High-grade serous ovarian cancer (HGSOC) is the most common type of ovarian carcinoma and the leading cause of death from gynecological malignancy. The gold standard therapy for women with HGSOC is a combination of surgery and platinum-based chemotherapy. Although the majority of patients initially respond well to this treatment, eventually their tumors recur and become resistant to the first line chemotherapy.
PARPs are cellular enzymes that normally help our cells to safeguard genetic information kept in the genome. Treatment with drugs that inhibit PARP functions can lead cancer cells to die. The use of PARP inhibitors (PARPi) as maintenance therapy in women with HGSOC has resulted in significant prolongation of disease-free survival, particularly in women with hereditary and sporadic ovarian cancers characterized by BRCA1 and BRCA2 mutations. However, 20% of patients with BRCA1/2-mutant ovarian cancers do not respond to PARPi. In addition, many of those that do respond eventually develop PARPi resistance, thus raising important issues about: i) promptly identifying patients most likely to derive benefit from PARP inhibition, and ii) finding new and alternative therapies for PARPi-resistant ovarian cancers.
Over the last few years, our laboratory has provided major breakthroughs in the understanding of how PARP functions in the cell. In particular, we characterized cellular proteins that control PARP functions, which we know modulate the efficacy of PARPi in vitro. In this proposal, we aim to apply and translate this new information to patients, specifically for identifying novel biomarkers of HGSOC and specific drug targets.
In particular, we propose to apply cutting-edge approaches to:
I. Develop PARP-modulating proteins as biomarkers of response and resistance to PARPi, whose determination may allow stratification of patients who are most likely to benefit from PARP inhibition and those who will not. This predictive approach will contribute to personalized treatments for women with ovarian cancer, which is likely to improve survival and quality of life, and, at the same time, avoid treatments that are unlikely to work.
II. Develop PARP-modulating proteins as drug targets in a particular subclass of PARP-resistant HGSOC, which we predict may benefit from this approach.
Together, our project is a highly coordinated, hypothesis-driven, multi-disciplinary effort that has enormous implications for detection of tumors suitable or not for PARPi–based chemotherapy and treatment of resistant ovarian cancers.
Dr. Ivan Ahel is a Senior Wellcome Trust Research Fellow at the Sir William Dunn School of Pathology, University of Oxford. Ivan obtained MSc in Biology at the University of Zagreb, Croatia in 2000, before undertaking a PhD with thesis work carried out at Yale University in Prof Dieter Söll’s group between 2000 and 2003. In 2004, Ivan joined the Cancer Research UK, London Research Institute as a postdoctoral Fellow in Dr. Stephen West’s laboratory investigating novel DNA repair protein factors. He was appointed in 2009 as a Junior Group Leader at the Paterson Institute for Cancer Research in Manchester, before moving to the Sir William Dunn School of Pathology, in 2013.
General interest of Ivan’s laboratory centres on the basic cellular mechanisms underlying genome stability and the signalling mediated by the poly(ADP-ribose) polymerase (PARP) family of enzymes. In addition, the laboratory is keen to understand how defects in these processes link to human diseases such as cancer and neurodegeneration. Ivan’s laboratory has been funded by major grants from the Wellcome Trust, Cancer Research UK, Biotechnology and Biological Sciences Research Council and Ovarian Cancer Research Alliance. Since 2012 Ivan is a member of the EMBO Young Investigator Programme and he is also recipient of the prestigious 2013 Cancer Research UK Future Leaders in Cancer Research Prize.