Genetic loss or acquisition of missense mutations within the phosphatase and tensin homolog (PTEN) gene is a frequent event in glioblastoma multiforme (GBM). Loss of PTEN activity leads to a robust activation of PI3K signaling due to its established role as a lipid phosphatase but also to an activation of the MAPK pathway. Missense mutations within PTEN that retain phosphatase catalytic activity are common in GBM and we demonstrate their capacity to drive gliomagenesis in vitro. The molecular mechanisms by which these mutations abrogate PTEN's tumor suppressive function are unknown and represent a crucial area of research in cancer. We hypothesize that phosphatase activity-retaining missense mutations are not synonymous to complete loss of PTEN or phosphatase activity dead missense mutants in their mechanisms of tumor suppression and represent distinct categories of PTEN driven cancers that will respond differently to PI3K- and MEK-centric treatment regimens. On this basis, we propose to 1) develop new PTEN genetically engineered mouse models of missense mutants and utilize these models to optimize targeted therapies against PI3K and MEK, and 2) create isogenic PTEN missense mutant human GBM PDX lines to uncover new PI3K and MEK inhibition strategies. The overall goal of the proposed research is to deliver on an effective translational use of genetically cutting edge models of GBM that accurately recapitulate human disease to direct research toward the development of new treatments.

Public Health Relevance

PTEN is a gene that is frequently inactive and heavily deregulated in cancers. We do not fully understand the details of how inactivation of PTEN leads to cancer and how specific mutations within PTEN dictate how certain therapies will be inefficient. The research proposed here aims at building new mouse models of specific PTEN mutations and how these mice are sensitive to therapies that are targeting PTEN. Results generated will point towards areas for development of new therapies for cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA245337-02
Application #
10056208
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Kondapaka, Sudhir B
Project Start
2019-12-01
Project End
2021-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215