Novel Mcl-1 Inhibitor for Combination Treatment of Refractory Multiple Myeloma - ABSTRACT
Multiple myeloma (MM) is a plasma cell malignancy. Treatment usually involves a proteasome inhibitor,
dexamethasone, and an immunomodulatory or chemotherapeutic treatment, with or without autologous stem
cell transplantation. Because of intrinsic or acquired medication resistance, all myeloma patients eventually
relapse. The expression of the prosurvival members of the Bcl-2 family, particularly Mcl-1, is a key process in
the survival of myeloma cells. Because Mcl-1 is a critical mediator of disease progression and an important
mechanism in the acquisition of resistance to therapy it is reasonable to ask if MM patients, particularly those
at relapse, would benefit from an Mcl-1-targeted therapy? A few selective Mcl-1 inhibitors are currently being
developed or are being tested in clinical trials, but unfortunately, most of the previous studies were terminated
because of undesirable side effects, especially cardiac toxicity. To address this need, we developed a novel
Mcl-1 inhibitor, KS18, to investigate the mechanistic underpinning of Mcl-1 role in MM, and to determine
feasibility of Mcl-1 inhibition as a therapeutic strategy. Therefore, the rationale for this research is to determine
whether our novel Mcl-1 inhibitor can be used along with the existing chemotherapeutic agents to effectively kill
resistant myeloma cells, thus, inhibit or prevent MM relapse. Our preliminary studies demonstrated that unlike
chemotherapy, KS18 kills resistant cells, suggesting that it could be combined with traditional chemotherapy to
treat MM while minimizing the possibility of resistance development more effectively. To evaluate the efficacy
and the likely mechanism of action of KS18 in combination with existing MM treatments, we propose the
following Specific Aims: First, is inhibiting Mcl-1 via KS18 sufficient to reverse the acquired chemotherapeutic
resistance in MM in vitro? We will test KS18 alone and in combination with therapeutic agents used in
treatment of MM, including with bortezomib, venetoclax or as a third agent in combination with bortezomib and
dexamethasone, which is part of clinical standard of care for MM patients. Second, can Mcl-1 inhibition
reverse bortezomib resistance in MM in vivo? We will determine how Mcl-1 inhibition modulates the acquired
resistance to chemotherapeutic agents, and third, what is the efficacy of Mcl-1 inhibitor and bortezomib
combination in refractory and relapsed patient samples? We will investigate the efficacy of the KS18 and
bortezomib combination in patient samples. These significant discoveries would demonstrate the efficacy of
targeting anti-apoptotic protein Mcl-1 in MM as well as other cancers for modulating relapse, providing needed
preclinical validation necessary for clinical translation. This contribution will be significant because it is
expected to have broad translational importance in the treatment of MM. Furthermore, this proposal will
enhance the infrastructure of research and education at Cooper Medical School of Rowan University
(CMSRU), offering biochemical and biomedical research experiences to underserved minority students, who
would otherwise lack such opportunities.
