Novel Targeted Therapy for Refractory Multiple Myeloma - ABSTRACT: Multiple myeloma (MM) is a plasma cell cancer that causes an overabundance of malignant, terminally developed B cells in the bone marrow. The outcomes for patients with MM have improved significantly due to advancements in innovative therapies such as proteasome inhibitors, immunomodulatory agents, and immunotherapy. However, relapse remains inevitable for nearly all patients, and long-term survival gains remain limited. One possible explanation for this conundrum is the concept of MM stem-like cells (MMSCs). ALDH is a class of NAD (P)-dependent intracellular enzymes involved in retinoic acid metabolism whose activity is elevated in MMSCs. In MM patients, ALDH overexpression is related with chemo-resistance, clonogenic potential, and a poor prognosis. Furthermore, ALDH shields MMSCs against the toxicity of chemotherapeutic medicines. We anticipate that regulating the ALDH pathway would be a viable technique for combating relapse and refraction in MM. Recently, we created the isatin-based small molecule inhibitor KS100, which targets many ALDH isoforms. The rationale for this project is to evaluate the ALDH isoforms responsible for the clonogenic potential and stem-like properties of MMSCs, determine whether KS100 effectively kills ALDH overexpressing MMSCs, and whether this multi- isoform ALDH inhibitor could be combined with a traditional proteasome inhibitor (bortezomib) to more effectively treat MM. To achieve this purpose, we propose the following Specific Aims. Aim 1, Determine the effect of ALDH inhibition on bortezomib resistance in a MM xenograft model. We intend to look into the influence of nano-KS100 (a liposomal version of KS100) on the growth and stemness of MM tumors. To evaluate the preclinical potential of nano-KS100, we will employ the NOD-SCID-IL2R gamma null (NSG) mouse model. We will investigate if nano-KS100 could be utilized in combination with bortezomib because combination regimens are an important aspect of MM treatment. Aim2, Determine the role of ALDH isoforms in maintaining the resistance and stemness of MMSCs. We will investigate the role of ALDH isoforms (ALDH1A1, ALDH2, and ALDH 3A1) in the aggressive phenotype of MMSCs. We will overexpress specific ALDH isoforms and study their impact on resistance and stemness. Finally, we will determine the extent to which KS100 affects the MMSC phenotype. These noteworthy discoveries would illustrate the usefulness of targeting ALDH enzymes in MM and other malignancies for regulating relapse, providing the requisite preclinical confirmation for clinical translation. This contribution will be significant since it is expected to have broad translational significance in the treatment of MM. Furthermore, this project will enhance the research and educational infrastructure at Cooper Medical School of Rowan University (CMSRU), providing students with valuable opportunities to engage in biochemical and biomedical research that might not otherwise be accessible to them.
