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.
| Brastianos, Priscilla K; Santagata, Sandro (2016) ENDOCRINE TUMORS: BRAF V600E mutations in papillary craniopharyngioma. Eur J Endocrinol 174:R139-44 |
| Tsvetkov, Peter; Mendillo, Marc L; Zhao, Jinghui et al. (2015) Compromising the 19S proteasome complex protects cells from reduced flux through the proteasome. Elife 4: |
| Calligaris, David; Feldman, Daniel R; Norton, Isaiah et al. (2015) MALDI mass spectrometry imaging analysis of pituitary adenomas for near-real-time tumor delineation. Proc Natl Acad Sci U S A 112:9978-83 |
| 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 |
| Brastianos, Priscilla K; Taylor-Weiner, Amaro; Manley, Peter E et al. (2014) Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet 46:161-5 |
| Santagata, Sandro; Ince, Tan A (2014) Normal cell phenotypes of breast epithelial cells provide the foundation of a breast cancer taxonomy. Expert Rev Anticancer Ther 14:1385-9 |
| 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 |
| Whitesell, Luke; Santagata, Sandro; Mendillo, Marc L et al. (2014) HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models. Proc Natl Acad Sci U S A 111:18297-302 |
| 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 |
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