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
Peterson, Teresa E; Kirkpatrick, Nathaniel D; Huang, Yuhui et al. (2016) Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. Proc Natl Acad Sci U S A 113:4470-5
Kloepper, Jonas; Riedemann, Lars; Amoozgar, Zohreh et al. (2016) Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci U S A 113:4476-81
Flavahan, William A; Drier, Yotam; Liau, Brian B et al. (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529:110-4
Curry Jr, William T; Gorrepati, Ramana; Piesche, Matthias et al. (2016) Vaccination with Irradiated Autologous Tumor Cells Mixed with Irradiated GM-K562 Cells Stimulates Antitumor Immunity and T Lymphocyte Activation in Patients with Recurrent Malignant Glioma. Clin Cancer Res 22:2885-96
Stevens, Mark M; Maire, Cecile L; Chou, Nigel et al. (2016) Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate. Nat Biotechnol 34:1161-1167
Verreault, Maite; Schmitt, Charlotte; Goldwirt, Lauriane et al. (2016) Preclinical Efficacy of the MDM2 Inhibitor RG7112 in MDM2-Amplified and TP53 Wild-type Glioblastomas. Clin Cancer Res 22:1185-96
Ni, Jing; Ramkissoon, Shakti H; Xie, Shaozhen et al. (2016) Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nat Med 22:723-6
Tateishi, Kensuke; Iafrate, A John; Ho, Quan et al. (2016) Myc-Driven Glycolysis Is a Therapeutic Target in Glioblastoma. Clin Cancer Res 22:4452-65
Cizmecioglu, Onur; Ni, Jing; Xie, Shaozhen et al. (2016) Rac1-mediated membrane raft localization of PI3K/p110β is required for its activation by GPCRs or PTEN loss. Elife 5:
Fathi, Amir T; Nahed, Brian V; Wander, Seth A et al. (2016) Elevation of Urinary 2-Hydroxyglutarate in IDH-Mutant Glioma. Oncologist 21:214-9

Showing the most recent 10 out of 44 publications