"Thanks to Sontag Foundation support, we have been able to confirm new cancer vulnerabilities that open up over 100 potential therapeutic targets across cancer types. In addition, the connections we have made through the Sontag Foundation have enabled us to begin to translate these vulnerabilities into potential therapeutics and spurred a series of collaborations resulting in new discoveries that have now been published in multiple highly cited papers."
- Dr. Rameen Beroukhim
- Assistant Professor, Medicine, Harvard Medical School
- Assistant Professor, Medical Oncology and Cancer Biology, Dana-Farber Cancer Institute
- Associate Member, Cancer Program, Broad Institute of MIT and Harvard
- Attending Physician, Medicine, Brigham And Women's Hospital
About DSA-Funded Research
To develop effective treatments for gliomas, we need to exploit differences between glioma cells and normal cells so that we can kill the glioma cells without harming patients. A major source of differences is extensive disruption of the DNA in the gliomas. Indeed, these disruptions cause gliomas to arise; many of the changes lead gliomas to grow uncontrollably. As a result, extensive effort has gone into defining the glioma genome.
However, in addition to these “beneficial” changes, many mutations in gliomas do not promote growth. In fact, some changes alter essential processes, potentially leaving gliomas open to treatments that target those processes. In particular, glioma cells often lose large parts of their DNA. Approximately one-sixth of the genome is present at reduced copies in a typical glioblastoma. This DNA includes many essential genes.
We have found that relative loss of essential genes can make cells more vulnerable to treatments that target those genes. For the proposed work, we aim to determine whether these vulnerabilities extend to gliomas and afford the potential for new treatment opportunities. We focus on genes in the proteasome and spliceosome, two complexes which are already the targets of anticancer therapies, but which have not been used effectively in gliomas. Over the short term our work will suggest alternative approaches to targeting these complexes and identifying patients who might benefit. Over the long term, our work is likely to establish a new universe of potentially novel therapeutic targets in brain cancer.
"Dr. Beroukhim is a very reflective, thoughtful and innovative person. He is one of a handful of physician-scientists who have a deep understanding of the computational and analytic issues in genomics."
Matthew Meyerson, M.D., Ph.D.
Dana-Farber Cancer Institute
"Dr. Beroukhim's prospects for success are splendid. In my view, he will be recognized as one of the emerging young leaders in glioma genetics within the next five years."
Charles D. Stiles, Ph.D.
Harvard Medical School
- Keith Ligon: multiple projects including small molecule profiling of glioma models, genomic characterization of adult and pediatric high and low-grade gliomas, and mechanisms of resistance to glioma treatments.
- Tim Chan: characterization of PARK2 mutations’ roles in oncogenesis across cancers
- Jason Huse: evaluation of telomere-related genetic alterations
- Bradley Pentelute: development of novel potential therapeutics to take advantage of the cancer dependencies we identified through Sontag funding
- Bandopadhayay P*, Ramkissoon LA*, Jain P*, Bergthold G*, Wala J, Zeid R, Schumacher SE, Urbanski L, O'Rourke R, Gibson WJ, Pelton K, Ramkissoon SH, Han HJ, Zhu Y, Choudhari N, Silva A, Boucher K, Henn RE, Kang YJ, Knoff D, Paolella BR, Gladden-Young A, Varlet P, Pages M, Horowitz PM, Federation A, Malkin H, Tracy AA, Seepo S, Ducar M, Van Hummelen P, Santi M, Buccoliero AM, Scagnet M, Bowers DC, Giannini C, Puget S, Hawkins C, Tabori U, Klekner A, Bognar L, Burger PC, Eberhart C, Rodriguez FJ, Hill DA, Mueller S, Haas-Kogan DA, Phillips JJ, Santagata S, Stiles CD, Bradner JE, Jabado N, Goren A, Grill J, Ligon AH, Goumnerova L, Waanders AJ, Storm PB, Kieran MW, Ligon KL1, Beroukhim R1, Resnick AC1. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat Genet. 2016 Mar;48(3):273-82.
- Ramkissoon SH*, Bi WL*, Schumacher SE, Ramkissoon LA, Haidar S, Knoff D, Dubuc A, Brown L, Burns M, Cryan JB, Abedalthagafi M, Kang YJ, Schultz N, Reardon DA, Lee EQ, Rinne ML, Norden AD, Nayak L, Ruland S, Doherty LM, LaFrankie DC, Horvath M, Aizer AA, Russo A, Arvold ND, Claus EB, Al-Mefty O, Johnson MD, Golby AJ, Dunn IF, Chiocca EA, Trippa L, Santagata S, Folkerth RD, Kantoff P, Rollins BJ, Lindeman NI, Wen PY, Ligon AH1, Beroukhim R1, Alexander BM1, Ligon KL1. Clinical implementation of integrated whole-genome copy number and mutation profiling for glioblastoma. Neuro Oncol. 2015 Mar 9. pii: nov015. [Epub ahead of print]
- Bergthold G*, Bandopadhayay P*, Hoshida Y, Ramkissoon S, Ramkissoon L, Rich B, Maire CL, Paolella BR, Schumacher SE, Tabak B, Ferrer-Luna R, Ozek M, Sav A, Santagata S, Wen PY, Goumnerova LC, Ligon AH, Stiles C, Segal R, Golub T, Grill J, Ligon KL, Chan JA1, Kieran MW1, Beroukhim R1. Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. Neuro Oncol. 2015 Mar 29. pii: nov045. [Epub ahead of print]
- Gong Y, Zack TI, Morris LG, Lin K, Hukkelhoven E, Raheja R, Tan IL, Turcan S, Veeriah S, Meng S, Viale A, Schumacher SE, Palmedo P, Beroukhim R, Chan TA. Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet. 2014 Jun;46(6):588-94.
- Bandopadhayay P*, Bergthold G*, Nguyen B, Schubert S, Gholamin S, Tang Y, Bolin S, Schumacher SE, Zeid R, Masoud S, Yu F, Vue N, Gibson WJ, Paolella BR, Mitra SS, Cheshier SH, Qi J, Liu KW, Wechsler-Reya R, Weiss WA, Swartling FJ, Kieran MW, Bradner JE, Beroukhim R1, Cho YJ1. BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma. Clin. Cancer Res. 2014 Feb 15;20(4):912-25.