Microtubule targeting agents (MTAs) are commonly prescribed to treat many types of cancers; yet their use for the treatment of glioblastomas (GBM) is limited by their poor brain penetrance. We developed a new series of MTAs (ST-compounds) that destabilize microtubules (MT) and kill GBM through a novel mechanism of action (MOA). Our recent results show that ST-compounds pass the blood brain barrier (BBB) and exhibits in vivo therapeutic efficacy in a preclinical mouse model of GBM. This new R01 uses complementary expertise and approaches to study how the novel MOA of ST- compounds differs from known MTAs and its therapeutic efficacy in several preclinical mouse model of GBM. Specifically, it leverages several innovative technologies, including live-cell imaging and artificial learning algorithms, to better understand why GBM are particularly sensitive to the antitumor activity of ST-compounds. Experiments will be performed on patient-derived GBM (PD-GBM) in culture and include measure of real-time changes in GBM cell migration, cell division and cell cycle fate as fundamental readouts of tumorigenesis. In vivo experiments will be done on both genetic orthotopic mouse models of GBM and orthotopic mouse model of PD-GBM.
Our aims are: 1: Differential impact of MTAs on the migration and mitosis of GBM in culture. 2: Differential impact of MTAs on the viability and fate of GBM in culture. 3: Therapeutic efficacy and mechanism of ST-401 in GBM models in vivo. Our immediate goal is to increase our understanding of the precise MOA by which MTAs regulate GBM tumorigenesis and how this interacts with standard care treatments. This work will help set a solid foundation for the development of a new class of MTAs for the safe treatment of patients diagnosed with GBM.

Public Health Relevance

New therapies are urgently needed to treat patients diagnosed with glioblastoma as current standard of care is rarely curative and often associated with side effects. This research project started by studying the antitumor activity of carbazole-based molecules and led to the development of a series of microtubule targeting agents (ST-compounds) that disrupt microtubule function and kills cancer cells through a unique mechanism that is particularly efficacious in glioblastomas. This new R01 grant will determine how ST-compounds inhibit the fundamental oncogenic behaviors of glioblastomas, including cell division and cell fate, and how this response both compares to known microtubule targeting agents and how it interacts with standard of care DNA- damaging therapies, a body of work that will set a solid foundation to further develop MTAs for the treatment of glioblastomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA244213-01A1
Application #
10049542
Study Section
Mechanisms of Cancer Therapeutics - 1 Study Section (MCT1)
Program Officer
Forry, Suzanne L
Project Start
2020-07-02
Project End
2025-06-30
Budget Start
2020-07-02
Budget End
2021-06-30
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Surgery
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195