PEBC Report - Programa de Epigenética y Biología del Cáncer

SPEAKERS BIOGRAPHY AND ABSTRACT
René Bernards
René Bernards received his PhD in
1984 from the University of Leiden.
He joined the laboratory of Robert
Weinberg at the Whitehead Institute
in Cambridge, USA for his postdoctoral
training. Here, he studied the
function of both oncogenes and
tumor suppressor genes. He continued
this work when he joined the
Massachusetts General Hospital
Cancer Center as an assistant professor in 1988. In 1992 he
was appointed senior staff scientist at the Netherlands
Cancer Institute. In 1994 he was appointed part time professor
of molecular carcinogenesis at Utrecht University, The
Netherlands. In the last six years, his laboratory has focused
on the development of new tools to carry out genome-wide
genetic screens to identify novel genes that act in cancerrelevant
pathways. In July of 2003 he co-founded
“Agendia”, a genomics-based diagnostic company that
started offering the first microarray-based diagnostic test for
the clinical management of breast cancer in 2004.
He received several awards for his research, including the
Pezcoller Foundation-FECS Recognition for Contribution to
Oncology, the Ernst W. Bertner Award for Cancer Research
from the M.D. Anderson Cancer Center, the ESMO Lifetime
Achievement Award in Translational Research in Breast
Cancer and the Spinoza award from the Netherlands
Organization for Scientific Research. He is a member of the
Royal Netherlands Academy of Arts and Sciences.
Division of Molecular Carcinogenesis,
The Netherlands Cancer Institute,
Amsterdam, The Netherlands
Finding mechanisms and biomarkers
of drug resistance in cancer
Unresponsiveness to therapy is remains a significant
problem in the treatment of cancer, also with the new
classes of targeted therapeutics. In my laboratory, we use
functional genetic approached identify biomarkers that
can be used to predict responsiveness to clinically-relevant
cancer therapeutics. We focus on the clinically-relevant
targeted cancer drugs such as trastuzumab
(Herceptin), PI3K inhibitors, mTOR inhibitors, Histone
Deacetylase inhibitors and retinoic acid. These drug target
specific molecules or pathways that are often activated
in cancer. Nevertheless, it remains poorly explained
why a significant number of tumors do not respond to the
therapy. We aim to elucidate the molecular pathways that
contribute to unresponsiveness to targeted cancer therapeutics
using a functional genetic approach. This will yield
biomarkers that can be used to predict how individual
patients will respond to specific drugs. Furthermore, this
work may allow the development of drugs that act in synergy
with the established drug in the treatment of cancer.
To identify biomarkers that control tumor cell responsiveness
to cancer therapeutics, we use both genome-wide
gain-of-function genetic screens (with cDNA expression
libraries) and genome wide loss-of-function genetic
screens (with RNA interference libraries) in cancer cells
that are sensitive to the drug-of-interest. We search for
genes whose over-expression or whose down-regulation
in cultured cancer cells confers resistance to the drug-ofinterest.
Once we have identified such genes, we ask if
their expression is correlated with clinical resistance to the
drug-of-interest using tumor samples of cancer patients
treated with the drug in question, whose response to therapy
is documented. Examples of loss-of-function genetic
screens to identify mechanisms of resistance to different
cancer drugs will be presented.
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