Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

Sarah Holstein

Abstract

Multiple myeloma (MM) is a hematological malignancy of the plasma cells which often results in lytic bone disease. Myeloma bone disease (MBD), characterized by diffuse osteopenia, bone lesions, or pathological fracture, results from MM mediated promotion of osteoclast resorption and dual inhibition of bone formation, drastically reducing bone strength and integrity. Development of MBD is known to significantly impact patient quality of life and increase risk of mortality. Considering that up to 80-95% of MM patients are expected to develop bone disease post-initial MM diagnosis, there is a significant need within this population for therapeutics which address both MM disease and bone health.

The geranylgeranyl diphosphate synthase (GGDPS) inhibitor, RAM2061, exhibits anti-tumor activity in MM cells through depletion of the metabolite, geranylgeranyl diphosphate (GGPP), and disruption of protein prenylation. RAM2061 possesses a unique bisphosphonate moiety indicating potential affinity for bone and furthermore, has a similar mechanism of action (MOA) to clinically used anti-resorptive agents, nitrogen bisphosphonates (NBP). NBP MOA is attributed to depletion of GGPP albeit through inhibition of the enzyme farnesyl diphosphate synthase (FDPS), upstream of GGDPS. Therefore, understanding RAM2061 to deplete intracellular GGPP and exhibit potential bone affinity, suggests anti-resorptive potential. The aims of this work were focused on interrogating the bone-specific affinity of RAM2061 and to characterize the molecular effects of treatment on osteoclast and osteoblast function.

Studies presented throughout this dissertation confirm RAM2061 bone affinity and disruption of osteoclast differentiation/resorption through inhibition of Rho GTPase geranylgeranylation. Anti-resorptive effects in vivo were less pronounced but validated by reduced osteoclast number in RAM2061 treated mice. RAM2061-treated osteoblast precursors displayed reduced differentiation activity and overall function. Finally, studies were pursued in which RAM2061 was combined with proteasome inhibitor bortezomib, as this commonly used anti-MM agent has been reported to have bone-protective effects. Preliminary studies presented here suggest no appreciable changes in RAM2061 effects on bone cells when used in combination with bortezomib, however studies under MBD-like conditions revealed the importance of evaluating drug efficacy in consideration of MM microenvironmental effects. Future studies aim to interrogate the in vivo application of RAM2061 in reducing both MM and bone disease morbidity and further elucidating translational effects underlying MOAs on overall quality of life and survival.

Comments

2025 Copyright, the authors

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