The Department of Radiation Oncology is committed to combining advances in clinical and laboratory research with developments in radiation physics. The goal is to promote a better understanding of the biology of cancer and normal tissues and to improve the treatment of cancer.
The unifying research aim of the Department is genomic instability in human cancer. A better understanding of this instability may lead to more tailored therapies for cancer patients. Departmental research is focused on the treatment of tumors by ionizing radiation and, ultimately, improving therapy through understanding radiation and other treatments at the molecular and cellular levels. Although the basic physical and biochemical mechanisms underlying radiation therapy are understood, the molecular and tissue-level responses that determine tumor cell fate during treatment have only recently come to light. The Department continues to make advances in the knowledge of the radiation response of cancer cells in tissue culture and within tumors.
Understanding chromosomal instability syndromes
Alan D'Andrea, MD, is studying the molecular signaling pathways that regulate the DNA damage response in mammalian cells. Disruption of these pathways, by germline or somatic mutation, leads to genomic instability and cellular sensitivity to ionizing radiation, as well as defective cell cycle checkpoints and DNA repair. These pathways are often disrupted in cancer cells, accounting for the chromosomal instability and increased mutation frequency in human tumors. D'Andrea's focus is the molecular pathogenesis of the human chromosomal instability syndromes: Fanconi anemia (FA), ataxia-telangiectasia, and Bloom syndrome. FA is an autosomal recessive cancer susceptibility disorder characterized by developmental defects and increased cellular sensitivity to DNA cross-linking agents. Thirteen FA genes have been cloned; the encoded FA proteins interact in a novel signaling pathway. Eight FA proteins form a nuclear protein complex required for the monoubiquitination of the D2 protein. Activated D2 is targeted to chromatin, where it interacts with the products of the breast cancer susceptibility genes, BRCA1 and BRCA2. The Department's research program addresses several aspects of this novel signaling pathway, including: the assembly, transport, and structure of the FA protein complex; the enzymatic monoubiquitination and de-ubiquitination of the D2 protein; the function of the chromatin-associated FA complex in cell cycle checkpoints and homologous recombination DNA repair; and the identification of novel interacting proteins in these complexes.
Identifying tumor signatures
Gerassimos (Mike) Makrigiorgos, PhD, is studying the identification and tracing of tumor signatures in cancer samples. His laboratory has a special interest in developing new technologies for cancer molecular diagnostics and molecular profiling for personalized medicine. He has developed a range of methodologies for evaluation of tumor-specific genetic changes, such as mutation and methylation. A recently developed method, COLD-PCR, has the ability to magnify traces of deleterious mutations in cancer samples containing excess normal cells so that they can be easily detected. In this way, mutation-based signatures of cancer cells can be identified and traced in small biopsies, body fluids such as plasma or sputum, and heterogeneous surgical specimens from cancer patients. These approaches may result in an early screening test for cancer-specific genetic alterations and may contribute toward understanding the evolution and biology of tumors.
Uncovering DNA repair mechanisms
Brendan Price, PhD, has made major advances in understanding the role of the ataxia-telangiectasia gene product (ATM) as a sensor of DNA damage and a regulator of radiation resistance in the irradiated cell. He has identified the Tip60 acetyltransferase as a key regulator of the ATM protein. ATM and Tip60 exist in the cell as an inactive complex. In response to DNA damage, the ATM-Tip60 complex is recruited to sites of DNA damage. Tip60 is then activated and acetylates ATM, leading to a rapid upregulation of ATM's kinase activity. The Price lab has revealed that this activation of Tip60's acetyltransferase activity involves specific interaction between Tip60 and methylated histones adjacent to sites of DNA damage. This work shows that histone methylation can modulate the activity of acetyltransferases. It also highlights the critical importance of chromatin structure and epigenetics in mediating DNA repair processes. Further, these findings offer great potential in the rational design of combination cancer therapy specifically targeting components of the ATM-Tip60 complex and the proteins that contribute to
maintaining histone methylation marks on the chromatin.
Dipanjan Chowdhury, PhD, is studying two aspects of the DNA damage response. One is dephosphorylation of DNA repair proteins via phosphatases, while the other is decreased expression of repair factors via microRNAs (miRNAs). His laboratory recently made the important observation that miRNAs impede DNA repair in terminally differentiated blood cells, facilitating apoptosis. However, these miRNAs, when aberrantly expressed in progenitor cells, may induce genomic instability leading to cancer. Conversely, their expression pattern in cancer cells may impact therapeutic response and clinical outcome.
Insights into pancreatic cancer
Alec Kimmelman, MD, PhD, is using mouse models and in vitro human systems to study the molecular pathogenesis of pancreatic cancer. His laboratory is especially interested in defining the underlying chromosomal and genomic instability of pancreatic tumor cells. His goal is to understand the mechanism behind their intense resistance to therapy and to develop potential sensitizers to chemotherapy and radiation. Other ongoing efforts include the study of cellular metabolism in pancreatic cancer cells and the elucidation of pathways that may lead to tumor-specific death due to altered cellular metabolism. Results from this work may provide novel vantage points of attack for this deadly disease.
The Department also performs a wide range of clinical studies across disease sites, including clinical trials of new therapeutic approaches, hypothesis-generating retrospective reviews, and outcomes and health services research.