Understanding the Molecular Mechanisms Driving Cancer Development and Therapy Resistance
Thomas Clark, Ph.D.
4/28/2026
Background:
The American Cancer Society projects that there will be over
two million new cases and over 600,000 cancer-related deaths in
the United States in 2025. Therefore, understanding the molecular
mechanisms driving cancer development and therapy
resistance is absolutely critical. DNA damage and genomic
instability are recognized as fundamental hallmarks of cancer.
The mission of my laboratory is to elucidate fundamental
mechanisms of DNA damage repair, and leverage these newly
uncovered mechanisms to aid the development of novel cancer
therapeutics. We use a series of complementary and orthogonal
approaches across molecular biology, cell biology, genomics,
and proteomics to further our understanding of how defects in
DNA damage repair contribute to genome instability and lead to
human developmental disease, premature aging, and cancer. My
laboratory is particularly interested in identifying novel chromatin-
interacting proteins that are involved in DNA damage repair.
A long-term goal of our research program is to understand how
chromatin re-establishment following DNA damage repair is
initiated and determine whether this process can be targeted as a
new therapeutic strategy in cancer.
Current Work:
Most recently, my laboratory has been investigating the structure,
function and regulation of novel chromatin associated
proteins in the context of genomic integrity maintenance. We are
currently exploring important questions related to the biological
function and mechanistic regulation of the zinc finger 280
protein family. Zinc finger proteins are encoded by as much as
5% of the human genome, however the majority of zinc finger
proteins remain uncharacterized, despite their implication in a
range of human diseases including human developmental
syndromes, neurodegeneration, and several different types of
cancer.
During the course of my Karin Grunebaum Faculty Fellowship,
my laboratory has uncovered key mechanisms that help to
understand how a previously uncharacterized protein, ZNF280A,
orchestrates DNA damage repair. Specifically, we have shown
that ZNF280A is critical for repairing a type of DNA lesion
known as a DNA double-strand break. DNA double-strand
breaks are among the most toxic of DNA lesions, and if
unrepaired can result in mutations that are known to drive human
disease including cancer. Interestingly, one copy of ZNF280A is
lost in a human developmental syndrome called 22q11.2 distal
deletion syndrome. Patients with this syndrome present with
clinical features including, microcephaly (abnormally small head
circumference), short stature and growth defects, global developmental
delay, immune deficiency, cognitive impairments and an
increased risk of developing cancer. Using cells derived from
these patients, we were able to demonstrate that these patients
have more DNA damage in their cells because they are defective
in DNA damage repair mechanisms. Therefore, we have been
able to uncover a potential mechanism driving the development
of this human developmental syndrome. This work has been
accepted for publication at Nature Cell Biology (Clarke et al,
Nature Cell Biology – In press).
In addition to this work, we have also uncovered another
uncharacterized zinc finger protein with important roles in DNA
damage repair. Importantly, the expression of this protein is
significantly reduced in breast cancer patients, particularly those
with one of the most aggressive and difficult to treat forms of the
disease, triple negative breast cancer. By understanding the
molecular mechanisms that this newly uncovered protein is
involved in, we are hoping to develop novel treatment strategies
for breast cancer patients.