# Geranylgeranyl diphosphate synthase inhibitor therapy for multiple myeloma

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $492,732

## Abstract

Project Summary
Multiple myeloma (MM) is an incurable bone marrow (BM) cancer characterized by the production of
monoclonal protein (MP). Development of drug resistance and off-target effects limits the efficacy of currently
available agents. Therefore, novel therapeutic strategies, including drug delivery strategies, are urgently
needed. We have focused on the novel strategy of targeting the trafficking of MP in MM cells by inhibiting the
enzyme geranylgeranyl diphosphate synthase (GGDPS). GGDPS inhibitors (GGSIs) disrupt Rab
geranylgeranylation, which results in intracellular MP accumulation, ER stress, induction of all three arms of
the unfolded protein response pathway and ultimately MM cell death. Our GGSI development efforts have
focused on isoprenoid triazole bisphosphonates and our structure-function studies have determined that
isoprenoid chain length and stereochemistry impact inhibitor potency as well as in vivo biodistribution.
Preclinical studies with our lead GGSIs have demonstrated key drug-like properties, including metabolic
stability, prolonged plasma half-life, systemic distribution, in vivo disruption of protein geranylgeranylation and
anti-tumor efficacy in a mouse MM xenograft model. Dose-finding and toxicology studies revealed hepatic
toxicity as dose-limiting with no effects on hematologic, renal, cardiac or neurologic function. Our preliminary
studies revealed that altering the molecular weight of a hyaluronic acid (HA) polymer can limit hepatic uptake
and enhance BM uptake and that MM cells readily take up HA. We therefore hypothesize that the therapeutic
potential of GGSIs can be optimized via linkage of our GGSIs to HA polymers, thus enhancing delivery of
GGSI to the BM and minimizing hepatic uptake and our preliminary studies support this hypothesis. To this
end, we will synthesize novel GGSIs that are are based upon our lead compound but either modified at the α-
position to allow conjugation to HA or linked to HA through phosphonate prodrug forms (Aim 1) We will perform
detailed structural studies, including protein crystallography studies with bound inhibitors, to clarify the
mechanisms by which these GGSIs interact with the target enzyme (Aim 1) which will aid in the design of
future generations of GGSIs. We will determine the pharmacokinetic/pharmacodynamic profiles and
biodistribution patterns of the novel linkable GGSIs and the corresponding HA polymer conjugates (Aim 2). We
will investigate the mechanisms regulating GGSI hepatic uptake and toxicity. The efficacy of the lead GGSI-HA
conjugates will be assessed in xenograft studies which model extramedullary and medullary disease
involvement (Aim 3). In vitro and in vivo studies evaluating the combination of GGSI therapy with clinically used
anti-MM agents will be performed. While our current focus is to develop GGSI therapy for treatment of MM,
these studies have added significance because this novel approach of drug conjugation to HA to alter
biodistribution c...

## Key facts

- **NIH application ID:** 10364685
- **Project number:** 5R01CA258621-02
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Sarah A Holstein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $492,732
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364685

## Citation

> US National Institutes of Health, RePORTER application 10364685, Geranylgeranyl diphosphate synthase inhibitor therapy for multiple myeloma (5R01CA258621-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364685. Licensed CC0.

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