Microtubule targeting agents (MTAs) are commonly prescribed to successfully treat many types of cancers; yet their use for the treatment of brain cancers, such as GBM, has been hindered by their inability to penetrate the brain in therapeutically-relevant doses. Recent evidence shows that GBMs are particularly sensitive to disruptions of microtubule (MT) functions and die by apoptosis, providing a rational to develop brain-penetrant MTAs. The laboratory of Dr. Nephi Stella at the University of Washington developed a new series of MTAs (ST compounds) and showed that these compounds destabilize MT through a different MOA from currently known MTAs. These MTAs kill GBM cells by triggering apoptosis both in vitro and in vivo. The work outline in this R21 grant proposal will provide foundational results on the novel MOA of ST compounds, as well as proof-of- concept in vivo efficacy results in preclinical model systems of PD-PGM, both of which will help develop this therapeutic approach for the treatment of GBM.
Our aims are Aim 1: Determine the MOA of ST compounds on tubulin and MT dynamics, as well as their ability to cross cell membranes Aim 2: Determine the therapeutic efficacy and mechanism of ST compounds in PD-GBM xenograft model Our long-term goal is to help better understand and develop novel therapeutics to treat devastating cancers such as GBM.
Brain cancers, such as glioblastoma multiform (GBM), have extremely poor prognosis and their treatment with standard of care results in a 5-year survival rate of less than 5.0%. Thus, new therapies are urgently needed to treat such devastating type of cancer. We developed brain-penetrant microtubule targeting agents that kill patient-derived GBM cells and exhibit a promising safety profile in mice. This grant is designed to further study the molecular mechanism of action (MOA) of these compounds and test their tumor-killing activity in preclinical mice models of GBM.
