We propose a SPORE initiative on adult glioblastoma at the Dana-Farber/Harvard Cancer Center (DF/HCC). Our objective is to improve the standard of care through the use of targeted therapies for this type of cancer. Towards this end, basic scientists from Harvard Medical School have joined with clinical/translational investigators from Brigham and Women's Hospital, Dana-Farber Cancer Institute and Massachusetts General Hospital. This initiative is supported by central cores for Pathology, Biostatistics and Administration and includes career and developmental programs. The study plan uses clinical materials and exploits a number of clinical trials to attack glioblastoma on four distinct fronts: Project one targets the tumor vascular system. A cancer biologist, Rakesh Jain, PhD and a neurooncologist, Tracy Batchelor, MD address a current impasse in vascular-based therapies for glioblastoma. Why are patient responses to bevacizumab generally transient and marginal? Jain and Batchelor will test the hypothesis that responses to VEGF pathway inhibitors can be augmented by concurrent or sequential suppression of the angiopoietin-2 signal transduction pathway. Project two targets the PI3K signaling axis - a signaling pathway that is activated in ~50% of glioblastomas. Biochemist Tom Roberts, PhD (a co-discoverer of PI3K) and neuro-oncologist Patrick Wen, MD address fundamental issues regarding PI3K signaling in glioblastoma that - when resolved - will greatly optimize the treatment of these tumors with small molecule antagonists of PI3K. Project three targets the IDH pathway. Malignant gliomas, including glioblastomas, may harbor gain-of-function mutations in isocitrate dehydrogenase 1 (IDH1) resulting in accumulation of 2-hydroxyglutarate (2- HG) promoting tumorigenesis. Molecular biologist William Kaelin, MD and neurosurgeon Daniel Cahill, MD, PhD will use clinical material to test the hypothesis that non-invasive measurement of 2-HG levels can serve as a surrogate for IDH mutant enzyme activity, and that targeting of IDH mutation and 2-HG can afford a breakthrough treatment for malignant glioma patients. Project four attacks the Olig2 transcription factor. Molecular biologist Chuck Stiles, PhD has demonstrated an oppositional relationship between the gliogenic transcription factor Olig2 and p53. Building upon these findings, Stiles and radiation oncologist Jay Loeffler, MD will use clinical materials to test the hypothesis that suppression of Olig2 will enhance radiation sensitivity of the major population of glioblastomas (~75%) that retain a structurally intact p53 gene.

Public Health Relevance

Glioblastomas are the third leading cause of cancer-related death among middle-aged men and the fourth leading cause of death for women between 15-34 years of age (http://www.CBTRUS.org). In the fullness of time, the work that we propose with targeted therapies could change the standard of care and improve patient outcomes for these tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA165962-02
Application #
8737806
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (M1))
Program Officer
Arnold, Julia T
Project Start
2013-09-19
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
$2,144,141
Indirect Cost
$524,182
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Carr, Jessica A; Franke, Daniel; Caram, Justin R et al. (2018) Shortwave infrared fluorescence imaging with the clinically approved near-infrared dye indocyanine green. Proc Natl Acad Sci U S A 115:4465-4470
Fukumura, Dai; Kloepper, Jonas; Amoozgar, Zohreh et al. (2018) Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 15:325-340
Zhao, Yingchao; Liu, Pinan; Zhang, Na et al. (2018) Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models. Proc Natl Acad Sci U S A 115:E2077-E2084
Bian, X; Gao, J; Luo, F et al. (2018) PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy. Oncogene 37:341-351
McBrayer, Samuel K; Mayers, Jared R; DiNatale, Gabriel J et al. (2018) Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175:101-116.e25
McKenney, Anna Sophia; Lau, Allison N; Somasundara, Amritha Varshini Hanasoge et al. (2018) JAK2/IDH-mutant-driven myeloproliferative neoplasm is sensitive to combined targeted inhibition. J Clin Invest 128:789-804
Shankar, Ganesh M; Kirtane, Ameya R; Miller, Julie J et al. (2018) Genotype-targeted local therapy of glioma. Proc Natl Acad Sci U S A 115:E8388-E8394
Arvanitis, Costas D; Askoxylakis, Vasileios; Guo, Yutong et al. (2018) Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound-induced blood-tumor barrier disruption. Proc Natl Acad Sci U S A 115:E8717-E8726
Li, Ben B; Qian, Changli; Roberts, Thomas M et al. (2018) Targeted Profiling of RNA Translation. Curr Protoc Mol Biol :e71
Nowosielski, Martha; Wen, Patrick Y (2018) Imaging Criteria in Neuro-oncology. Semin Neurol 38:24-31

Showing the most recent 10 out of 84 publications