# Tunneling Nanotube Inhibitors for Cancer Immunotherapy

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $153,677

## Abstract

Project Summary
Prostate cancer (PCa) is the second-most common cancer in American men1. Early diagnosis and advances in
therapeutic strategies have significantly improved overall survival; however, therapeutic resistance and cancer
cell metastasis remain a challenge. Indeed, the development of castration-resistant prostate cancer (CRPCa),
an aggressive form of PCa after Androgen Deprivation Therapy (ADT) portends a poor prognosis, with overall
survival standing at 1.5 years.
The overall goal of our laboratory research is to develop bioengineered tools for targeted cancer therapy. We
recently discovered the existence of tunnelling nanotubes (TNTs) between breast/prostate cancer cells and
endothelium that promote phenotypic changes allowing for increased metastasis7. These TNTs are actin
mediated and inhibition of Sec3, an exocyst complex, inhibited their formation and consequent alteration of
cancer cells into an aggressive phenotype. We then discovered that there further exists intercellular nanotubes
between breast cancer cells and natural killer T cells that hijack mitochondria, consequently dampening the
immune response. This mechanism, we postulate, could be one of many that lower the efficacy of
immunotherapy for cancers, necessitating research into its pathophysiology and consequent identification of
pharmacological target(s)
For PCa, we propose investigating the existence of TNTs and their inhibitors in improving response. We will
utilize Field Emission Scanning Electron and Confocal Microscopy to investigate TNTs in PCa/CRPCa cell lines
LNCaP, PC3 co-cultured with effector murine CD8, NK T-cells; before probing human PCa tissue patient derived
xenograft (PDX) models. We will then establish the role of endosidins, novel exocyst complex inhibitors, in
ameliorating TNT formation and hence mitochondrial transfer in the above models. The expected outcomes of
this research are evaluation of a novel therapeutic class of drug against PCa/CRPCa cells at least via inhibition
of TNTs. Its result will offer a synergistic tool in promoting immune mediated control of tumors, at least in
PCa/CRPCa progression. The broader positive impact of this project is to promote efficacy of current
immunotherapy efforts in PCa/CRPCa.

## Key facts

- **NIH application ID:** 11062228
- **Project number:** 3R01CA276525-02S1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Shiladitya Sengupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $153,677
- **Award type:** 3
- **Project period:** 2023-07-19 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11062228

## Citation

> US National Institutes of Health, RePORTER application 11062228, Tunneling Nanotube Inhibitors for Cancer Immunotherapy (3R01CA276525-02S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11062228. Licensed CC0.

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