Dr. Cohn’s research interests are focused on understanding the biology of neuroblastoma, a clinically heterogeneous childhood cancer, and identifying new potential therapeutic targets. One research project ongoing in Dr. Cohn’s laboratory involves the analysis of angiogenesis in neuroblastoma. Dr. Cohn’s laboratory was the first to report the correlations between high vascular density in neuroblastoma tumors and advanced stage disease, unfavorable histology, MYCN amplification, and poor outcome. These studies also demonstrated that the vascularity of stroma-rich tumors is low. More recent studies have demonstrated structural abnormalities including vascular endothelial cell proliferation (VEP) in neuroblastoma tumors that are clinically aggressive.   Interestingly, VEP was not detected in Schwannian stroma-rich tumors, further suggesting that angiogenesis is regulated differently in Schwannian stroma-rich versus stroma-poor NB tumors. Dr. Cohn’s 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.   The Cohn lab has 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 angiogenesis, interactions between malignant cells and other tissues in the tumor stroma also 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. The Cohn 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 the Cohn 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.

Dr. Cohn's Links of Interest