# Mechanism-based drug repurposing and novel treatments for glioblastoma

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $352,275

## Abstract

Glioblastomas (GBMs) are among the most deadly cancers known, with only limited improvements in
treatment outcomes despite extensive efforts. GBMs exhibit resistance to chemotherapeutic agents, irradiation
and other cell death inducers, colonize brain tissue far removed from the tumor's primary origin, and exhibit
intrinsic intra-tumor heterogeneity, the presence of a robust tumor initiating cell (TIC) compartment and multiple
other obstacles to treatment. Still a further significant challenge in developing effective GBM treatments is that
normal CNS progenitor cells and oligodendrocytes are more vulnerable to most anticancer therapies than are
cancer cells themselves. Adverse neurological side effects of cancer treatment are increasingly recognized as
important problems, thus emphasizing the importance of developing treatments that are selectively toxic for
transformed cells. While some new therapies offer benefit to a subset of individuals, with ongoing efforts to
better identify such individuals in advance, most GBM patients remain without effective treatment. Thus,
development of therapies that can overcome the multiple mechanisms of therapeutic resistance of GBM cells
without causing unacceptable toxicity to normal cells of the CNS is thus a central need in this field.
 The central hypotheses of this research are that (i) restoring the ability to activate the c-Cbl ubiquitin ligase
in GBM cells, and in particular using a non-canonical oxidation pathway to activate c-Cbl, enables targeting of
multiple critical regulators of GBM cells with a single therapeutic intervention; (ii) agents that restore c-Cbl
function in GBM cells can be identified by mechanism-based drug repurposing; (iii) c-Cbl restoration therapies
provide a foundation for rational combinatorial treatments that are more toxic for GBM cells than for normal
glial progenitors; (iv) this approach provides clinically relevant therapies that re effective in treating established
human GBMs growing intra-cranially in immune-deficient NSG mice; and (v) it is possible to prospectively
identify GBMs that are likely to respond to specific therapies developed in this research. Preliminary data to
support each of these hypotheses is provided,
 To further develop this promising avenue of investigation, we now propose the following aims: Aim 1 tests
the hypothesis that candidate CRAs (of which we thus far have ten) increase sensitivity to compounds relevant
to GBM treatment, enable simultaneous targeting of multiple proteins and biological activities critical in GBM
cell function and tumor generation and achieves these outcomes without increasing the sensitivity of normal
glial progenitor cells to relevant therapeutic agents. Aim 2 tests the hypothesis that CRA-based therapies
enable effective treatment of human GBMs, growing in immunodeficient mice, in a clinically relevant manner.
Aim 3 tests the hypothesis that the presence of complexes between c-Cbl and Cool-1/ß-pix predicts sensitivity
to ...

## Key facts

- **NIH application ID:** 10105303
- **Project number:** 5R01CA214066-05
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** MARK D NOBLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,275
- **Award type:** 5
- **Project period:** 2017-03-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105303

## Citation

> US National Institutes of Health, RePORTER application 10105303, Mechanism-based drug repurposing and novel treatments for glioblastoma (5R01CA214066-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10105303. Licensed CC0.

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