MTI-101 for the treatment of relapsed myeloma

Multiple Myeloma (MM) is a malignant plasma cell disorder, clinically characterized by osteolytic lesions, immunodeficiency, and renal disease. The incidence of MM is around 20,000 new cases per year in the United States; MM represents 1.   Despite dramatic advances in novel agents to treat the disease (I.E. proteasome inhibitors), disease relapse is inevitable, and MM remains incurable. Thus, clinical outcomes strongly support the need for novel target identification and therapeutic agent development to treat MM long-term.  It is clear that the tumor microenvironment contributes to de-novo resistance associated with the disease. Our laboratory contributed to understanding mechanism associated with cell adhesion mediated drug resistance or CAM-DR as well contribution of the Jak/Stat3 pathway in mediating resistance to hematologic malignancies in the context of the tumor microenvironment.

A current major focus of our laboratory is further development of a novel class of inhibitors that binds a Beta 1 integrin/CD44 complex and induces necrotic cell death.  We initiated these studies with a linear peptide referred to as HYD1 and showed this linear all d-amino acid peptide killed myeloma cells independent of caspase activity and the novel molecule demonstrated robust activity as a single agent using in vitro and in vivo models.  Importantly this class of compounds is more active in primary patient specimens obtained from relapsed patients.  In collaboration with our chemistry colleagues, Mark McLaughlin we increased the potency of the molecule via cyclization strategies and coined the second generation compound MTI-101.   Our mechanistic studies have let us to a novel hypothesis that progression and maintenance of MM require balanced CD44 signaling, which controls intracellular Ca2+ pools. In support of this concept, our preliminary data indicate that MTI-101 provokes a toxic increase in intracellular Ca2+ levels thereby triggering MM cell necrosis. We are currently defining the contribution of intracellular release via the IP3 receptor and store-operated channel in mediating MTI-101 induced cell death.

This work is supported by the NCI R01CA195727-01 and the CTSI