Held in Toronto from May 15th – 18th, 2010 in partnership with Gynecologic Oncology Canada (GOC) and Ovarian Cancer Canada (OCC), this meeting was uniquely dedicated to presenting all aspects of ovarian cancer research within Canada and around the world, and provided an exceptional forum in which all ovarian cancer researchers, from scientists to clinicians, could present and discuss their recent work. The conference featured renowned Canadian and international researchers presenting in symposia ranging from biomarker discovery and validation, cells of origin and models of ovarian cancer to susceptibility, risk factors, novel therapies, and current and emerging clinical trials for ovarian cancer. Two exciting workshops brought together expert physicians and scientists and provided a national forum in which to discuss the latest challenges facing banking of tissue, blood and fluid specimens for research purposes and in the successful management of clinical trials as we enter the era of molecular medicine and targeted therapies. The main conference was preceded by a highly-successful, interactive, one-day workshop for trainees, and introduced a well-received half-day workshop for survivors and their caregivers.
The outstanding quality and impact of the research presented was truly inspirational; the knowledge gained in the four days will surely bring the field ever closer to understanding how ovarian cancer develops, and how to stop it dead in its tracks. Featured in this article are studies by two renowned researchers making headlines for their work on ovarian cancer. Dr. Alan Ashworth, PhD, a Professor of Molecular Biology and Director of The Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research in London, UK, presented his work on the new class of drugs called PARP inhibitors currently in clinical trials for ovarian cancer; and Dr. Christopher Crum, MD, Professor of Pathology and Director, Women’s and Perinatal Pathology at the Brigham and Women’s Hospital in Boston, USA, presented his findings in support of the theory that high-grade serous ovarian cancers originate in the fallopian tube.
Leaving ovarian tumours without a leg to stand on
Mutations in the BRCA1 and BRCA2 genes are known to confer significant hereditary risk factors for developing ovarian cancer. From several years of fundamental research, we now understand that the cellular process that BRCA1 and BRCA2 control in normal cells is the accurate repair of DNA damage. There are several different ways that a cell goes about repairing damaged DNA, with the BRCA genes being involved in one of the most critical ones. It is from this knowledge that a new idea has emerged and can be applied to targeted therapeutics in ovarian cancer. If an ovarian tumour has mutations in BRCA genes, then the other less-efficient DNA repair pathways are still working in the cancer cells to try and keep these malignant cells alive. An alternative DNA repair pathway which is present in ovarian cancer cells uses a molecule called PARP. Research out of Dr. Ashworth’s laboratory has developed new drugs called PARP inhibitors and tested them in cancers where BRCA function is lost. In fact, cells that have lost BRCA function are hundreds to thousands of times more sensitive to PARP inhibitor treatment and these cells die. However, the other normal cells and tissues of the body are insensitive to PARP inhibitors because DNA repair controlled by BRCA is still partially functional.
At first glance this would imply that women with ovarian cancer and known BRCA1 or 2 mutations would be the only ones to benefit from this new PARP inhibitor drug. However, it has been identified recently that over half of ovarian tumours, particularly the most common and aggressive high-grade serous subtype, have found other ways of shutting down the BRCA1 or BRCA2 genes. This has been defined by researchers in the field as the “BRCAness” of ovarian tumours, often reflected in the generally unstable nature of DNA in these cancer cells. Given that, PARP inhibitors have great potential to be effective in a broader application to many if not all high-grade serous ovarian tumours.
The exciting future potential of PARP inhibitors was further purported by Dr. Ashworth in his presentation. For example, the utility of PARP inhibitors in other ovarian cancer types could be discovered by testing them in tumour cells with different gene mutations (e.g. the PTEN gene that is frequently mutated in endometrioid ovarian cancers). Another particularly attractive idea would be to incorporate a biomarker screening test to detect an ovarian tumour’s response to DNA damage and thereby expose its Achilles heel. This would have the power of predicting which patients would be best treated with a PARP inhibitor drug due to the underlying defects in DNA repair in their ovarian tumour.
With the testing of PARP inhibitors making its way through early clinical trials in ovarian cancer patients, it is exciting to envision its future impact on the survival of women with ovarian cancer.
Uncovering the hidden origin of high-grade serous ovarian cancers
An ever-present issue with ovarian cancer is that it is very difficult to detect at an early stage, partly because how it develops is still largely unknown. However, if detected early, women have a much greater chance of survival. Therefore immense efforts are being invested into identifying the cells or tissues that could give rise to ovarian cancer, in the hopes of developing diagnostic tests and screening strategies to detect early ovarian cancers, where the prognosis is much improved.
High-grade serous tumours are the most common type of ovarian cancer, but also show the worst survival. Women carrying a mutation in the BRCA1 or 2 genes are at higher risk of developing this type of cancer. On the other hand, advances in genetic counseling and testing for BRCA gene mutations has identified many women at risk for developing ovarian cancer but who are still asymptomatic (showing no overt signs of disease). In many cases, to prevent the development of ovarian cancer, these women are counseled to have their ovaries and fallopian tubes surgically removed after having children (around age 40). This presents a unique window of opportunity for ovarian cancer researchers to carefully study these organs, even though no cancer may be easily seen, in order to pinpoint where and how ovarian tumours could develop.
Dr. Crum and his research team has developed the SEE-FIM protocol (Sectioning and Extensively Examining the Fimbriated end) to microscopically examine the ovaries and the ends of the fallopian tubes closest to the ovaries to identify any abnormal cells, which could indicate the early formation of a tumour. In fact, they have identified in a high percentage (80%) of these otherwise asymptomatic at-risk women, very small defects that resemble early serous ovarian cancers. Fallopian tubes of women with confirmed high-grade serous ovarian cancer were also carefully examined, and small tumors were indeed found in the fallopian tube. The cells in these early defects of the fallopian tube have the same mutations in the p53 gene (a gene commonly involved in ovarian cancers) as in neighbouring ovarian tumours, and Dr. Crum’s team has now defined this as “the p53 signature”. This signature can help them in identifying very early cancer cells at the molecular level, even before there is presence of a small tumor. Dr. Crum’s findings demonstrate that for women carrying BRCA gene mutations, their ovarian cancers may in fact originate from the fallopian tube and not the ovary.
His extensive evidence on early ovarian cancers has turned the research field on its head, and forced researchers to literally “think outside the ovary” when contemplating the origins of ovarian cancer. Dr. Crum’s landmark studies have expanded into broader implications for all high-risk women for other types of ovarian cancers too. To address this gap in knowledge about the role of the fallopian tube in the early ovarian cancer, Dr. Crum has initiated the Pelvic Ovarian Cancer Interception Project (Point Project), an international consortium involving gynecological oncologists and pathologists, formed to collect and study more tissue samples from at-risk women. This new and promising area of research could lead to the development of new screening strategies to recognize and treat small tumours in the fallopian tube, ultimately improving the prognosis of women with ovarian cancer.