Six Ovarian Cancer ITRAC Projects Aim to Improve Treatment and Prevention Options
Ovarian cancer is the leading cause of mortality among gynecological malignancies. With current treatment, the majority of patients succumb to their disease. Using the ITRAC (IU Simon Cancer Center Translational Research Acceleration Collaboration) initiative, the cancer center awarded six grants to researchers leading ovarian cancer studies. The ITRAC projects aim to improve treatment and prevention options available for ovarian cancer patients by uncovering new agents and new targets that will improve the efficacy and reduce toxicity of the therapies. ITRAC is a unique and novel initiative that is being utilized by the IU Simon Cancer Center to facilitate and increase the velocity of new projects from the bench to the clinic.
One of the front-line chemotherapy regimens for ovarian cancer includes combination treatment with cisplatin and paclitaxel. However, paclitaxel often has serious side effects including degeneration of the nervous system, which may be due to unwanted action against a protein normally used in both the nervous system and in dividing cells. As an alternative Claire Walczak, PhD is pursuing a different target protein that is utilized only in dividing cells in her pilot project. She is using high-throughput assays of the Chemical Genomics Core Facility to screen for small molecule inhibitors (SMIs) in the study's target protein. In collaboration with the Dr. Kenneth Nephew laboratory, these SMIs will then be tested for their efficacy in inhibiting cell division in a series of ovarian cancer cell lines as well as for their ability to induce hypersensitivity to such agents as paclitaxel. Together these studies will uncover new agents that can then be tested in animal models of ovarian cancer and ultimately have potential clinical use for the treatment of ovarian and other cancers.
Yan Xu, PhD, will focus her pilot project on determining the role of certain enzymes in host cells on ovarian cancer tumorigenesis and metastasis. Outside the scope of this project, Xu and colleagues will also test the role of these enzymes in tumor cells and the potential interplay among tumor cells and host cells. The long-range goal of the studies and their ongoing research focus is to define mechanisms of ovarian cancer metastasis and, in doing so, identify novel targets for therapy and/or prevention. There is increasing recognition that the enzyme under investigation regulates numerous biological processes in ovarian cancer cells; the proposed studies will determine the therapeutic potential of the enzyme’s intervention by inhibiting the source in the host’s microenvironment.
Daniela Matei, MD, and colleagues found that transglutaminase 2 (TG2), a protein that is involved in cross-linking interchain glutamine and lysine residues, is overexpressed in ovarian cancer cells and tumors. The functional role of TG2 has not been studied in ovarian cancer, but preliminary data suggests that the interaction between TG2 and fibronectin is important for cancer cell adhesion and migration. Matei and colleagues also showed that the protein knockdown decreased cell attachment, cell migration and tumor dissemination in the peritoneal cavity or space within the abdomen. Based on these preliminary data, Samy Meroueh, Ph.D., Matei and colleagues will explore the hypothesis that blocking the interaction between TG2 and fibronectin, which is active at the interface between ovarian cancer cells and the tumor microenvironment, will prevent the promotion of peritoneal metastasis. In this project, they will search for small molecules that will inhibit the TG2/fibronectin interaction, with the goal of limiting ovarian cancer metastasis within the peritoneal cavity.
Death receptor-mediated apoptosis, or programmed cell death, is deficient in resistant ovarian cancer cells. Therefore, uncovering strategies to lower the threshold for triggering apoptosis may lead to novel and useful therapeutics to treat ovarian cancer. TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a promising cancer therapeutic that binds to its receptors, DR4 and DR5, and induces apoptosis. However, some ovarian cancer cells express resistance to TRAIL. The target he is studying is a major TRAIL-resistance factor in human malignancies, including ovarian cancer. Ahmad Safa, PhD, and colleagues propose to validate the novel target for developing innovative therapeutic strategies to overcome the dose-limiting toxicity of chemotherapy for ovarian cancer. This project may lead to novel modalities of ovarian cancer therapy with improved efficacy and less toxicity.
Lindsey Mayo, PhD, will investigate a novel ovarian cancer protein which is
, deleted in approximately 80% of late stage ovarian cancers. Largely, the protein has been described in prior in a system of gross overexpression in ovarian cell-induced cell cycle arrest. It is unclear exactly how it mediates this affect. Investigation of the protein playing a role in replication, DNA repair, or genomic instability has yet to be investigated. This circumstantial evidence suggests that the function of the protein is integrated into the BRCA1 tumor suppressive network. It will become important to understand how the protein functions downstream of BRCA1 by either signaling to downstream repair proteins or activating transcription factors that induce genes important for inducing cell death.
Ken Nephew, PhD, Daniela Matei MD, and Curt Balch, PhD, will conduct a phase I/II trial involving the drug 5-aza-dC (decitabine). It will monitor the biochemical response to this drug in ovarian cancer patients and identify those patients who respond to this epigenetic therapy involving the modification of gene expression. This therapy has the potential to reverse the properties of malignant tumors and their resistance to chemotherapy. Previously, Nephew and colleagues demonstrated that 5-aza-dC inhibits ovarian cancer cell growth. They investigated the biochemical effects of 5-aza-dC and showed that treatment of ovarian cancer cells with the drug results in demethylation as well as reactivation of tumor suppressor genes. They found that decitabine pretreatment of platinum-resistant ovarian cancer cells was capable of reversing drug resistance, resulting in platinum re-sensitization. This is an important concept for the treatment of ovarian cancer where platinum remains the mainstay of chemotherapy and decitabine has the potential serve as a sensitizer to carboplatin in platinum- resistant recurrent ovarian cancer. If re-sensitization to platinum occurs via demethylation of resistance related genes, Nephew and colleagues expect higher response rates and clinical benefit.