# Targeting therapeutic resistance in glioblastoma

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2024 · —

## Abstract

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor associated with extremely poor prognosis
and survival. Although relatively rare in the US general population, GBM is the third most common cause of
cancer death in the US active-duty military. The relatively transient nature of clinical responses to currently
available therapies underlines the urgency for the development of additional therapeutic strategies. Multiple
studies have demonstrated the existence of aggressive cancer stem cell (CSC) subpopulations in GBM and
characterized their contribution to GBM progression, therapeutic resistance and recurrence; however, efforts to
eliminate or functionally modulate these therapy-refractory subpopulations have thus far met with limited
success. ATP-binding cassette, sub-family B (MDR/TAP), member 5 (ABCB5), an integral plasma membrane
protein first cloned and characterized by the applicant (Frank et al. J Biol Chem. 2003), is highly expressed by
normal tissue-specific stem cells and CSCs in several malignancies, including GBM. ABCB5 is expressed in
primary GBM tumors, in which its expression is significantly correlated with the CSC marker CD133 and with
overall poor survival (Lee et al. J Biol Chem. 2020). In GBM-CSCs, ABCB5 has been shown to mediate
clinically relevant drug resistance to temozolomide (TMZ). ABCB5 blockade inhibited CD133-positive GBM-
CSC self-renewal and abrogated TMZ-induced G2/M arrest. Recently, the applicant identified a novel critical
anti-apoptotic function of ABCB5 required for normal stem cell maintenance (Ksander et al. Nature 2014) and,
as a corollary, for CSC-driven tumor growth, invasion and therapeutic resistance, involving, in part, ABCB5-
dependent regulation of signal transduction of the RTK AXL (Guo et al., J Biol Chem. 2018). Importantly, the
applicant’s most recent preliminary studies further revealed that ABCB5 serves as a novel receptor for
Phosphatidylinositol 4,5-bisphosphate (PIP2), with ABCB5/PIP2 binding shown to be required for PIP3
phosphorylation. PIP2-derived PIP3 serves as a critical mediator of receptor tyrosine kinase (RTK) signaling,
and hence activation of the downstream PI3K/AKT signaling cascade. Remarkably, inhibition of ABCB5-PIP2
binding through ABCB5 monoclonal antibody blockade or ABCB5 gene knockout (KO) inhibits PIP2
phosphorylation, blocks PIP3 production and interrupts down-stream pAKT activation of the PI3K/pAKT
signaling pathway, impairing RTK signal transduction on ABCB5-positive GBM-CSC. Based on this newly
identified central mechanism, we hypothesize that ABCB5 is critically required for multiple RTK-dependent
functions in human GBM, including stem cell-intrinsic self-renewal, anti-apoptotic, pro-angiogenic and invasive
capacities, and stem cell-driven epigenetic evolution and therapeutic resistance associated cell cycle arrest
(Lee et al. J Biol Chem. 2020). The proposed studies will further support the development of ABCB5 as a novel
therapeutic target in GBM and sh...

## Key facts

- **NIH application ID:** 10841396
- **Project number:** 5I01BX006004-02
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** NATASHA Y FRANK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841396

## Citation

> US National Institutes of Health, RePORTER application 10841396, Targeting therapeutic resistance in glioblastoma (5I01BX006004-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10841396. Licensed CC0.

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