A study published in the journal of Nature Communication is an important breakthrough in furthering more personalized care and matching the right type of treatment to each individual patient.
Over the last three decades, ovarian cancer survival rates have seen very little improvement. The current five-year survival rate for ovarian cancer is 43%, a low percentage that is a result of the fact that this type of cancer is difficult to detect and often goes undiagnosed until it has reached an advanced stage. Like multiple other types of cancers, research shows that it is not a simple single disease, but rather numerous diseases driven by a wide range of molecular alterations.
Now, a new study reveals that more targeted treatment options is part of the answer to tackling this ‘silent killer’. The study, published in the journal of Nature Communications, is an important breakthrough in furthering more personalized care and matching the right type of treatment to each individual patient.
“Switching off” the gene
BRCA1 is a human tumor suppressor gene. Mutations in this type of gene predispose individuals to developing ovarian and breast cancer at younger ages, as opposed to that of the general population. Seeing as how the BRCA1 gene is responsible for repairing DNA, the occurrence of mutation may lead to the improper repair of DNA, which can ultimately lead to the development of cancer.
For individuals diagnosed with ovarian cancer with this “faulty DNA repair”, a group of drugs known as PARP inhibitors have been effective, but not for everyone. “This drug has been around for over 10 years now and it has been a very exciting development because it’s the first targeted drug used in ovarian cancer and has shown a lot of promise in patients with ‘faulty DNA repair’” said Dr. Olga Kondrashova, lead researcher of the study and postdoctoral fellow at the Walter and Elza Hall Institute of Medical Research in Parkville, Australia.
Other researchers involved in the study included Professor Clare Scott, Dr. Monique Topp, and Dr. Matthew Wakefield from the Walter and Elza Hall Institute of Medical Research, in partnership with Alexander Dobrovic, associate professor from the Olivia Newton-John Cancer Research Institute and LaTrobe University School of Medicine.
The research team aimed to understand why PARP inhibitors were not effective for all patients with BRCA1 methylation, a molecular correspondent of BRCA1 mutation. Methylation, also known as molecular silencing, is an epigenetic signaling tool that can stimulate genes in the “off” position.
A “Eureka” moment
Dr. Kondrashova and fellow colleagues looked at a small number of tissue samples (before and after treatment) from 12 patients at the Royal Women’s Hospital in Melbourne, the Peter MacCallum Cancer Centre, and the Royal Melbourne Hospital. “Rather than studying a lot of patients, we studied a few in great detail” said Dr. Kondrashova.
Using patient-derived xenograft models, which are models of cancer that have been refined so they are pure cancer cells, the team observed differences in the patients’ epigenetics. “Like ‘snap shots’ in time, PDX models allow us to accurately track how each patient’s cancer is changing or responding to treatment. The success of this approach shows that a long-term, detailed analysis is invaluable for providing better patient care” said Professor Scott.
As a result, the researchers were able to divide the patients into two separate groups. The first group of patients had complete methylation on all copies of BRCA1 genes in their cancer, meaning that the gene had been completely switched off. The other group of patients only had partial methylation, meaning that the gene had been partially switched off. “If you’re just looking at a surgical sample, which most previous studies have done, the normal cells can mask the methylation signals. But in our models, we could look purely at the cancer cells, which allowed us to observe these two separate states of methylation” said Dr. Kondrashova.
As it turned out, partial methylation is not sufficient enough to trigger faulty DNA repair in cancer cells, which explains why the PARP inhibitor was ineffective in that specific group of patients. “At the same time, those in the group who had ‘complete’ BRCA1 methylation in their cancer were responsive to PARPi confirming to us that the treatment should not be discounted” said Dr. Kondrashova.
The research team suspected that in the second group of patients who had partial methylation and who did not respond to the drug, the cancer may have been resistant due to response to chemotherapy. “We think they might have actually had complete methylation, with the BRCA1 gene switched off, at an earlier stage of the disease, but that has changed in response to chemotherapy, which is always the first course of treatment” said Dr. Kondrashova. “We’re looking into designing a clinical trial that will be done earlier in the disease, ideally before this resistance has developed, to test if this is the case” she added.
Paving the way for better patient care
While the findings were directed at ovarian cancer, in theory, they also show promise in the area for breast cancer treatments, where BRCA1 methylation is also seen. Currently, the researchers are involved in a phase II trial, known as the EMBRACE study, which is testing the oral drug olaparib in the treatment of HR-deficient metastatic breast cancer and relapsed ovarian cancer in patients without BRCA1/BRCA2 gene mutations.
Further research also aims to discover better, personalized treatments for ovarian cancer. “There is no ‘one size fits all’ approach for ovarian cancer care. We need to keep making these strides in understanding so we can better match patients with the right treatment for their cancer” said Prof. Scott. At present, the researchers are looking into using combination treatments. They are involved in a clinical trial that is looking at combining a PARP inhibitor with immunotherapy, where the immune system of the body can be ‘reprogrammed’ to tackle the cancer.
Although chemotherapy is likely to remain the number one treatment option for ovarian cancer for quite some time, the ultimate goal is to develop more personalized treatments that can be used earlier in the disease. “It can take time for research discoveries to translate into a clinical setting. But our research adds to a lot of exciting discoveries in ovarian cancer, and I would hope to see improvements in its survival rates in the not-too-distant future” said Dr. Kondrashova.