Gliomas constitute the most lethal class of primary CNS malignancies. Many therapeutic approaches seek to target specific components of signaling pathways that are aberrantly activated by mutation, yet mounting evidence demonstrates that tumor survival is also critically dependent on non-mutated, non-oncogene systems that impact global cellular processes;a phenomenon termed non-oncogene addiction. The cellular components that regulate protein homeostasis are among the most prominent mediators of non-oncogene addiction and targeting these functions with HSP90 and proteasome inhibitors results in robust anti-glioma activity. Moreover, our group has revealed another unexpected mediator of non-oncogene addiction, Heat Shock Factor 1 (HSF1), the main transcription factor regulating the heat shock response (HSR), which acts a powerful multifaceted regulator of signaling pathways relevant to gliomagenesis. In this proposal, I will test the hypothesis that modulating protein homeostasis by high-throughput techniques will provide a powerful strategy for identifying lead compounds to drive the development of effective anti-glioma therapeutics. To explore this, we have used the HSR as a biosensor in two high-throughput cell-based phenotypic screens of 100,000 compounds and have identified 100 compounds that induce and 50 that inhibit the HSR. The following specific aims are proposed to test our hypothesis:
Aim 1 : to determine the effects of pharmacological modulation of the HSR on proliferation and survival in 'stem cell'based models of glioma;
Aim 2 : to characterize the mechanism of action of active compounds to identify those with novel targets;
Aim 3 : to assess the potential of active compounds to cross the blood brain barrier;
Aim 4 : to assess the potential of small molecule modulators of protein homeostasis to inhibit glioma growth in vivo. The candidate is an M.D., Ph.D. trained in Anatomic/Neuropathology who seeks mentorship in the chemical biology of gliomas from Dr. Susan Lindquist. Outlined in the proposal is a research plan using the extensive resources of the Whitehead, Broad and Dana Farber Cancer Institutes and a career development plan for achieving academic independence. Relevance: High-grade gliomas are among the most aggressive forms of cancer and current treatments do not markedly improve patient prognosis. By characterizing the chemical biology of the HSR in gliomas we aim to identify lead molecules with anti-glioma activity. Of additional relevance, some of these HSR modulating drugs may have application in classic protein folding CNS disorders such as neurodegenerative and prion diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS064168-05
Application #
8308011
Study Section
NST-2 Subcommittee (NST)
Program Officer
Fountain, Jane W
Project Start
2008-09-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$188,107
Indirect Cost
$13,934
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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Santagata, Sandro; Eberlin, Livia S; Norton, Isaiah et al. (2014) Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery. Proc Natl Acad Sci U S A 111:11121-6
Scherz-Shouval, Ruth; Santagata, Sandro; Mendillo, Marc L et al. (2014) The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell 158:564-78
Santagata, Sandro; Thakkar, Ankita; Ergonul, Ayse et al. (2014) Taxonomy of breast cancer based on normal cell phenotype predicts outcome. J Clin Invest 124:859-70
Eberlin, Livia S; Norton, Isaiah; Orringer, Daniel et al. (2013) Ambient mass spectrometry for the intraoperative molecular diagnosis of human brain tumors. Proc Natl Acad Sci U S A 110:1611-6
Santagata, Sandro; Mendillo, Marc L; Tang, Yun-chi et al. (2013) Tight coordination of protein translation and HSF1 activation supports the anabolic malignant state. Science 341:1238303
Brastianos, Priscilla K; Horowitz, Peleg M; Santagata, Sandro et al. (2013) Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 45:285-9
Santagata, Sandro; Xu, Ya-Ming; Wijeratne, E M Kithsiri et al. (2012) Using the heat-shock response to discover anticancer compounds that target protein homeostasis. ACS Chem Biol 7:340-9
Eberlin, Livia S; Liu, Xiaohui; Ferreira, Christina R et al. (2011) Desorption electrospray ionization then MALDI mass spectrometry imaging of lipid and protein distributions in single tissue sections. Anal Chem 83:8366-71
Santagata, Sandro; Hu, Rong; Lin, Nancy U et al. (2011) High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc Natl Acad Sci U S A 108:18378-83

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