Roles of STAT1 and STAT3 in Mediating Ovarian Cancer Progression and Treatment

Rationale, Objective, and Aims: Ovarian cancer is the most lethal form of gynecological cancers and is the fifth leading cause of cancer-related deaths in women. Therapeutic management for nearly all newly diagnosed ovarian cancer patients includes debulking surgery and aggressive chemotherapy. Fortunately, the majority of patients initially respond to these treatments; however, recurrence is inevitable for approximately 75% of all women. Following recurrence, treatment options are extremely limited, prognosis is grim and patients rapidly progress and ultimately die of their disease. For these reasons, it is critical to identify new treatments that are effective in both chemotherapy-sensitive and -resistant forms of the disease that elicit minimal side effects, are well tolerated by women, and significantly extend overall survival and ideally cure some of our patients. Towards this goal, we conducted a small molecule drug screen and identified a compound called lestaurtinib that rapidly induces cell death across a panel of sensitive and resistant ovarian cancer cell lines and patient derived xenograft models. Lestaurtinib has been shown to have a low toxicity profile in humans, but has never been studied in the context of ovarian cancer. Mechanistically, we found that lestaurtinib suppresses JAK/STAT signaling in these cells to suppress proliferation and induce cell death.

Based on these and other findings, we hypothesize that selective and precise inhibition of JAK/STAT signaling represents a robust and durable approach for the treatment of ovarian cancer. To address this hypothesis, we propose three specific aims. In Aim 1, we will elucidate the molecular mechanisms by which STAT1 and STAT3 independently function to support ovarian cancer cell viability and growth promotion. In Aim 2, we will determine the effects of JAK/STAT signaling on cancer cell/stroma cross-talk, drug-responsiveness, and ovarian tumor growth. Finally, in Aim 3, we will evaluate STAT1 and STAT3 protein levels in ovarian tumors and determine their association with clinicopathological features, chemotherapy response, and long-term patient outcomes.

Critical Problems Addressed: We will address multiple critically important problems through completion of the proposed studies:

1. We do not currently understand the ways in which ovarian cancer cells and tumors develop resistance to various forms of chemotherapy and PARP inhibitors. A handful of genetic alterations and mutations have been identified and are causally linked to resistance, but these are found in the minority of patients. Given our discovery that components of the JAK/STAT pathway are highly expressed and active in chemotherapy and PARP inhibitor resistant models, it is possible that this pathway drives resistance and therefore serves as a viable therapeutic target to treat or reverse resistant forms of ovarian cancer.

2. The large majority of preclinical studies fail to consider the roles of the tumor microenvironment in mediating drug response. Cancer-associated fibroblasts represent a predominant cell type in the tumor microenvironment of ovarian cancers and are known to express high levels of proteins that act on cancer cells to induce JAK/STAT pathway activity. Therefore, it is essential to better understand the roles of cancer associated fibroblasts in mediating resistance to standard-of-care therapies, to carefully determine how cancer associated fibroblasts communicate with cancer cells to regulate the JAK/STAT pathway, and to identify how drugs that target JAK/STAT signaling impact the tumor promoting functions of these fibroblasts.

3. Unfortunately, the large majority of clinical trials are deemed a failure due to low response rates or intolerable side effects. The success of clinical trials can be substantially improved through the development and use of clinically relevant biomarkers that will allow for the identification of patients most likely to respond to a given drug. As part of this application, we will identify biomarkers of the JAK/STAT pathway that predict response to JAK/STAT targeting drugs. We will also assess their expression profiles in ovarian tumors and determine their associations with specific tumor characteristics and patient outcomes. Ultimately, these studies will aid in precision medicine approaches for the stratification of patients in future clinical trials that utilize JAK/STAT targeting drugs.

Innovation: This proposal is highly innovative and will use cutting-edge and state-of-the art technologies to address critical problems in ovarian cancer. Broadly, JAK/STAT signaling is understudied in this disease and no one has examined the differential roles of STAT1 vs STAT3 in disease progression and response to therapy. Further, it is not understood how different phosphorylation profiles on these STAT proteins impacts their mechanisms of action. Clinically, only one JAK/STAT targeting drug (ruxolitinib) is been tested in clinical trials for ovarian cancer patients. Problematically, our preliminary data have demonstrated that this compound is ineffective even when utilized at high doses. Mechanistically, no studies have evaluated the precise functions of STAT1/3 in the tumor microenvironment of ovarian cancers, nor have they determined how STAT1/3 activity in the tumor microenvironment affects response to standard-of-care therapies or JAK/STAT targeting drugs. These research directions and clinically relevant issues highlight the innovative aspects of this proposal.

Relevance to OCRP and Impact: This application is directly in line with the vision and stated goals of the OCRP. We propose high-impact and cutting-edge research that directly addresses multiple unmet clinical needs. Funding of this proposal will improve our understanding of the progression of multiple types of ovarian cancer and will evaluate the roles of the tumor microenvironment in mediating progression and drug response. Further, our research utilizes precision medicine and computational approaches and seeks to develop and validate novel predictive biomarkers that will lay the groundwork for future clinical trials. Finally, support from the DOD will enhance the pool of ovarian cancer scientists, given my laboratories' very recent entry into this field of research.