U01: PI3K Signaling and Biology of Therapeutic Response in Brain and Prostate Tumors
Eric Holland, MD, PhD
Charles Sawyers, MD
Cameron Brennan, MD
Ingo Mellinghoff, MD
Brett Carver, MD
Jason Huse, MD, PhD
This grant project involves the use of genetically engineered mouse models (GEMMs) for understanding cancer biology for preclinical testing leading to human trials. It investigates the biology of therapeutic response in solid tumors with particular interest in the PI3K pathway and cells that are resistant to standard-of-care treatments. It compares and contrasts three tumor types in which the PI3K pathway contributes to oncogenesis and therapeutic resistance, namely medulloblastoma, glioma, and prostate cancer.
In the first part of the project, several drug combinations are being compared to determine optimal strategies for complete blockade of this signaling pathway in medulloblastoma, glioma, and prostate tumors in vivo. The second part investigates the character of cells that survive radiation in the case of the brain tumors and androgen depletion in the case of prostate cancer, and determines what role PI3K might play in their stemlike and resistant properties.
Finally, the mouse models will be used to identify gene expression pathways as biomarkers for therapeutic response that could then be taken from the mouse into human trials. The comparison between these tumor types is expected to be cross-informative and potentially to help identify fundamental aspects of solid tumor biology that have therapeutic implications.
U01: Using Mouse Models to Probe the Relationship of Oncogenesis to Development
Eric Holland, MD, PhD
Hans Guido-Wendel, MD
Yi-Chieh Nancy Du, PhD
This grant was awarded for the investigation of parallels between the development and response of tumors to oncogenes and therapies in three different tumor types, including glioma.
In one project, the response of B cell lymphoma to therapy and mechanisms of resistance is being investigated as a function of the tumor genotype. In a second project, the effect of oncogenic signaling from the polyoma virus middle T antigen (that activates many of the same pathways as seen in glioblastoma multiforme) is being investigated in various cells of the pancreas in the development of pancreatic cancer.
The third project investigates the effects of radiation on the various cell types of gliomas. In addition, the mechanisms of resistance to radiation and the cells that survive radiation are being characterized. Our hope is that we will be able to improve the response to radiation for at least some molecular subsets of glioblastoma multiforme.