Associate Professor of Medicine
Harvard Medical School
Clinical Director and Disease Center Leader,
Medical Gynecologic Oncology
Dana-Farber Cancer Institute
Areas of Focus: Treatment and Tumor Biology
Co-Investigators: Ross Berkowitz, MD, and Panagiotis Konstantinopoulos, MD, PhD, Dana-Farber Cancer Institute and Brigham & Women’s Hospital/Harvard Medical School, Boston, MA
- Studies are focused on improving response to PARP inhibitor therapy in breast and ovarian cancer.
- Laboratory and clinical studies are conducted to test combination approaches to improve response to PARP inhibitors.
- These studies may benefit patients with triple negative breast cancer, as TNBC tumors share common biology with ovarian cancer.
Ovarian cancer is an aggressive disease with few treatment options. A class of drugs called PARP inhibitors has been approved for treatment of ovarian cancers caused by mutations in the BRCA genes. Resistance to PARP therapy, however, reduces the clinical benefit of these drugs. Drs. Matulonis, Berkowitz and Konstantinopoulos are studying ways to increase the effectiveness of PARP inhibitors for patients with ovarian cancer as well as an aggressive form of breast cancer called triple negative.
Full Research Summary
Drs. Matulonis, Berkowitz, and Konstantinopoulos have joined forces to study the common genetic features of breast and ovarian cancers. Using information from collaborative clinical trials, publicly available data from researchers around the world, and emerging technologies, they are leveraging discoveries made in one disease to benefit the other. They then use this information to better understand drug resistance and to identify new biomarkers and therapeutic targets.
PARP inhibitors are a class of drugs that interfere with repair of damaged DNA and have been effective in ovarian cancers that harbor BRCA mutations. With the expanded use of PARP inhibitors following FDA approvals in recurrent ovarian cancer and breast cancer, the Dana Farber/ Brigham and Women’s Hospital team is focused on understanding and overcoming the underlying mechanisms that allows the cancer cell to become resistant to PARP inhibitors.
They are conducting laboratory studies to test combination strategies that if found promising will be further tested in clinical trials. Of particular interest are combinations of PARP inhibitors with other biologic agents that inhibit DNA repair that can convert a cancer cell from one that can repair DNA (and is resistant to PARP inhibitors) into one that does not repair DNA.
With the approval of olaparib (Lynarza®) for advanced BRCA breast cancer–most of which are of the triple negative subtype, findings from these studies have the potential to benefit more patients with aggressive breast and ovarian cancers.
Ursula A. Matulonis, MD, is Chief and Director of the Division of Gynecologic Oncology at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School. She is the first recipient of the Brock-Wilson Family Chair at the Dana-Farber Cancer Institute. She co-leads the ovarian cancer program within the Dana-Farber/Harvard Cancer Center. Her research focuses on developing new targeted therapies for gynecologic malignancies, with a specific interest in ovarian cancer and endometrial cancer.
Dr. Matulonis has led several PARP inhibitor, anti-angiogenic agent, immunotherapy, and combination trials for ovarian cancer in the United States and internationally. Dr. Matulonis serves on the Massachusetts Ovarian Cancer Task Force, the NRG ovarian committee, and the Scientific Advisory Board for the Ovarian Cancer Research Foundation and the Clearity Foundation. She received the Dana-Farber Dennis Thompson Compassionate Care Scholar award, the Lee M. Nadler “Extra Mile” Award, the Clearity Foundation award, and the Zakim Award at Dana-Farber for patient advocacy.
After receiving her MD from Albany Medical College, she completed an internship and residency at the University of Pittsburgh, followed by a medical oncology fellowship at the Dana-Farber Cancer Institute in Boston, MA.
Tell us about yourself as a scientist and how you became interested in cancer research. Did you ever seriously consider another kind of career than that of the sciences?
Growing up I always envisioned myself becoming a physician. This probably dated back to my mother, who wanted to be a doctor when she was a child but wasn’t allowed to go to medical school. I attended a six-year B.S./M.D. medical program and, after graduation, did my Internal Medicine residency at the University of Pittsburgh. At Pitt, I discovered that I really was interested in leukemias and malignant hematology. I then did my oncology fellowship at Dana-Farber Cancer Institute in Boston which broadened my exposure of oncology to solid tumors. During my fellowship, I worked on immunotherapy approaches towards leukemia, including chronic myelogenous leukemia (CML). That was when I really realized that I loved clinical medicine as well as the science behind it.
Directly after my fellowship, I ended up staying at Dana-Farber and saw both breast and gynecological (GYN) cancer patients. Around 2004, I was asked to lead the GYN cancers program at Dana-Farber; I saw an opportunity in GYN cancers to make progress because gynecologic malignancies have been understudied compared to other cancers such as breast cancer. More science and funding need to be infused into GYN cancers. In running and overseeing our GYN program at Dana-Farber, I wear a number of different hats. One is purely administrative, such as tending to the day-to-day operations of the program as well as more long term projects such as new patient access and fundraising for the program. The second is my clinical research hat, making sure that our clinical research portfolio is as robust as it possibly can be by offering our patients the best possible therapies and thus hope. The third is a translational research hat. Although I’m not a basic scientist, I help guide and interpret laboratory research that’s promising and exciting into something clinically translatable and usable. The bottom line is that I really love my job, and I love seeing patients, which I do two days a week. It’s a pretty busy schedule but I really do love it.
I think it’s important for the science of GYN cancers to catch up to breast cancer where there have been important strides in just a few short years. And when you look at all the GYN cancers, including ovarian, cervical, and endometrial (uterine) cancers, unfortunately, the survival rates have not substantially changed in over a decade. We are making progress, but it’s slow. So there’s so much work to be done in GYN cancers. This is what excites me about coming to work every day.
So, did I seriously consider another kind of career? No, I never did. But, my career has taken on different twists and turns over time, and what I’m doing now is not what I thought I’d be doing when I was back in med school.
Briefly describe your BCRF-funded research project. What are some lab and/or clinical experiences that inspired your work and research focus on the link between ovarian and breast cancers? What are your primary goals for this research?
This project, made possible by BCRF’s grassroots supporters affiliated with Play for P.I.N.K., resulted from a longstanding research interest of mine on the study of the BRCA1 and BRCA2 genes, which affect both ovarian and breast cancer risk. At Dana-Farber, we see many patients with germline (inherited) BRCA1 or BRCA2 mutations, and we also have many basic science researchers, like Dr. David Livingston, our fellow BCRF grantee, who work on the pure basic science of BRCA1 and BRCA2.
The ovarian cancer subtype called “high-grade serous cancer” is the most common type of ovarian cancer, and it’s also very sensitive to platinum drugs, such as carboplatin and cisplatin. Women who are diagnosed with high-grade serous cancers tend to have a higher chance of having a germline or inherited BRCA 1 or 2 mutation compared to other histologic subtypes such as clear cell or mucinous. Also, a subtype of breast cancer called triple negative breast cancer is seen more commonly in women with inherited BRCA mutations. I work closely with Dr. Judy Garber who is a colleague of mine at Dana-Farber and also a member of BCRF’s Scientific Advisory Board; she pioneered the use of cisplatin for triple negative breast cancer patients showing excellent response rates, paralleling the results of the use of platinum drugs in high-grade serous cancer of the ovary. So, all of these clinical observations prompted Charles Wang, Dirk Iglehart, Andrea Richardson, and me to look at the genetic similarities between triple negative breast cancer and high-grade serous ovarian cancer. We focused on the loss of heterozygosity (LOH), which provides a sense of the genetic instability of the cancer and found that the higher LOH, the more sensitive that cancer is to platinum. This means that the patient whose cancer has higher LOH tends to benefit more from platinum chemotherapy and has a better outcome than someone with low LOH. We examined this within our patients in Boston and in other populations of patients, including one from Australia. Our study is important because it may be a way of helping clinicians to predict the sensitivity of cancers to platinum drugs, and this really weaves together the genetic similarities between triple negative breast and high-grade serous ovarian cancer. Our findings were published in Clinical Cancer Research last year.
Currently, with our new grant from BCRF, we are examining LOH as it relates to PARP inhibitors which are drugs that block a cancer cell’s ability to repair its DNA. These drugs appear to be very effective for women with high-grade serous ovarian cancer, particularly in BRCA mutation carriers. In several phase 2 trials of PARP inhibitors, specifically olaparib, in ovarian cancer, roughly half of the women responded to this drug. PARP inhibitors do show promise in breast cancer but they haven’t been studied as much in breast cancer. We’re asking the question why some ovarian and breast cancers respond very well to PARP inhibitors and why some don’t. And secondly, could you use a test such as LOH or other genetic markers to help predict if a particular patient, regardless whether she has triple negative breast or high-grade serous ovarian cancer, is going to respond to a PARP inhibitor? We are in the process of collecting tumor samples retrospectively from a trial done at Dana-Farber for both breast and ovarian cancer patients that tested the PARP inhibitor olaparib to help us answer these questions. It may be that a specific subgroup of ovarian and breast cancers will respond better, and we just have not figured that out yet. That is exactly what our group is hoping to do.
Are there specific scientific developments and/or technologies that have made your work possible? What additional advances can help to enhance your progress?
What has helped is the drop in price of doing gene sequencing and other genetic studies; this has certainly made additional research efforts possible. I think the price tag of laboratory procedures coming down is certainly a good thing, such as the LOH and genetic work we’ve done. Whole genome sequencing is still very expensive, but for many of these genetic tests, the price decrease will help scientific progress since research budgets are being cut because of reduced grant funding, especially from government sources.
What is also important is how team science has really helped scientific developments move forward faster. One example is a trial combining the use of PARP inhibitors with a PI3kinase inhibitor that I’m the principal investigator of. This research effort has included many investigators, along with our fellow BCRF grantees, Drs. Eric Winer, Lewis Cantley, Gerburg Wulf, and José Baselga. This trial became possible because of exciting preclinical work that these scientific teams were able to accomplish thanks to the help of BCRF and other non-profits. We were able to leverage that data, even before it was published, to approach two pharmaceutical companies and ask for the drugs to run this trial. Today, everyone understands the importance of collaboration and not working in a vacuum anymore.
What direction(s)/trends do you see emerging in cancer research in the next 10 years?
We need to focus more on understanding how cancer cells become resistant to different drugs, and we need to pin down why that happens. We have to be able to detect treatment resistance at the earliest point possible so the next most effective treatments can be selected for individual patients and we can stay one step ahead of the cancer. Combining therapies is going to be really key in our research and clinical efforts, and that’s why many of my current research initiatives include drug combinations with a focus on mechanisms of resistance.
I also think that the importance of team science and collaboration will continue. Scientific teams need to include a variety of members such as basic scientists, translational investigators, patient advocates, and clinicians so that all areas of expertise are represented. Clinicians can help with translation of scientific findings as well as clinical trial design. This collaboration extends not only to individual scientists and medical institutions, but also to pharmaceutical and biotech companies. All of us including companies and academic centers will need to work together if we are going to beat cancer.
Another direction for ovarian cancer research is immunotherapy. Unlike melanoma, where immunotherapy has really blossomed, many other cancers, including ovarian and breast, have been a little bit behind. Immunotherapy is something our GYN program will be focusing on over the next several years.
What other projects are you currently working on?
My team at Dana-Farber is also looking at other novel combinations of biologic agents that may be more powerful from an anti-cancer standpoint compared to either agent alone and can possibly overcome mechanisms of resistance. I am very excited about these projects given the success of the collaboration with Drs. Gerburg Wulf, Lewis Cantley, and Eric Winer in the project that combines a PARP inhibitor and a PI3kinase inhibitor that I previously mentioned. Another project I am working on along with a large team of scientists at Dana-Farber is growing human ovarian cancer cells in laboratory models. For many years, our group at Dana-Farber has been collecting samples from our patients with ovarian cancer who develop ascites, which is excess abdominal fluid. With the patients’ consent at the time ascites is removed, their ascites is collected and the cancer cells that are retrieved are then frozen. After the cells are thawed at a later date or in some circumstances taken directly from the patient that day, these ovarian cancer cells are injected into models and we’ve successfully been able to grow them. We’re now starting to test different combinations of targeted agents; these preclinical studies can be done quickly since the tumors grow quickly. Our ultimate goal is to devise interesting and successful combinations of agents to serve as a preclinical basis/data for a future clinical trial.
How close are we to preventing and curing various forms of ovarian and/or breast cancer?
To prevent ovarian cancer, we may have a potential avenue besides the standard of care for BRCA-carriers, which involves surgery to remove both ovaries and fallopian tubes.
Dr. Ronny Drapkin at Dana-Farber discovered an ovarian cancer precursor called Serous Tubal Intraepithelial Carcinomas (STICs) which are located at the end of the fallopian tube which is the part closest to the ovary. These STICs appear to be the precursor for the most common type of ovarian cancer, high-grade serous ovarian cancer. Because the fallopian tube drapes over the ovary, the fallopian tube cells that become cancerous are shed and then stick to the ovary. Dr. Drapkin’s lab is now studying how a normal fallopian tube can become cancerous. As a way of preventing ovarian cancer in high risk women (i.e. BRCA mutation carriers), it may be possible to remove just the fallopian tubes, instead of both the ovaries and tubes, which is the standard practice today. Obviously this has to be studied better to make sure it’s safe and effective, but this may be the future. This approach may simultaneously reduce a woman’s risk of developing ovarian cancer and also save her from going through extensive surgery and significant side effects, such as early menopause especially in younger patients.
Curing cancer will be harder but is something we all need to strive for. I think curing patients really has to do with finding the Achilles’ heel within cancer cells. We have several new drugs, such as PARP inhibitors and PI3K inhibitors as well as other targeted agents, which are promising in ovarian cancer, even against recurrence. Because cancer cells use many different ways to survive in the human body, we’re going to need to target several mechanisms simultaneously that allow cancer cells to survive such as important signaling pathways within the cell, the cell’s microenvironment which may help them hide from treatment and allow them to survive, and helping the immune system to fight off cancer, just to name a few.
In your opinion, how has BCRF impacted cancer research?
I think BCRF is a great organization. Through the annual meeting, BCRF brings together people who are very collaborative and team-oriented with the goal of really making inroads into cancer research, beyond breast cancer and also both in terms of treatment and prevention. So I think BCRF has had a huge impact.
In this day and age of reduced funding, I often see scientists leaving labs, some labs cutting back personnel, young scientists migrating to companies where jobs are available, or young and even older scientists leaving science altogether. Why this is happening is because funding has greatly diminished for their research. The sequestration and the NIH budget cuts are having a significant impact on scientific and medical progress for this generation and the next generation, because people are being pulled away from basic science and we are losing people who are doing really good science. We are poised to make huge advances in cancer treatment, and the timing of NIH budget cuts couldn’t come at a worse time. So for BCRF to have such a pure motive and give such high percentages of its revenue back to science and researchers, is truly impressive. I really wish we had something like this in ovarian cancer and other GYN cancers, because it would do a huge amount of good. BCRF is allowing researchers to keep doing their important work and is emphasizing the message that funding science leads to improved cancer treatment. It’s important for donors to understand the importance of BCRF and how crucial this organization is for finding better cancer treatments that will eventually one day lead to eradication of breast and other cancers.