# Targeted Suppression of Microtubule Dynamics for Treatment of Metastatic Castration-Resistant Prostate Cancer

> **NIH CA R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2026 · $567,145

## Abstract

PROJECT SUMMARY
The goal of this proposal is to develop a targeted therapy for treatment of metastatic castration-resistant prostate
cancer (mCRPC). There is currently no cure for this disease and available therapies leave significant room for
improvement based on dismal survival rates. Prostate-specific membrane antigen (PSMA) is a clinically validated
molecular target for diagnostic and therapeutic purposes based on its significant overexpression in PCa tissue
compared to normal cells. Glutamate-ureido-based small molecules have exceptional affinity for PSMA and have
been labeled with radionuclides to enable targeted tumor detection and therapy. The small molecule 177Lu-
PSMA-617 (cytotoxic beta radiation emitter) recently gained FDA-approval for PSMA-targeted radioligand
therapy (RLT) of mCRPC. However, despite its initial antitumor activity, disease progression following 177Lu-
PSMA-617 RLT occurs in virtually all patients and led to the development of the more potent RLT agent 225Ac-
PSMA-617, where the alpha-emitting radionuclide 225Ac provides stronger DNA damaging capabilities. Although
recent clinical data with 225Ac-PSMA-617 showed favorable responses, disease progression was still observed.
Furthermore, non-tumor binding of 225Ac-PSMA-617 causes considerable damage to the salivary glands and
leads to life-long xerostomia in a large percentage of patients. Since PSMA expression often remains actionable
as a tumor target following RLT, the development of a non-radioactive targeted therapy could extend the
therapeutic benefits of PSMA targeting without the associated risk of organ irradiation. Given the absence of a
validated PSMA-targeted drug conjugate, we used PSMA-617 as the foundation for a drug conjugate containing
the microtubule inhibitor monomethyl auristatin E (MMAE) and a custom macrocyclic linker known as MMC
(multimodality chelator) to enable direct radiolabeling for imaging and quantitative analyses. We provide strong
preliminary evidence of PS

## Key facts

- **NIH application ID:** 11321671
- **Project number:** 5R01CA298343-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Ali  Azhdarinia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $567,145
- **Award type:** 5
- **Project period:** 2025-04-15T00:00:00 → 2030-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11321671

## Citation

> US National Institutes of Health, RePORTER application 11321671, Targeted Suppression of Microtubule Dynamics for Treatment of Metastatic Castration-Resistant Prostate Cancer (5R01CA298343-02). Retrieved via AI Analytics 2026-05-19 from https://api.ai-analytics.org/grant/nih/11321671. Licensed CC0.

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