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Appointments:
Professor
Department of Pediatrics
Section of Hematology/Oncology
Director, Clinical Sciences
Committee on Cancer Biology
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Education:
M.D., University of Illinois at
Chicago 1980
B.A., Northwestern University
1976
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Contact:
Phone: (773) 702-2571
Fax: (773)
834-1329
E-Mail:
scohn@peds.bsd.uchicago.edu
Address:
The University of Chicago
AMB N114, (MC 4060)
5841 South Maryland Avenue
Chicago, Illinois 60637
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Related Research Interests:
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Susan L. Cohn, M.D.
Biology of Neuroblastoma and Potential Therapeutic
Targets
Research Summary
The
over-all
research focus of the Cohn laboratory involves investigating the role
of angiogenesis in neuroblastoma pathogenesis. Previous work has
demonstrated differences in blood vessel density in clinically
aggressive versus more benign neuroblastoma tumors. More
recently, we have shown evidence of abnormal vessel structure and
vascular endothelial cell proliferation (VEP) in clinically aggressive
tumors. In contrast, VEP was not detected in the more favorable
Schwannian stroma-rich neuroblastoma tumors, suggesting that
angiogenesis is regulated differently in Schwannian stroma-rich versus
stroma-poor NB tumors. Our lab has determined that Schwann cells,
derived from stroma-rich neuroblastoma tumors, produce a number of
angiogenic inhibitors including Secreted Protein Acidic and Rich in
Cysteine (SPARC). Preclinical studies have shown that SPARC is
capable of inhibiting angiogenesis and neuroblastoma growth, and potent
anti-angiogenic activity is also seen with a peptide that was designed
to correspond to the epidermal growth factor-like module of the
follistatin domain of SPARC. We have also shown that treatment
with a number of anti-angiogenic agents are capable of “normalizing”
the architecture and function of neuroblastoma blood vessels,
suggesting that this treatment strategy may also allow for more
efficient cytotoxic drug delivery.
In addition to blood vessels, we are also investigating how other
tissues within the tumor stroma influence tumor growth. The
normal host microenvironment is non-permissive for neoplastic
progression, whereas tumor-reactive stroma, characterized by the
presence of activated fibroblasts, promotes neoplastic growth and
metastasis. Our lab has recently shown that SPARC prevents
fibroblast activation, suggesting that in addition to blocking
angiogenesis, SPARC may inhibit tumor growth by promoting the assembly
of stroma that is non-permissive for tumor progression. Studies
elucidating the mechanisms by which SPARC modifies the tumor stroma
leading to a non-permissive microenvironment for tumor growth are
ongoing.
Epigenomics is a second area of research emphasis in our lab. The
methylation status of genes that are frequently epigenetically
inactivated in adult cancers have been evaluated in neuroblastoma cell
lines and primary tumors. The tumor suppressor gene RASSF1A is
epigenetically inactivated in a subset of neuroblastoma tumors and
cells lines. RASSF1A methylation is significantly associated with
poor survival, suggesting that abnormal silencing of this gene may play
a role in neuroblastoma pathogenesis. Additional studies on
primary neuroblastoma tumors have shown that methylation of CASP8, DCR2
and Hin-1 are also associated with high-risk disease and poor
outcome. Studies analyzing the prognostic and functional
significance of epigenetically silenced genes in neuroblastoma are
ongoing.
Selected Papers
Burke
M and Cohn SL. Rituximab for Treatment of Opsoclonus-myoclonus Syndrome
in Neuroblastoma. Pediat. Blood Cancer,50:679-680, 2006.
Chlenksi A, Guerrero LJ, Yang Q, Tian Y, Salwen HR, and Cohn SL. SPARC
Enhances Tumor Stroma Formation and Prevents Fibroblast Activation.
Oncogene, 26:4513-4522, 2007.
Yang Q, Tian Y, Liu S, Zeine R, Chlenski A, Salwen HR, Henkin J, and
Cohn SL. Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid
is an Effective Anti-Angiogenesis Strategy in Neuroblastoma. Cancer
Res., 67:1716-1724, 2007.
Yang Q, Kiernan CM, Tian Y, Salwen HR, Chlenski A, Brumback BA, London
WB, and Cohn SL. Methylation of CASP8, DCR2, and HIN-1 in Neuroblastoma
is Associated with poor outcome. Clin. Cancer Res., 13:3191-3197, 2007.
Peddinti R, Zeine R, Luca D, Seshadri R, Chlenski A, Cole K, Pawel B,
Salwen HR, Maris JM, Cohn SL. Prominent Microvascular Proliferation in
Clinically Aggressive Neuroblastoma. Clin. Cancer Res., 13:3499-3506.
2007.
Nair PN, McArdle L, Cornell J, Cohn SL, and Stallings RL. Differential
Methylation of the SEMA3B Tumor Suppressor Gene in Neuroblastoma and
Association of Expression with Differentiation. Cancer Genet
Cytogenet., 174:100-110, 2007.
Sano H, London WB, Matthay KK, Cohn SL, Maris JM, Shimada H. Prognostic
impact by MYCN status and International Neuroblastoma Pathology
Classification in Peripheral Neuroblastic Tumors: An Experience from
the Cooperative Study Group in North America. Pediatric Cancer
(Japan). 44:1-8, 2007 (in Japanese).
Fox E, Maris JM, Widemann BC, Goodspeed W, Goodwin W, Kromplewski M,
Fouts ME, Medina D, Cohn SL, Krivoshik A, Hagey AE, Adamson PC, and
Balis FM. A Phase I Study of ABT-751, an Orally Bioavailable Tubulin
Inhibitor, Administered Daily for 21 Days every 28 Days in Pediatric
Patients with Solid Tumors. Clin. Cancer Res., in press.
Schneiderman J, London WB, Brodeur GM, Castleberry RP, Thomas AT, and
Cohn SL. Clinical Significance of MYCN Amplification and Ploidy
in “Favorable” Stage Neuroblastoma. J.Clin.Oncol., in press.
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