Ovarian cancer is the leading cause of death from gynecological malignancy. Novel treatment approaches directed against key oncogenic drivers and/or the use of a novel drug combinations to prevent/overcome platinum resistance are promising opportunities to combat this disease. Our lab has developed a strong interest in short-form Ron (sfRon) in the context of ovarian cancer pathogenesis. The sfRon is an alternative, N-terminally truncated, isoform of the Ron receptor tyrosine kinase that has been previously implicated in ovarian cancer progression. We made the striking and unexpected discovery that sfRon expression is necessary for development of carcinogen-driven ovarian tumors in mice. To our knowledge, this study is the first to show that lack of sfRon completely protects mice from ovarian cancer. Our preliminary in vitro and in vivo studies support the role of sfRon as an important contributor to ovarian cancer. Importantly, our preliminary data using a large cohort of high-grade serous ovarian cancer (HG-SOC) patients revealed that significantly more patients in the cisplatin refractory/resistant group express high levels of Ron receptors (Ron and sfRon), compared to patients in the cisplatin sensitive group. We hypothesize that sfRon plays a central role in ovarian cancer pathogenesis, and that inhibition of sfRon may reduce or prevent tumor progression and cisplatin resistance. In this proposal, we seek to investigate a new, potent anti-tumor therapeutic strategies with the potential to overcome resistance to platinum chemotherapy in high-grade serous ovarian cancer.
Specific Aim 1, we will use a panel of selected small molecule inhibitors to block sfRon signaling pathway and perform in vitro biological assays to unravel the underlying mechanism of sfRon-driven ovarian cancer progression. In addition, we will perform in vivo studies using ovarian cancer xenografts treated with sfRon pathway inhibitors to identify and optimize the best combinational treatment strategies that suppress ovarian tumor progression.
In Specific Aim 2, we will determine which of the Ron isoforms is specifically associated with platinum resistance. To identify the best treatment regimens that sensitize ovarian cancer cells expressing sfRon to cisplatin, we will perform drug dose response assays using our carefully selected panel of small molecule inhibitors that target sfRon pathway in combination with cisplatin treatment.
In Specific Aim 3, we will use a highly clinically relevant patient-derived high-grade serous ovarian cancer models to identify the most effective treatment strategies that inhibit tumor progression and sensitize cancer cells to cisplatin or prevent/delay acquisition of cisplatin resistance. Completion of this proposal will validate the role of sfRon in progression of ovarian cancer and provide a new promising therapy that has potential to benefit both chemotherapy-sensitive and -resistant ovarian cancer patients.
Our work revealed short-form Ron (sfRon) receptor as a novel contributor to ovarian cancer pathogenesis with potential role in resistance to platinum-based chemotherapy. We will use a panel of selected drugs to block sfRon signaling pathway in combination with cisplatin treatment in order to identify the best combinational treatment strategies, which in addition to anti-tumor effect will sensitize resistant ovarian tumors to platinum- based chemotherapy.
