Orthopaedic Oncology
Program
The University of Chicago has a long
history of leadership in orthopaedic oncology, dating back to
the founding of the Department of Surgery by Dr. Dallas
Phemister in 1924. Dr. Phemister pioneered the use of
autografts to reconstruct segmental bone defects for extremity
bone tumors, helping to lay the conceptual foundation for
limb-sparing procedures that are a mainstay of treatment today.
With the recruitment of Dr. Howard Hatcher, he also
founded a line of prominent orthopaedic oncologists that have
been at the leading edge of clinical practice and research in
orthopaedic oncology to this very day.
For the past two decades, the orthopaedic
oncology has evolved into an integrated clinical, research, and
educational program under the leadership of Dr.
Michael A. Simon.
Clinically, the care of patients with bone and soft tissue
tumors is a truly multidisciplinary effort. Our efforts are
complemented and supported by specialists in several related
fields such as medical/pediatric oncology, radiation oncology,
pathology, radiology, plastic surgery and surgical oncology. In
spite of this multi-disciplinary approach, however, the
treatment of patients with primary benign and malignant
musculoskeletal tumors has been hampered by our poor
understanding of these neoplasms, a consequence of their
relative rarity, enigmatic biology, and enormous histologic
diversity compared to tumors arising in other organ systems.
Advances in the field, therefore, rest upon improving our
understanding of musculoskeletal tumors, and translating of
these results into clinically meaningful treatments. The
program in orthopaedic oncology at the University of Chicago
has, therefore, created a seamless interface between clinical
investigation and basic science designed to facilitate the
translation of laboratory breakthroughs into innovative
treatments. This integration has been further facilitated by
the collective efforts of Drs. Simon,
Terrance Peabody, and Anthony G. Montag, who have
established and maintained extensive tissue and database of bone
and soft tissue tumors for almost 20 years.
Our basic research efforts are led by
Drs. T.-C. He,
Rex C. Haydon and Hue H. Luu, but encompass more
than 10 postdoctoral researchers, graduate students, residents,
medical students and undergraduates. In order to define the
critical events responsible for the initial tumorigenesis of
osteosarcoma as well as its later metastatic spread, we have
taken two complementary approaches. In the first approach, we
have analyzed the possible involvement of some known
cancer-related genes in bone tumors. As an example, we found
that b-catenin
deregulation occurred in nearly 70% of cases of osteosarcoma.
Selective tyrosine inhibitors such as STI-571 (Gleevac) are able
to block abnormal b-catenin
signaling by preventing disassociation of
b-catenin from the E-cadherin
complex. Although the precise role of
b-catenin deregulation
in bone tumorigenesis remains to be defined, aberrant
b-catenin activation is
the initiating event during human colon cancer development. We
are investigating the role of tyrosine phosphorylation in
regulating b-catenin
activity in human cancer (including bone tumors), which is
expected to receive NIH support as an R01 project. In the
second approach, we believe that understanding the molecular
mechanisms of bone formation is pivotal for studying the
pathogenesis of bone tumors. We are interested in elucidating
the molecular mechanisms through which regulate the lineage
commitment and terminal differentiation of osteoblast progenitor
cells, or mesenchymal stem cells (MSCs). We have conducted a
comprehensive analysis of osteogenic activity of 14 types of
bone morphogenetic proteins (BMPs) and identified the previously
uncharacterized BMP-9 as one of the most osteogenic inducers of
MSCs. From extensive gene profiling analyses, we have
identified several important signaling mediators of BMP-induced
bone formation, many of which are deregulated in human cancer,
including bone tumors. This line of investigation has also led
to the acquisition of an NIH K08 award and several grants from
OREF, Brinson Foundation, Aircast Foundation, and MTF.
We have also explored the biology of
metastasis in osteosarcoma, finding an association between
expression of S100A6 and the development of metastasis in a
cohort of 50 patients. In the search for novel treatments for
osteosarcoma, we have demonstrated the efficacy of
differentiation therapy with retinoic acid and PPARg agonists to induce terminal differentiation. To explore
whether these strategies can be used for therapeutic purposes,
we have developed a novel orthotopic animal model of
osteosarcoma which closely parallels the clinical course of
osteosarcoma, beginning with local development and invasion, and
followed by pulmonary metastases. Using this model, we have
shown that BMPs, morphogens that normally help to induce
differentiation, actually induce proliferation in osteosarcoma
cells and may promote metastasis. These data support our theory
that defects in terminal differentiation may be a critical
feature of osteosarcoma that can be exploited for the purposes
of treatment. To this end, we are currently using the same
model to examine the ability of PPARg
agonists, retinoic acid and/or STI-571 to override this block to
differentiation and act as potential chemotherapeutic and/or
chemopreventive agents.
Finally, we have helped to explore novel
treatments through clinical trials. In collaboration with
Dr. Ralph Weischelbaum in the Department of Radiation
Oncology, we have participated in a clinical trial of TNFerade,
a radiation-inducible adenoviral vector that expresses TNFa,
for the treatment of soft tissue sarcomas. Based on initial
data, this vector induces significant necrosis internally that
may represent a new approach to the treatment of soft tissue
sarcomas.
Above and beyond the research mission of
the program, the educational component represents the true heart
of the program. This is best exemplified by the fellowship
program in orthopaedic oncology. Founded by Dr. Michael
Simon in 1985, the fellowship has produced eighteen
orthopaedic oncologists, sixteen of whom have gone on to
academic careers in musculoskeletal oncology at major
universities and cancer centers across the country. The
fellowship is one of the most highly sought after in the
country. Drs. Terrance Peabody and Rex Haydon
underwent training in this fellowship and are currently among
the faculty. The success of this program is based on the
extensive exposure it affords, not only to patients with both
bone and soft-tissue tumors, but also to an extensive clinical
database for bone and soft-tissue tumors for clinical research
and a multidisciplinary team of clinicians and scientists.
Both the research and educational
components of the oncology program in orthopaedics help to
ensure that we can provide the highest quality care to patients
with bone and soft tissue tumors. From investigating molecular
signatures of individual tumors that may help to stratify risk
among patients to the most advanced limb-salvage procedures for
functional restoration of the extremities, the orthopaedic
oncology program is comprehensive and well-integrated.
Recently, we have established the Suzanne
Berman Memorial Lectureship to bring prominent researchers
and physician scientists to The University of Chicago to discuss
the underlying causes of sarcomas and to develop new approaches
to diagnosis and
treatment
of these tumors. The clinical and research
infrastructure in place is a reflection of Dr. Phemister’s
original vision, a legacy that will continue forward.
Last update:
January 10, 2010
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