Moon Shot helps corner aggressive-variant prostate cancer

Prostate cancer is the most common cancer diagnosed in American men, and the second leading cause of cancer death in men. While hormone-based therapies are effective for many men, there remain an estimated 20% of patients who will not benefit and have significantly worse outcomes.

These patients have a subtype of prostate cancer known as aggressive variant prostate cancer (AVPC), which does not respond to therapies that block androgen receptor (AR) signaling.

Developing a better understanding of AVPC and identifying new therapeutics options is a focus of the Prostate Cancer Moon Shot®. The effort is part of MD Anderson’s Moon Shots Program®, a collaborative effort designed to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Ana Aparicio, M.D., associate professor of Genitourinary Medical Oncology, is one of the faculty leaders of the AVPC project, and she spoke with Cancer Frontline about their work to advance prostate cancer treatment.

Q: Can you briefly describe aggressive variant prostate cancer and how it fits within the prostate cancer landscape?

A: Most prostate cancers are driven by androgens, and these typically respond very well to hormonal therapies which are the backbone of prostate cancer therapy. However, the AVPC do not respond well to hormonal therapies. They also grow and spread more rapidly, often to places prostate cancer doesn’t typically spread. Because of this, and because they have fewer treatment options, their prognosis is much worse than that of the typical prostate cancers.

Q:  What has the Prostate Cancer Moon Shot contributed thus far to our knowledge of AVPC?

A: One of the things about prostate cancer that is different from other cancers is that we don't have biomarkers that can classify it into its different subsets. If you look at breast cancer, for example, you have ER/PR-positive, triple-negative, and HER2/Neu-positive subsets, and they each have different treatments. With prostate cancer, even though we can see in the clinic that it is a heterogeneous disease, we call it one name and we treat it like it is one disease.

The problem with this is that if you have a therapy that might benefit greatly one of those subsets, but not the others, and you test it in everyone, you dilute its effect and most of the time you end up with a negative clinical trial. But even if your clinical trial is positive, you are now going to subject a whole bunch of people that are unlikely to benefit to potentially toxic treatments. Therefore, a big effort of our Moon Shot has been to try to classify the disease into its therapeutically relevant subsets so that we can make progress more efficiently.

With the support of the Moon Shot, we developed a molecular signature for the AVPC and found that men whose tumors had this signature benefitted greatly from the use of platinum-based chemotherapy. We’re working to get this molecular signature into a CLIA-certified assay so that it can be used to select patients for clinical trials and to help guide patients’ treatment.

Q: What are the primary goals for your team’s work to advance our understanding and the treatment of AVPC?

A: Within the AVPC subtype, we expect there will be heterogeneity, and we’re focused now on trying to dissect out that heterogeneity within these aggressive variants. Our overall goal is to define these different subsets molecularly and work to identify therapeutic vulnerabilities within each.

We’re looking forward to working with the Therapeutics Discovery teams to develop new medicines based on what we learn so that we have more effective treatment options for our patients with AVPC.

Q: How will that work benefit patients this subtype of disease?

A: This will be an important step in helping us to develop a therapeutic plan for our patients. There’s a distinction to be made – there is drug development and then there is therapy development, which is about how you combine or sequence treatments, which may not all be drugs.

For example, one of our questions is whether the primary tumor of a patient presenting with de novo metastatic disease, should be treated? For patients with AVPC, we think that treating the primary tumor may help to control the cancer down the line, whereas we don’t believe this is beneficial to patients with typical prostate cancer. We’re actually conducting a Phase III trial to help us answer that question.

So it’s not all about drugs. It is about optimally integrating the therapies that are available or are in development, in an effort to control the disease definitively. To this end, we need to understand what our treatments do to the biology of the tumor. Each of these treatments we’re giving to our patients is changing the biology of their tumor, so understanding what the best sequences and combinations of those treatments are, will be key to improving outcomes.

Q: What aspects of the project are you currently particularly excited about?

A: It’s all very exciting! One avenue that we have recently opened up is understanding what the particular immunological features of the AVPC are. With others on the Moon Shot team, we’re collaborating with the immunotherapy platform to define the immune profile of these aggressive variants and see how we can harness the immune system to address this subset.

Q: How has your work been enabled by the Moon Shots Program and its infrastructure?

A: The Moon Shot has been key because it’s provided a strong framework to ask the right questions and put together the right investigators. There are lots of questions related to AVPC, and I think the biggest value in my mind has been able to build that framework in which everyone is contributing their piece of the puzzle. It fosters collaboration within our team of investigators, which I think is key. We can’t do it alone.

We’ve also gotten funding support to do a number of the correlative and preclinical studies that helped us arrive at the definition of the AVPC molecular signature. It’s hard to get extramural funding for this type of research, but you need this information to generate hypotheses that lead you to the next step. I think it’s been extraordinarily valuable.