Interdisciplinary Initiatives Program Round 9 - 2018
Erinn Rankin, Radiation Oncology and Obstetrics & Gynecology
Sarah Heilshorn, Materials Science & Engineering
Oliver Dorigo, Obstetrics & Gynecology
Our long-term goal is to identify and develop novel therapeutic strategies for the treatment of recurrent chemoresistant HGSOC. Ovarian cancer is the 5th leading cause of cancer related deaths among women in the United States. Despite advances in surgical and cytotoxic therapies, there remains a significant unmet need for effective therapies in the treatment of ovarian cancer. The majority of women (70%) diagnosed with high-grade serous ovarian cancer (HGSOC) present with stage III or IV disease in which the tumor has disseminated beyond the ovaries and pelvic organs to the peritoneum and abdominal organs including the diaphragm, stomach, omentum, liver, and intestines. While the initial clinical response of ovarian cancer patients to surgical debulking and platinum-based chemotherapeutic agents is often positive, 80% of patients with advanced HGSOC develop recurrent, chemoresistant disease resulting in a 5-year survival rate of 30%. Thus, alternative options for the treatment of chemoresistant disease are urgently needed.
The mechanisms underlying chemoresistance in HGSOC are poorly understood. Most studies have focused on tumor intrinsic factors including genetic alterations, apoptosis, and drug metabolism, none of which has offered an efficient route to alleviate chemoresistance. Meanwhile, there are increasing reports on altered extrinsic factors throughout the development of tumors and metastases. This includes changes in the tumor microenvironment (TME) such as hypoxia, remodeling of the extracellular matrix (ECM) and increased deposition of ECM components. Importantly, these changes have recently been associated with poor patient survival and immune suppression in HGSOC. However, the changes that specifically occur within the HGSOC metastatic microenvironment during chemoresistance have not been defined or exploited therapeutically. To address this unmet need, we propose that we will 1) integrate a unique set of advanced technologies including coherent anti-Stokes Raman Scattering (CARS) microscopy to define the molecular, cellular, chemical, and structural features of the chemoresistant ovarian TME within human clinical samples and a unique murine model of HGSOC chemoresistance and based on that 2) develop in vitro 3D models of the HGSOC chemoresistant TME that will enable hypothesis-driven and mechanistic studies to elucidate the interplay between the TME and cancer cells in HGSOC chemoresistance, leading to identification of therapeutic targets. These studies will (a) identify novel mechanisms of chemotherapy resistance in HGSOC mediated by the TME; (b) develop three-dimensional (3D) matrices complemented with co-cultures of tumor-immune-stromal cells that define the chemotherapy-treated TME; (c) have the potential to lead to intellectual property on a novel 3D culture platform for screening drugs for chemoresistant HGSOC; and (d) eventually lead to the identification of novel therapeutic strategies to reverse resistance to platinum-based drugs.