Friday, April 19, 2024
4/19/2024
PROJECT SUMMARY/ ABSTRACT Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable in the vast majority of patients with a median survival of 5-7 years. While FDA-approval of proteasome inhibitors (PIs) in combination with immunomodulatory agents and traditional drugs has significantly improved patient outcomes, the development of PI-resistance remains a primary reason for patient demise. There is also a significant fraction of newly diagnosed MM patients who are refractory even to PIs and have not benefited from recent therapeutic advancements. The transforming growth factor (TGF)-ß pathway is a key driver in cancer and TGF-b¿-responding cells resist anti-cancer therapeutics leading to drug resistance, tumor recurrence and reduced survival. Understanding the mechanistic role of TGF-b¿1 to promote acquired PI-resistance in MM represents a clinically- relevant gap in knowledge and an unmet need and immediate translational impact. Here, we evaluated the TGF- b¿ type I receptor (TGF-b¿RI) as a new target for clinical application in MM and the biological effects of the TGF- b¿RI inhibitor Vactosertib on PI-resistant MM cells. Elevated TGF-b¿1 levels in MM patient sera correlates with chemoresistance, disease progression, metastasis and poor prognosis. TGF-b¿1 also upregulates the expression of PSMB5, the proteasome catalytic subunit that is inhibited by PIs. TGF-b¿1 also induces the accumulation of myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment. These observations led us to explore the potential for Vactosertib to disrupt the TGF-b¿ pathway and, thereby, overcome tumor intrinsic and extrinsic mechanisms of PI-resistance in MM. Vactosertib is a recently developed, novel, orally available small molecule inhibitor of TGF-ßRI kinase activity. Our results show that Vactosertib reduces PSMB5 expression and proteasomal catalytic activity in MM cells, reduces the growth and induces apoptosis of MM cells, suppresses myeloma growth in murine models in vivo and in combination with PIs overcome drug resistance. In the proposed studies, we will first determine the effect of TGF-b¿1 on the expression of proteasome genes and subunits in PI- sensitive and resistant MM cells and MM patient tumor cells (Aim 1). We will then determine the effect of Vactosertib on the level of proteasome subunits in MM cell lines and patient tumor cells. We have utilized the well-characterized 5T33MM murine model to explore the impact of specifically targeting TGF-ß signaling on MM progression. Our preliminary data reveal Schlafen-4 (Shlf-4) is a TGF-ß-regulated gene associated with MM progression, whose expression is abrogated by Vactosertib. We will determine the effects of Vactosertib on MDSC depletion in 5T33MM mice, as well as the effects on MDSC functional activity and Shlf-4 levels in MDSCs (Aim 2). We will then validate the murine studies and determine the effect of Vactosertib on MDSCs and tumor cells isolated from human MM patients. Successful pursuit of the specific aims will improve our understanding of the mechanisms underlying acquired PI-resistance in MM and facilitate the design of clinical trials to evaluate the efficacy of Vactosertib combined with PIs.
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