Optimizing Geranylgeranyl Diphosphate Synthase Inhibitor (GGSI) Therapy for Multiple Myeloma

Author

Ashruti Pant, University of Nebraska Medical CenterFollow

ORCID ID

0009-0008-5366-2012

Graduation Date

Spring 5-10-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Aaron M Mohs

Abstract

Multiple myeloma (MM) remains an incurable cancer despite significant therapeutic advances, constituting roughly 13% of all blood cancers. It is characterized by accumulation and proliferation of plasma cells in the bone marrow. Currently available potent anti-myeloma drugs have several limitations, including off-target toxicity and poor physiochemical properties. This dissertation focuses on optimizing geranylgeranyl diphosphate synthase inhibitor (GGSI) therapy, which targets geranylgeranyl diphosphate synthase (GGDPS) in the isoprenoid biosynthetic pathway, using polymer-drug conjugates and combination therapy strategies. Several triazole bisphosphonate-based GGSIs have demonstrated metabolic stability and anti-tumor activity in myeloma xenograft models, but hepatotoxicity limits the therapeutic potential. To overcome this, we have developed and optimized PEGylated GGSI and hyaluronic acid-drug conjugates to enhance circulation and improve targeting to MM cells. Various parameters, including PEG or HA chain length, activation agents, and reaction conditions, have been optimized to create polymer-drug conjugates that has potential to improve drug circulation and targetability while reducing liver uptake and associated toxicity.

Recognizing the potential of combination therapy in MM, targeting isoprenoid biosynthetic pathway and fatty acid synthesis pathway could be beneficial, given their impact on MM proliferation. GGDPS plays a pivotal role in isoprenoid biosynthetic pathway that helps in Rab-mediated protein trafficking. Similarly, fatty acid synthase (FASN) is a key enzyme involved in neoplastic lipogenesis and may be associated with tumor growth and survival. Cytotoxicity assays revealed synergistic or additive effects in MM cell lines and enhanced induction of apoptosis was also observed following combination treatment. When effects on energy metabolism were evaluated, the combination therapy inhibited mitochondrial function more effectively than either drug alone. Metabolomics studies utilizing an LC-MS/MS methodology revealed alteration of several key metabolic pathways due to combination therapy. Preliminary in vivo studies confirmed the safety and feasibility of combination therapy with RAM2061 and cerulenin administered to CD-1 mice. In aggregate, these data provide rationale for further studies exploring combination therapy with GGSI and FASN inhibitor for the treatment of MM

Comments

2025 Copyright, the authors

Recommended Citation

Pant, Ashruti, "Optimizing Geranylgeranyl Diphosphate Synthase Inhibitor (GGSI) Therapy for Multiple Myeloma" (2025). Theses & Dissertations. 946.
https://digitalcommons.unmc.edu/etd/946