# Chemosensitization of Glioblastoma by Propentofylline

> **NIH NIH R41** · OLEOLIVE, INC. · 2022 · $399,998

## Abstract

SUMMARY
Glioblastoma (GBM) is the most common primary tumor of the CNS with limited treatment options and a poor
clinical prognosis. Standard of care treatment, including surgical resection, radiation therapy and concurrent
temozolomide (TMZ) treatment followed by adjuvant TMZ, produces a median survival in newly diagnosed GBM
of ~15 months. Tumor recurrence happens due to therapy resistant tumor cells; therefore, therapeutic strategies
that improve tumor cell sensitivity to chemotherapy are needed to improve patient outcomes.
 TROY (TNFRSF19), a member of the TNF receptor superfamily, has recently been discovered to impact GBM
progression. Briefly, TROY expression increases with increasing glial tumor grade and inversely correlates with
patient survival. Increased expression of TROY stimulates GBM cell migration/invasion in vitro and in vivo and
increases resistance to TMZ or radiation in vitro, while knockdown of TROY expression inhibits cell invasion,
increases sensitivity to TMZ, and prolongs survival in a murine patient-derived xenograft (PDX) model. These
and additional studies indicate that TROY represents a potential novel therapeutic target for GBM.
 Propentofylline (PPF), a drug that has been studied in numerous clinical trials for several non-GBM
indications, downregulates TROY, inhibits GBM invasion and increases sensitivity in vitro and in vivo to TMZ
and radiotherapy. PPF exhibits a well-characterized pharmacological profile, including good brain distribution
and favorable safety metrics. Repurposing PPF could be faster to clinical trials, less risky and less costly than
the traditional drug development pathway for new chemical entities.
 The primary goal of this proposal is to test the ability of PPF to sensitize GBM to TMZ. Secondary goals
include assessing: the necessity of TROY for PPF activity, the mechanisms of action for PPF-induced TROY
downregulation, and the impact of PPF treatment and TROY expression on tumor-promoting microglia.
 The following aims have been designed to answer these questions. Specific Aim 1: Test the ability of PPF
to sensitize TMZ resistant GBM tumors to therapeutic treatment in intracranial PDX models and a
syngeneic model. The ability of PPF to sensitize GBM cells to TMZ will be evaluated in five TMZ resistant PDX
mouse models and one immunocompetent syngeneic model. IVIS-monitoring of tumor growth, duration of
survival as well as histopathological and molecular analysis of tumor and tumor microenvironment will be
evaluated. Specific Aim 2: Characterize the cellular and molecular targets of PPF to predict clinical
responsiveness. Live-cell automated imaging and molecular techniques will be used to help define the cellular
and molecular targets of PPF. We will test the ability of PPF to sensitize a diverse panel of 20 human GBM PDX
lines, representing varied molecular and prognostic subtypes, to TMZ treatment ex vivo and assess the effects
of PPF on microglia in vitro.

## Key facts

- **NIH application ID:** 10480470
- **Project number:** 1R41CA268286-01A1
- **Recipient organization:** OLEOLIVE, INC.
- **Principal Investigator:** Nhan L Tran
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $399,998
- **Award type:** 1
- **Project period:** 2022-08-10 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10480470

## Citation

> US National Institutes of Health, RePORTER application 10480470, Chemosensitization of Glioblastoma by Propentofylline (1R41CA268286-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10480470. Licensed CC0.

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