Engineering Biomaterials to Modulate the Bone Marrow Microenvironment in Multiple Myeloma

PROJECT SUMMARY Multiple myeloma (MM) accounts for ~23% of all hematologic malignancies with a 2.1% of cancer-related deaths in the United States in 2022. Despite tremendous efforts to develop effective therapies, MM remains largely incurable, and virtually all patients develop resistance to current therapies. Thus, there is an urgent clinical need

for innovative and improved MM therapeutics. It has been demonstrated that bone marrow endothelium is critical to MM cell homing, progression, survival, and drug resistance. Specifically, cyclophilin A and E-selectin, a homing factor and adhesion receptor, respectively, expressed by bone marrow endothelial cells, are critical to

MM survival. Thus, inhibition of cyclophilin A and E-selectin provides a potential therapeutic strategy to abolish MM dissemination and resistance. However, direct- and specific-inhibition of cyclophilin A and E-selectin by small molecules has been elusive. Thus, cyclophilin A and E-selectin are promising candidates for combination

RNA interference (RNAi) therapy, which inhibits traditionally undruggable targets by directly reducing their messenger RNA (mRNA) expression. The challenge of utilizing small-interfering RNA (siRNA) is the need for safe and effective delivery methods, as siRNA degrades in the bloodstream and does not readily cross

membranes. During my predoctoral studies, I have engineered a library of polymer-lipid hybrid biomaterials, that in combination with polyethylene glycol (PEG)-lipid conjugates and siRNA, assembled into nanoparticles (NPs) via microfluidic mixing. Through high-throughput in vivo screening, I identified a NP formulation with potent gene

silencing in bone marrow endothelial cells in vivo. This formulation was used to encapsulate cyclophilin A siRNA, and showed inhibition of MM progression in vivo, and sensitized MM cells to the proteasome inhibitor bortezomib, a current therapeutic modality to treat MM. During the F99 phase, I will improve our NP design by incorporating

bone marrow endothelial-targeting ligands on the NP’s surface to enhance their specificity to bone marrow endothelium, minimizing off-target effects. I will use our targeted NP to co-encapsulate cyclophilin A and E- selectin siRNA sequences, and evaluate their inhibition in vitro through adhesion and transendothelial migration

assays, to determine the invasive abilities of MM cells. Further, I will test our co-delivery siRNA nanotechnology through a survival study in a validated mouse xenograft model of MM and quantify its effects either alone or in combination with bortezomib. This technology is expected to provide with a broadly enabling platform to target

other bone marrow-homing cancers. For the K00 phase, I will identify a renowned cancer biology laboratory to study cell-cell interactions in the bone marrow immune microenvironment utilizing high-dimensional single-cell approaches and tissue-engineered models, with the aim to determine mechanisms that drive cancer progression

and drug resistance. Completion of this project will successfully prepare me to launch an NIH-funded research laboratory that focuses on drug delivery targeting the tumor microenvironment as means of cancer therapy.