oncogenesis. Thus we hypothesize that Jumonji inhibition will block SCLC growth and overcome therapeutic resistance in clinically relevant disease models, by reprogramming neuroendocrine lineage transcription factor gene programs. This work will thus open a new paradigm for SCLC treatment.