Ovarian Moon Shot team battles highly recurrent disease

September is Ovarian Cancer Awareness Month, an annual time to bring attention to the impact of the disease. This year, more than 22,000 women will be diagnosed with ovarian cancer and roughly 14,000 will die from the disease, according to the American Cancer Society. It ranks fifth in cancer deaths among women and accounts for more deaths than any other gynecologic malignancy.

Despite the emergence of new targeted therapies in recent years, the majority of patients will develop recurrent disease that becomes resistant to available drugs. In response, MD Anderson’s Ovarian Cancer Moon Shot™ team is working on innovative treatment strategies that will yield lasting results and cures for more patients. The effort is part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Shannon Westin, M.D., associate professor of Gynecologic Oncology and Reproductive Medicine and co-leader of the Ovarian Cancer Moon Shot, is directing clinical and research efforts to uncover mechanisms of disease resistance and identify new treatment options that will be effective in these patients. She spoke with Cancer Frontline about her research.

Q: What is the current impact of ovarian cancer and how has this changed over time?

A: Ovarian cancer is the second-most common gynecologic malignancy, and what's important to know is the incidence has changed very little. We have not made major strides in reducing the incidence of ovarian cancer — it has remained quite stable. Approximately 22,000 women will be afflicted with the disease this year.

What's most concerning about that, of course, is that the majority of those patients will die. It's the most lethal gynecologic malignancy, and the mortality rates have remained very stable. We've made progress in the expansion of treatment options and with keeping people alive longer, but we have not increased our cure rates.

Q: What are the biggest challenges for treating ovarian cancer?

For a new diagnosis of ovarian cancer, treatment generally will be a combination of surgery and chemotherapy. What we have struggled quite a bit with the order in which patients should receive those therapies. Should they get the surgery first or the chemo first, and which patients should get what treatment? We know that the one-size-fits-all treatment paradigm does not work.

Now we're also working out maintenance strategies. We know that about 80 percent of the time, after a combination of chemotherapy and surgery, the disease is gone clinically. However, about 70 percent of the time, it will recur.

Therefore, we’re trying to implement new maintenance strategies and identify new targeted therapies that potentially can help extend that time, to keep that cancer away, to basically get that patient to a cure.

The other issue is knowing the appropriate treatment when patients recur. We've had great successes over the last three or four years with some of the targeted therapies such as PARP inhibitors and bevacizumab. They've gotten FDA approvals and they're clearly active, and now most patients will receive them at some point in the cancer continuum. So we know there's going to be the development of resistance. That's one of our major Moon Shot projects, to explore mechanisms of resistance to these treatments and how to overcome that resistance to extend that benefit for these patients.

Q: Can you explain how your Moon Shot team is working to improve the management of recurrent disease?

We have been able to create a series of trials that are designed to overcome resistance to either PARP inhibition or bevacizumab, an anti-angiogenic.

Specifically, from the PARP inhibition standpoint, we have taken advantage of our novel trials to conduct a series of studies on untreated human tissue. Basically, we’ve looked at the change in this tissue after PARP inhibitor treatment and identified which pathways appeared to be activated. Our thought is those pathways potentially could be mechanisms of resistance. Then we take that clinical data back to the lab to ask, “OK is this in fact what we’re seeing? Is this pathway important?”

Utilizing these mechanisms, we established the Combinatorial Adaptive Resistance Treatment (CART) platform. The CART platform enables us to use tissue from patients, then go to cell lines, and then back to patients. Using this, we've been able to identify a series of potential mechanisms of resistance, and now we're taking that to the clinic. 

We start with early phase trials to make sure we can target these pathways safely and then push that out into a larger scale phase II trial where we put our hypotheses to the test. We take someone that's become resistant to PARP and treat them with one of our novel combinations and determine if we can overcome that resistance.

Q: What successes have you seen from your work thus far, and what ongoing or future projects are you excited about?

We just completed our very large Phase IB trial, investigating a combination of a PARP inhibitor with two agents targeting the PI3K pathway. We saw great successes, patient by patient. We saw people that were previously resistant to PARP inhibitors, or had no reason that their tumor would respond to PARP to begin with, that had sustained responses.

I have a patient that's been on for almost four years now. This was a woman who had multiple recurrences, multiple lines of terapy, somewhere around 5 or 6 prior lines of therapy. Now she's living her life. She's going around and teaching people about this now. Those are the kinds of successes we're seeing. 

Also from that particular trial, we were able to build our next trial. We now have a trial which combines PARP inhibition with a MEK inhibitor in appropriately selected patients. It's so great to see the research not only makes an impact on the patient but also is building the next trial and the next step of these evaluations.

Q: How has the Moon Shots Program enabled you to conduct novel trials and projects in a way you weren’t able to previously?

It’s important to do the clinical piece, there’s no doubt about that. But we need to be forming and planning our next steps. It's not enough to say we have a great new combination therapy. We need to understand why it works, who it works for, and what options are available when it doesn’t work.

We couldn't do that without the Moon Shots Program. We just couldn't. It gives us a strength and ability to do the really novel and extensive translational piece to this research that then informs what we should be doing next.

The Moon Shots Program also allowed us to build some really amazing industry collaborations. Our industry partners typically help fund the clinical trials, but the Moon Shots provides funding for all the translational, more interesting stuff. It’s hard to get industry or grant funding for that part. We’re often scrambling to support that research – to do the important part — and the Moon Shots Program has made that possible.