At the 2023 Society of Gynecological Oncology’s Annual Meeting on Women’s Cancer in Tampa, Florida, Michael Goodheart, MD, and Adam Dupuy, PhD, University of Iowa, Iowa City, Iowa, discuss the use of CRISPR technology to identify new potential treatment combinations for low-grade serous ovarian cancer.

Drs Goodheart and Dupuy discussed the limitations of animal models when studying ovarian cancer which led them to the use of CRISPR technology to identify kinase deletions which might synergize with trametinib treatment, with the aim of finding new drug combinations or targets.

Transcript

Michael Goodheart:

Hello, my name is Michael Goodheart. I'm a gynecologic oncologist at the University of Iowa, and I'm here with collaborator Dr Dupuy. We've worked together for probably greater than 10 years, working on a wide variety of gynecologic malignancies. He's a basic scientist. I'm a clinician. We have a fellowship program where our fellows come into his lab and work. We are here at the 2023 SGO Annual Meeting on Women’s Cancer in Tampa, Florida learning, and we have some posters and talks.

Adam Dupuy:

I'm Adam Dupuy. I have a PhD and Masters in bioinformatics. My lab is mostly focused on cancer genetics in a variety of tumor types. Through our collaboration with Dr. Goodheart, we've been involved in several gynecologic oncologic malignancies including recently low-grade serous ovarian cancer. The successful trial with trametinib was what got us interested in low-grade. Part of my lab also does research in melanoma, which is another sort of classically MAP kinase driven malignancy that's quite effectively treated with kinase inhibitors, BRAF and MEK inhibitors.

We were curious about low-grade serous ovarian cancer. While the mutations are similar [to melanoma], the response to these drugs is not. We were presenting a poster here at SGO describing a strategy where we took a panel of low-grade serous ovarian cancer lines, treated them with trametinib. Then using CRISPR technology, deleted every kinase in the genome to see which kinase deletions would synergize with trametinib treatment to try and find new drug combinations or drug targets that would work effectively in combination with trametinib. That's the work we're presenting here.

Dr Goodheart:

We clearly know that there's a large difference between high-grade serous ovarian cancers, which is what we usually see, versus low-grade serous cancers. Low-grade serous cancers are usually defined as about 10% of the serous cancers. They typically do not respond favorably to chemotherapy. Surgical cytoreduction is a huge component of the treatment. Then after that, we're a little bit unsure as to where to go. Hence, the reason why I think it's important for clinicians and basic scientists to collaborate on this.

We provide tumor samples and patient information to Dr Dupuy and his team, and then we work collaboratively on these efforts together. I think that's an important thing. I think that most of these tumors are not as responsive as we wish we would to the therapies that we have, so trying to find newer and better therapies is always important for patient care.

Dr Dupuy:

Then from my perspective, I'm quite interested in the biology of ovarian cancer. To step back, in the melanoma field, we were 15 years ago in the same place as we are with ovarian cancer. There are not very many effective treatments. The 5-year survival was quite low, and then 2 things happened. There is the realization that BRAF mutations are the initiating mutation in half of tumors, and then immunotherapy happened. Those 2 things really shifted things in melanoma. I feel like ovarian cancer is just waiting for that sort of breakthrough discovery to try and figure out what is the underlying biology.

Part of the struggle has been that Dr Goodheart and I struggled for years to build animal models of ovarian cancer. It was a real tough nut to crack. We never got there for a whole host of technical reasons. The mouse ends up being just not a tremendous model for ovarian cancer. That's really held back sort of more of the basic science stuff that we could do that's been beneficial for our other types of cancer. We've had to pivot and go to other models, xenograft models and such, where we can start to delve into the basic biology. Hopefully, we can get there. We can make some basic insights that will improve these outcomes.

Dr Goodheart:

I agree. We have worked for years to try to make these animal models that just, again, never really worked out. But I think that hopefully, we've got some exciting information and some data. We'll see, we'll see. Hopefully, we can push patient care forward and come up with some better treatment strategies for these patients.

Dr Dupuy:

From my perspective as a cancer geneticist, I look at cancer always through the genetics lens. In my view, what we understand about ovarian cancer BRCA deficiency, deficiency in homologous repair, these things likely just enable other mutations that are potentially the oncogenic driver of the disease. Unfortunately, Cancer Genome Atlas analysis exome sequencing did not identify a major target, except in some rare subtypes like endometrioid ovarian cancer, KRAS mutation, PTEN deficiency.

In high-grade serous, there's no clear mutational target that is the predominant biological driver. We have some suspicions about what that might be and how we could get that information. For low-grade MAP kinase pathway mutations, they're common. Biologically, it's not clear if they have the same role in low-grade serous ovarian cancer as they do in other epithelial malignancies. We have some suspicions that that might not be the case. The way they respond to the inhibitors is not very similar, and the propensity for multiple MAP kinase mutations is unusual in epithelial cancer. We suspect there might be something different about that pathway in low-grade serous ovarian cancer.

Dr Goodheart:

Clinically, we really struggle to treat these patients. They typically are anywhere between 10 to 20 years younger than our high-grade serous ovarian cancers. Surgical cytoreduction is an important part of that. It's one of the things that we know unfortunately what doesn't work, but we're not exactly sure what does work. We still treat these patients with classic cytotoxic chemotherapy that we use for high-grade serous cancers, but it unfortunately just doesn't work as well.

There is a fair amount of data that would suggest that some type of hormonal manipulation because most of these tumors do have some type of steroid receptor positivity, so placing them on some kind of hormonal manipulation is also standard of care. I think that we've still got a lot of ways to look at this and hopefully a lot more alternative therapies that we can come up with. Because our toolbox of how we treat these patients is just very, very limited unfortunately so.

Dr Dupuy:

In terms of collaboration, one of my other roles at the University of Iowa is I'm the director of the cancer biology program. I'm often looking for opportunities with students to put together translational research projects. I've found that in gynecologic oncology, our group there is very heavy on the surgery side. That's a very demanding specialty. The time they have available for collaboration and development, honestly, to develop the skills necessary to run a competitive research program for National Cancer Institute funding, et cetera, that’s an unrealistic expectation. Collaboration is really the best way to make that happen.

For us, what has worked best is to have frequent meetings and develop collaborations where we get ideas from talking to the clinicians about what the needs are clinically. Then we go back and think about projects that could move the bar there.

Dr Goodheart:

Yes, I agree. Again, I'm the fellowship director at the University of Iowa for our gynecologic oncology fellowship. Part of the requirements of that 3-year fellowship is a year doing some kind of research project. A large portion of our fellows do come into the lab experience in Dr. Dupuy's lab and work with their grad students and postdocs. That gives them a flavor of the painstaking amount of work that goes in to develop a drug.

There's just so much work that goes into it. It's unbelievable. But I think they get a nice flavor of that, they can help, they get a nice project out of it. I think this collaboration that we've had for 10-plus years is good synergy between both of us. Both the clinicians and the basic scientists get a lot out of it.