In the United States, there are approximately 23,000 new cases of ovarian cancer diagnosed per year, and over 15,000 women die from the disease. Reasons for this high lethality include the late stage at which women are diagnosed and the inherent aggressive biology of this cancer. Ovarian cancer cells are genomically unstable. They are initially sensitive to chemotherapeutic drugs but become refractory to these drugs over time. The molecular basis of platinum sensitivity and acquired resistance remains largely unknown. A better understanding of these mechanisms could facilitate the generation of new drugs that re-sensitize ovarian cancer cells to cisplatin. A significant proportion of ovarian cancers demonstrate abnormal DNA repair pathways. Some of these pathways are responsible for repairing the DNA damage caused by chemotherapy.
Our laboratory at the Dana-Farber Cancer Institute is a leading laboratory in the area of DNA repair research. We have recently shown that a particular DNA repair mechanism- namely the so-called FA/BRCA homologous recombination repair pathway- is abnormal in many human ovarian tumors. Abnormalities in this pathway result in the upregulation of a specific gene product, the Polymerase Q (aka POLQ). Interestingly, we have found that silencing or inhibition of POLQ results in increased killing of ovarian tumor cells. Hence, POLQ may be a suitable novel target for anti-ovarian tumor drug development. The purpose of this project is to analyze the role of elevated POLQ in ovarian tumor cells and to determine whether women with this specific class of ovarian tumor, which have upregulated this POLQ target protein, have a characteristic prognosis or response to therapy.
This grant was made possible in part thanks to a generous donation from Teal There’s a Cure.
Dr. Raphael Ceccaldi is in the first year of a post-doctoral fellowship in Dr. D’Andrea’s laboratory at Dana Farber Cancer Institute. He recently graduated from Dr. Soulier’s laboratory in Paris, France where he conducted translational research on Fanconi anemia, working on the molecular basis of cancer progression in those patients. In addition to his training in science, he has a doctorate degree in Pharmacy, which provides a clinical context for his translational research efforts.
He is particularly interested in understanding the molecular interaction between different DNA repair pathways. He has focused his post-doctorate research on investigating potential compensatory mechanisms associated with defects in Homologous Recombinational DNA repair observed in ovarian cancer. The identification and characterization of those mechanisms will enable a better understanding of cancer progression and potentially inform therapeutic decisions in the treatment of ovarian cancers. He received the Medal of Residency in Medical Biology, Paris Hospital (2009), the award for best translational poster at the Annual Symposium of The Fanconi Anemia Research Fund (FARF, 2011), the Award Laurette Fugain for young researchers in the field of leukemia (2011), and the National Alexandre Joël award from the “Fondation ARC pour la Recherche sur le Cancer.” (2012)