RESEARCH

1. Epigenetic changes in Adult gliomas

2. Targeting childhood gliomas by interrupting epigenetic and metabolic pathways

Diffuse intrinsic pontine gliomas (DIPGs) are lethal tumors and over 90% of patients die within 1.5 years of diagnosis. A major challenge in the lack of effective treatments is because therapies that work in adults or other types of childhood cancers either produce no effect or only marginally improve survival for DIPG patients. There is an urgent and unmet need to develop effective therapies for children with DIPG. Cancer cells exhibit aberrant and accelerated metabolism that can be leveraged to kill tumor cells. We have discovered that the frequently-found histone H3K27M mutation (~80%) in DIPGs alters how DIPG cells metabolize nutrients. We aim to target this metabolic pathway as a potential therapy that simultaneously tackles two dysfunctional pathways in DIPGs, thus improving chances of therapeutic success by overcoming the ability of cancer cells to resist treatment via redundant biological pathways. We propose a research program that will (a) help uncover a critical but yet uncharacterized central epigenetic and metabolic pathway in DIPG tumor cells and (b) provide the groundwork for innovative therapies that simultaneously interrupt critical and interrelated pathways in DIPGs.

Childhood Posterior Fossa-type A (PFA) ependymomas are devastating tumors and have limited treatment options resulting in significant morbidity and mortality. We and others have reported that an epigenetic state of global H3K27me3 reduction, similar to that observed in H3K27M-gliomas (such as DIPGs), is a defining feature of PFA ependymomas. Three independent groups have recently demonstrated that overexpression of the protein EZH Inhibitory Protein (EZHIP) drives global H3K27me3 reduction in PFA ependymomas. However, the mechanisms by which EZHIP/ low H3K27me3 cause cancer remain obscure. Elucidation of the molecular mechanisms by which EZHIP-mediated H3K27me3 reduction drives oncogenesis and the precise mechanisms that regulate global H3K27me3 could elucidate potential therapeutic targets. 

We study the interplay between cancer metabolism and epigenetics in brain tumors. Tumor suppressor genes or oncogenes in tumors reprogram metabolism to modulate many cellular functions including epigenetic regulation as well as enhancing proliferation. We evaluate the effects of altered metabolism on histone and DNA methylation in tumors and pursue to find cancer therapies targeting epigenetic modification and metabolic regulation. 

1. Panwalkar P*, Tamrazi B*, Dang D*, Chung C*, Sweha S*, Natarajan SK*, Pun M, Bayliss J, Ogrodzinski MP, Pratt D, Mullan B, Hawes D, Yang F, Lu C, Sabari BR, Achreja A, Heon J, Animasahun O, Cieslik M, Dunham C, Yip S, Hukin J, Phillips JJ, Bornhorst M, Griesinger AM, Donson AM, Foreman NK, Garton HJL, Heth J, Muraszko K, Nazarian J, Koschmann C, Jiang L, Filbin MG, Nagrath D, Kool M, Korshunov A, Pfister SM, Gilbertson RJ, Allis CD, Chinnaiyan AM, Lunt SY, Blüml S, Judkins AR, Venneti S. (2021) Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas. Sci Transl Med.13(614):eabc0497. *These authors contributed equally

2. Sweha SR, Chung C, Natarajan SK, Panwalkar P, Pun M, Ghali A, Bayliss J, Pratt D, Shankar A, Ravikumar V, Rao A, Cieslik M, Wilder-Romans K, Scott AJ, Wahl DR, Jessa S, Kleinman CL, Jabado N, Mackay A, Jones C, Martinez D, Santi M, Judkins AR, Yadav VN, Qin T, Phoenix TN, Koschmann CJ, Baker SJ, Chinnaiyan AM, Venneti S. (2021) Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas. Sci Transl Med. 13(615):eabf7860

3. Chung C, Sweha SR, Pratt D, Tamrazi B, Panwalkar P, Banda A, Bayliss J, Hawes ​D, Yang F, Lee HJ, Shan M, Cieslik M,​Qin T, Werner CK, Wahl DR, Lyssiotis CA, Bian Z, Shotwell JB, Yadav VN, Koschmann C, Chinnaiyan AM, Blüml S, Judkins AR, Venneti S. (2020) Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas. Cancer cell, 38(3):334-349

4. Panwalkar P *, Pratt D *, Chung C *, Dang D, Le P, Martinez D, Bayliss JM, Smith KS, Adam M, Potter S, Northcott PA, Mascarenhas L, Shows J, Pawel B, Margol A, Huang A, Judkins AR, Venneti S. (2020) SWI/SNF complex heterogeneity is related to polyphenotypic differentiation, prognosis, and immune response in rhabdoid tumors. Neuro Oncol., 22(6):785-796.    *These authors contributed equally.

5.  Panwalkar P, Clark J, Ramaswamy V, Hawes D, Yang F, Dunham C, Yip S, Hukin J, Sun Y, Schipper MJ, Chavez L, Margol A, Pekmezci M, Chung C, Banda A, Bayliss JM, Curry SJ, Santi M, Rodriguez FJ, Snuderl M, Karajannis MA, Saratsis AM, Horbinski CM, Carret AS, Wilson B, Johnston D, Lafay-Cousin L, Zelcer S, Eisenstat D, Silva M, Scheinemann K, Jabado N, McNeely PD, Kool M, Pfister SM, Taylor MD, Hawkins C, Korshunov A, Judkins AR, Venneti S. (2017) Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol., 134(5):705-714