Department of Radiation Oncology
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.
Research themes
Jay Harris, MD, Chair 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.
Research themes
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 role of DNA repair in brain tumors
Clark Chen, MD, is focusing on the cause and treatment of human
brain tumors, including glioblastoma multiforme, and brain
metastasis. The laboratory aims to integrate genomic studies of
brain cancer derived from patient tumor specimens, siRNA/shRNA
screening, and novel mouse models (both xenograft and transgenic).
The goals of Chen's group are to: understand the role of DNA repair
in brain tumor carcinogenesis and brain cancer stem cell biology;
explore therapeutic approaches based on DNA repair defects incurred
during brain tumor progression; develop prognostic and diagnostic
biomarkers; and apply small-molecule inhibitors of DNA repair as
monotherapy or in con junction with radiation and chemotherapy for
brain cancer treatment.
Other research
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.