Research in the Burma laboratory is focused on the responses of mammalian cells to DNA double-strand breaks (DSBs). These responses are of paramount importance in the field of cancer biology - on one hand DSBs cause cancer, while on the other hand these breaks are induced by radiation or chemotherapy to treat the disease.
The overarching goal of the laboratory is to comprehensively understand the network of cellular responses to DSBs, collectively called the DNA damage response (DDR). The Burma laboratory is involved in studying DDR events triggered both by terrestrial radiation (gamma rays) as well as by radiation in outer space (HZE particles), with three synergistic research projects that aim to comprehensively understand DDR events and their cancer implications:
- Roles of PI3K-like kinases (ATM, ATR, DNA-PK) in DNA repair, cell cycle arrest and apoptosis.
- Genetic basis of glioblastoma radioresistance: impact of oncogenic events on DNA repair pathways.
- Genetic changes underlying cellular transformation triggered by HZE particles (NASA project).
We hope that a more mechanistic understanding of DDR events will emerge from these studies, providing important insights into how cancer is triggered, and leading to the development of more effective cancer therapies.
- Mukherjee, B. et al.,Targeting non-homologous end-joining (NHEJ) through epidermal growth factor receptor (EGFR) inhibition: rationale and strategies for radiosensitization, Sem Rad Oncology (2010)
- Burma, S. et al.,Role of non-homologous end-joining (NHEJ) in maintaining genomic integrity, DNA Repair (2006)
Genetic Basis of Glioblastoma Radioresistance
Glioblastomas (GBMs) are lethal brain tumors that are highly resistant to radio and chemotherapy. We are systematically examining the contributions of key GBM-specific genetic alterations to therapy resistance using state-of-the-art mouse GBM models. We are particularly interested in the two key oncogenic events driving gliomagenesis: amplification of EGFRvIII and loss of PTEN (recently validated by the Cancer Genome Atlas Network study). Research in our and other laboratories has helped formulate a seminal concept in radiation oncology, i.e., "oncogenic events in glioblastomas and other cancers bolster DNA repair mechanisms that allow the tumor to survive endogenous and exogenous DNA damage." By mechanistically understanding these novel connections between receptor tyrosine kinase signaling and DNA repair events, we hope to uncover vulnerable signaling nodes that can be targeted for effective GBM therapy.
- McEllin B. et al.,PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res(2010)
- Mukherjee, B. et al., EGFRvIII and DNA double-strand break repair: a molecular mechanism for radioresistance in glioblastoma. Cancer Res.
Particle Radiation and Carcinogenesis (NASA)
Under the auspices of grants from NASA, we are studying both early and late cellular responses to complex DNA damage inflicted by HZE (High-Z, High-Energy) particles that are the most deleterious component of galactic cosmic rays. We find that mammalian cells are unable to repair a significant portion of DSBs induced by HZE particles and, as a consequence, these ions are highly tumorigenic compared to gamma rays. We are currently examining the genomic and gene expression changes underlying HZE-induced carcinogenesis and find that loss of the Ink4a/4b/Arf tumor suppressor locus is a critical event in particle-induced tumorigenesis. Our research on HZE particles is very pertinent to NASA as the decision to launch future long-duration space missions hinges upon the accurate estimation of cancer risks to astronauts from these particles. Moreover, this research will have a far reaching impact on cancer therapy due to the increasing use of charged particles for targeted tumor therapy in the clinic.
- Camacho, CV et al.,Loss of p15/lnk4b accompanies tumorigenesis triggered by complex DNA double-strand breaks. Carcinogenesis (2010)
- Mukherjee, B et al.,Modulation of the DNA-damage response to HZE particles by shielding. DNA Repair