Multiple myeloma (MM) is a slowly proliferating tumor of post-germinal center plasma cells that causes bone destruction, marrow failure, immuneparesis and renal failure and results in over ten thousand deaths each year in the USA. For many years a class of drugs termed immunomodulatory drugs (IMiDs) have been used in the clinic with remarkable activity against MM and a few other hematopoietic neoplasms (Chronic Lymphocytic Leukemia, NonHodgkin Lymphoma and Myelodysplastic Syndrome with 5q- deletion). Although many patients have a favorable initial IMiD response, most will eventually relapse with loss of sensitivity to the IMiD (acquired resistance to IMiDs). Patients also differ in their initial responses to IMiD therapy. While some enjoy `exceptional' responses to IMiD treatment (defined as time to progression of 72 months or longer) others exhibit innate resistance and thus never respond. The exact mechanism of IMiD action and resistance in MM remains elusive, although it is clear that IMiDs trigger the CRBN-dependent degradation of the hematopoietic transcription factor Ikaros. Almost every MM tumor is characterized by super enhancer-mediated oncogene dysregulation via insertion of such enhancers into the MYC locus or via recurrent IgH enhancer translocations to a number of oncogenes. Our preliminary data further indicate that many these critical super-enhancers driving oncogene expression in MM exhibit high Ikaros occupancy, and that their enhancer function is consequently often Ikaros-dependent. Our hypothesis is that tumor cell-autonomous IMiD resistance is caused by super-enhancers driving oncogene expression that retain their function in the presence of IMiDs. The work presented here studies IMiD resistance using three different approaches. First, with the goal of identifying genetic determinants of innate and acquired IMiD resistance, we will examine structural variations (primarily DNA translocations) that mobilize super-enhancers to oncogenes in patient samples that have been banked in the Mayo Clinic biobank. Secondly, we have >80 genetically annotated MM cell lines with a range of responses to IMiDs that will be tested for their response to IMiDs in terms of proliferation and changes in gene expression/protein levels (including MYC). Additionally we will examine synergies between IMiDs and a number of novel rational drug partners including next generation BET inhibitors (BETi), CBP/p300 inhibitor and a combination BETi/p300 inhibitor. Thirdly, IMiD response mediated by the inter-play between tumor cell and host will be studied in an orthotopic, immunocompetent humanized mouse model of MM in which both the tumor and the host are capable of responding to IMiDs. Our ultimate goal is to rationally optimize the activity of IMiDs, which would have a profound impact on the clinical history of MM, both avoiding IMiD resistance in newly diagnosed patients and reversing IMiD resistance in relapsed patients.
PROJECT 2 NARRATIVE While multiple myeloma responds well to therapy, seldom are the cancerous plasma cells completely eradicated since many patients relapse. Our hypothesis is that one cause of tumor cell-autonomous IMiD resistance results from super-enhancers driving oncogene expression that retain their function in the presence of IMiDs. To test this hypothesis we will examine super-enhancer dysregulating oncogenes in IMiD resistant patient samples and myeloma cell lines in addition to studying resistance in a clinically relevant, humanized, orthotopic, fully immune-competent mouse model.
