Lee J. Helman, M.D.
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Biography
Dr. Helman received his M.D. from
the University of Maryland School of
Medicine in 1980 magna cum laude,
and was elected to Alpha Omega
Alpha. He completed his internship
and residency in Internal Medicine
at Barnes Hospital Washington
University, serving as the Chief
Resident, Washington University VA
Medical Service in 1983. He began
his Fellowship training at the
National Cancer Institute (NCI) in
1983, where he has remained. He
became the head of the Molecular
Oncology Section of the Pediatric
Oncology Branch, NCI, in 1993, and
Chief of the Pediatric Oncology
Branch, NCI, in 1997. He was also
named a Deputy Director of the
Center for Cancer, National Cancer
Institute, in 2001. He was named
Acting Scientific Director for
Clinical Research, Center for Cancer
Research, National Cancer Institute,
in 2005, and named as the permanent
Scientific Director in 2007.
Dr. Helman's laboratory currently
focuses on three major themes
related to the biology and treatment
of pediatric sarcomas: (1) the role
of insulin-like growth factors on
the biology of these tumors; (2)
identification of the molecular
mechanisms of metastases using
animal models of spontaneously
metastatic tumors; and(3)
translation of these findings into
treatments to improve the outcome of
patients with pediatric sarcomas.
Research
Our laboratory research focuses
on three major themes related to the
biology and treatment of pediatric
sarcomas. The first area is the
pathophysiological consequences of
insulin-like growth factor (IGF)
signaling in Ewing's sarcoma (ES),
rhabdomyosarcoma (RMS) and
osteogenic sarcoma (OS). We are
currently investigating mTOR
signaling, which we previously have
shown to be at least in part
responsible for IGF-II-mediated
resistance to apoptosis, and which
we now have linked to the metastasis
signaling protein, ezrin. We have
been studying the feedback
activation of Akt upon mTOR
inhibition, which is linked to IGF-I
Receptor (IGF-IR) signaling. The
relevance of the mTOR signaling
pathway was demonstrated in our
retrospective analysis of Stage III
RMS patients in which we performed
global proteomic analysis of primary
tumors at presentation in samples
obtained from the Children's
Oncology Group. We determined that
activation of mTOR signaling at
diagnosis portended a significant
poorer prognosis. Blocking these
pathways in patients is a potential
therapeutic strategy and for this
reason, we have been testing the
potential of combining mTOR
inhibition with both standard
cytotoxic agents as well as IGF-IR
inhibitors in RMS cell lines and
xenograft models.
Our second major focus is the
identification of molecular
mechanisms of metastasis using OS as
a model system. We previously
identified the cytoskeletal linker
protein ezrin as a major component
of metastatic behavior in a mouse
model of OS. More recent
collaborative studies have
identified ezrin as a major
contributor to metastatic behavior
in a mouse genetic model of RMS,
further demonstrating the importance
of ezrin in multiple mouse models of
metastasis. Our work has suggested a
link between ezrin activity and mTOR
signaling, which has created an
obvious link between our studies of
IGF signaling and our studies of
metastasis. We also recently linked
ezrin to beta4 integrin and are
actively studying this relationship.
Our third major focus is on the
translation of these findings into
treatments to improve the outcome of
patients with ES, RMS and OS. We
continue to work on immunotherapy,
and second-generation vaccine
studies are planned. In addition,
our finding of the importance of
mTOR in the aggressive behavior of
sarcomas contributed to the use of
rapamycin in the early
post-engraftment period in our
allogeneic transplant studies in
patients with sarcomas. We are
interested in both the
immunosuppressive and anti-tumor
effects of rapamycin. Our laboratory
interest in the role of IGF-I in
sarcomas has led to collaborations
with several pharmaceutical
companies that have developed
humanized monoclonal antibodies
directed against the IGF-I receptor.
In this connection, we are working
to develop early therapeutic trials
of these monoclonal antibodies in
pediatric sarcomas, which because of
their relative rarity, are not major
commercial targets. As above, we aim
to move quickly to test the effects
of IGFIR blockade with mTOR
inhibition in recurrent disease. We
hope to test novel therapeutic
approaches to the treatment of
pulmonary metastases in patients
with OS where activated pathways
identified in our preclinical
metastatic models can be targeted
using innovative study designs.
Finally, we hope to employ intensive
genetic and proteomic analyses of
tumor samples from as many patients
as possible to better sub classify
tumors in ways that support the use
of individualized, targeted therapy.
