Denise C. Connolly, PhD
Office Phone: 215-728-1004
1. Signaling pathways mediating ovarian cancer progression and metastasis
When EOC is diagnosed at early stage, it is essentially a curable disease. However, the vast majority of patients are diagnosed at advanced stage, when disease has spread beyond the ovary. Most of these patients initially respond well to surgery and standard chemotherapy, but the 5-year survival rate is only 30-40% and the emergence of drug-resistant disease is common. At this point, there are few effective therapeutic strategies and the treatment becomes palliative. This grim reality underscores the persistent unmet need to identify signaling pathways that can be targeted for therapeutic intervention. Therefore, a significant focus of the laboratory is to identify key signaling pathways that contribute to EOC progression and dissemination.
AURKA mediates EOC cell migration, adhesion and ovarian tumor growth. Recent studies in the laboratory have demonstrated a novel role for Aurora kinase A (AURKA) in mediating EOC dissemination by regulating cell migration and adhesion. The mechanism underlying these effects is due at least in part to AURKA-mediated activation of SRC. We also showed that targeted inhibition of AURKA resulted in decreased tumor growth and dissemination, and that the effects of alisertib were potentiated by the addition of paclitaxel. These studies provided preclinical data supporting the concept for a clinical trial that is currently enrolling patients (http://clinicaltrials.gov).
STAT3 activation contributes to EOC development and progression. In ongoing studies, we have investigated the contribution of signal transducer and activator of transcription 3 (STAT3) in EOC progression. Because of the common activation of STAT3 in EOCs, we have been analyzing the efficacy of novel JAK2/STAT3 pathway inhibitors (e.g., AZD1480) in vivo, and shown highly significant tumor growth inhibition in TgMISIIR-TAg transgenic mice, in part mediated by effects on the tumor microenvironment (Gritsina et al, manuscript in preparation). Our results suggest that JAK2/STAT3 pathway inhibition may be an effective therapeutic strategy for patients.
The role of NEDD9 in EOC. NEDD9/HEF1/Cas-L (NEDD9) is a molecular scaffolding protein that mediates cellular signaling from focal adhesions during interphase and at centrosomes during mitosis. Alterations in expression of NEDD9 have been shown to play a significant role in cancer metastasis of several human tumors and recent studies have shown that NEDD9 is commonly overexpressed in advanced stage serous EOC. Importantly, several oncogenic proteins that are activated by NEDD9 have also been shown to be activated or overexpressed in EOC. Among these are focal adhesion kinase (FAK), Src and signal transducer and activator of transcription 3 (STAT3), though an association of NEDD9 overexpression to activation of these proteins in ovarian cancer has yet to be established. In collaboration with Dr. Erica Golemis, the goal of our ongoing studies is to understand the cellular mechanisms by which NEDD9 overexpression influences ovarian carcinoma development, progression and metastasis and ultimately to validate NEDD9 and the signaling pathways activated by NEDD9 as targets for therapeutic intervention in ovarian cancer patients (Gabbasov, et al, unpublished data).
Network analyses identify HSP90 as a central mediator of EOC cell signaling. In collaborative studies with Drs. Erica Golemis and Lainie Martin (supported by the FCCC-PENN Ovarian SPORE), we identified a signaling network centralized around heat shock protein 90 (HSP90), which we defined as a key regulator of ovarian cancer cell viability. We have shown that an HSP90-targeted small molecule inhibitor, ganetespib, has significant efficacy in multiple EOC cell line xenograft models and TgMISIIR-TAg mice. We have identified pivotal signaling nodes disrupted by targeted HSP90 inhibition, including key tumor-associated proteolytic enzymes involved in ovarian carcinoma dissemination (O’Brien, et al, manuscript in preparation). We are currently working toward moving ganetespib from the laboratory bench into the clinical arena in an investigator initiated Phase I/II trial of ganetespib plus paclitaxel, leveraging our discovery of HSP90 as a central mediator of ovarian cancer cell growth and viability.Top
2. Mouse models and preclinical therapeutic studies
Model development: Although human cancer cell lines grown as xenografts are valuable preclinical models, therapeutic efficacy in cell line xenografts does not always predict efficacy in patients. To generate more predictive preclinical models, many laboratories are moving toward evaluation of novel therapeutics in direct ‘never seen plastic’ patient-derived xenograft (PDX) models. Our laboratory has begun to develop PDXs EOC patient ascites and tumors. The morphology, structure and protein expression PDX tumors are very similar to the original patient tumor specimen. Ongoing efforts are aimed at continued derivation of new PDX models that will be benchmarked against the human tumors by histopathologic and genomic analyses. Validated PDX models will then be used for the evaluation of novel therapeutic agents and combination therapies. PDXs that represent different individuals coupled with direct assessment of investigational drugs for EOC is likely to more accurately predict specific histological subtypes and/or individual ‘molecular profiles’ of tumors that are responsive to targeted therapeutic agents, versus those that are not. The availability of successively passaged PDX models will also provide the opportunity for discovery of mechanisms of tumor progression and drug resistance using isogenic tumors.Top
3. Small Animal Imaging
Fluorescent molecular tomography detection of integrin avb3 expression in ovarian tumors in mice
Combined fluorescent molecular tomography and magnetic resonance imaging of ovarian tumors in mice.