The Foundation awards a grant of $180,000 to Dr Michelle Monje, Stanford University, to study a combinatorial approach to target cellular subpopulations in Diffuse Intrinsic Pontine Glioma.
The Foundation has approved a grant to Michelle Monje, MD, PhD, Assistant Professor of Neurology and Neuro- Oncology, Stanford University.
The study seeks to test the hypothesis that it is necessary to target multiple cellular subpopulations to achieve a survival benefit in DIPG and outlines three specific aims:
The research team provided the following overview:
Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating childhood cancer. We have recently developed the first available cell culture and orthotopic xenograft models of DIPG. These invaluable resources, together with our parallel studies of normal brainstem development, have led to the discovery of a DIPG tumour-initiating cell type. The tumour-initiating cell, or "cancer stem cell (CSC)", of DIPG is a small subpopulation that is responsive to the powerful signalling pathway Hedgehog. The classic cancer stem cell hypothesis posits that the cancer stem cell is solely responsible for tumour propagation, as though the CSC population is like the tumour’s "engine", giving rise to a rapidly proliferating transit amplifying cell type and more "differentiated" cell types downstream in the cellular hierarchy. Without the CSC, all daughter cell types would be expected to burn out and the tumour to become indolent.
We have targeted the DIPG tumour initiating cell population using pharmacological Hedgehog pathway inhibition. We have now shown that while Hedgehog pathway inhibition has dramatic effects on tumour cell self-renewal in vitro, and does slow tumour growth for about a month in vivo, it does not change the ultimate size of the tumours that diffusely infiltrate the brainstem in our DIPG orthotopic xenograft model nor does it significantly alter survival. Hedgehog inhibitor therapy does, however, appear to deplete or eliminate the tumour-initiating cell population in vivo. In other words, the "cancer stem cell" is gone, but the tumour still grows enough to kill the mouse. It may be that DIPG tumour cell behaviour does not conform precisely to the cancer stem cell hypothesis, or it may be that in DIPG the time required for transit amplifying cell "burn out" is not tolerated by the functionally critical, relatively small and confined brainstem. Either way, these findings point to a paradigm shift from the classic cancer stem cell hypothesis, and so a novel strategy is needed.