Primary brain tumors in adults represent a heterogeneous and often fatal group of tumors. Current treatment of primary brain tumors heavily relies on surgery, radiation, and chemotherapy and is associated with cognitive impairment and other toxicities. Unlike in many other human cancers, inhibitors of oncogenic kinases have shown inconsistent clinical activity in brain tumor patients and it remains unclear which genetic alterations are critical for tumor maintenance in specific brain tumor types. The goal of this research program is to establish therapeutic strategies that exploit the most common genetic alterations is three specific tumor types, namely mutant isocitrate dehydrogenase (IDH) in low grade glioma, Bruton's Tyrosine Kinase (BTK) in Primary CNS Lymphoma (PCNSL), and EGFR in glioblastoma (GBM). Our research program incorporates the evaluation of tumor biopsies from patients being treated with inhibitors of these pathways, genetic and pharmacological studies in newly-derived experimental brain tumor models, and the development of state-of-the art approaches to quantify intratumoral heterogeneity in cancer signaling and tumor evolution. We believe that our research program will narrow the current knowledge gap regarding oncogene ?addiction? in primary brain tumors and provide a framework for mechanism-based combination therapies targeting these signaling nodes and other signaling pathways.

Public Health Relevance

The current treatment for brain tumors is often not effective and causes substantial side-effects. Molecular profiling of these tumors in recent years has uncovered genetic alterations which may render them sensitive to drugs targeting these alterations. The goal of our research program is to determine how to exploit these potential vulnerabilities with new drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Unknown (R35)
Project #
5R35NS105109-04
Application #
10059276
Study Section
Special Emphasis Panel (ZNS1)
Program Officer
Fountain, Jane W
Project Start
2018-01-01
Project End
2025-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
4
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
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Yu, Andrew; Faiq, Nadia; Green, Stacey et al. (2017) Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study. J Neurooncol 134:357-362
Grommes, Christian; Pastore, Alessandro; Palaskas, Nicolaos et al. (2017) Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma. Cancer Discov 7:1018-1029