Lynn Matrisian, PhD, MBA
For 25 years, Lynn Matrisian, PhD, MBA, was a leader in cancer biology research in the School of Medicine at Vanderbilt University. She also served as president of the American Association for Cancer Research and as special assistant to the director of the National Cancer Institute at the National Institutes of Health. In an interview with OncologyLive®
, Matrisian described how her desire to have a more tangible impact on patients led her to join the Pancreatic Cancer Action Network (PanCAN) in 2011, where she leads the advocacy group’s scientific and medical affairs teams.
In its fight against pancreatic cancer, PanCAN aims to improve current survival and double survival by 2020. Matrisian described how the group pursues a combination of research, advocacy, patient support, and community activity to achieve this goal. She outlined several of PanCAN’s unique initiatives, including the Know Your Tumor program and Clinical Trial Finder. Approximately 25% of patients with pancreatic cancer have actionable alterations, and these initiatives help to identify these patients through molecular analysis and to guide treatment on the basis of that knowledge. PanCAN’s newest initiative is Precision Promise, which aims to improve outcomes for pancreatic cancer patients through a patient-centric clinical trial and research platform that continuously and rapidly evaluates novel treatment options.
Why has there been such difficulty in achieving clinical success with novel drugs in pancreatic cancer?
There are many different reasons, including the fact that it is diagnosed late, so most patients are already metastatic or will be soon. We are not good at curing metastatic disease in any cancer type. Another difficult feature is the stroma, which is unusually dense and fibrotic and has been shown to increase the pressure inside the tumor, preventing chemotherapy drugs from getting to the tumor cells. Molecularly, KRAS
is mutated 95% of the time, but we don’t have a good drug to target KRAS
activity, and KRAS
mutations prevent some drugs we do have from working effectively. Finally, it is an immunologically “cold” tumor type, and this has meant that it has not responded to immunotherapy like some other tumor types.
How is the landscape changing?
We have had some success in using chemotherapy before surgery so more patients can have their tumor removed, giving them the best chance for long-term survival. We have had advancements in all the challenging areas I mentioned. A drug has been developed that disrupts the stroma and improves the effectiveness of chemotherapy [PEGPH20]. We’ve discovered that there are molecular alterations in about 25% of pancreatic tumors that have a drug that is targeted to that alteration, and there are some initial signs that these can be effective for those select patients. Lastly, there is a lot of research ongoing to find immunotherapies that can make a cold tumor “hot.”
What are the key pathways and cellular processes being targeted for pancreatic cancer therapy?
Therapies targeting the DNA damage repair pathway, which is often defective in pancreatic cancer, stromal disruption, and immunotherapy; in particular, those focused on the complex interactions between different cell types within the immune system.
In your opinion, what are the most promising current therapeutic strategies?
I think all of the above are promising. We are particularly excited about targeting hyaluronic acid. PEGPH20 is in phase III trials right now and the phase II trials looked good. Although it’s the cancer cells themselves that started this whole process, the tumor conscripts neighbors and other cells into the process, and that can drive a tumor to become more aggressive and metastatic and to grow faster.
Hyaluronic acid is part of that stromal response to the tumor. It’s one of the components in your joints that helps give you that ability to bounce back when you walk, that sponginess. But in a tumor, it blocks the blood vessels and the tumor cells have to adapt in order to survive without having very many nutrients or much oxygen. Also, drugs designed to kill tumor cells can’t get into the tumor.
PEGPH20 delivers the enzyme that breaks down hyaluronic acid in the tumor, which relives the pressure of collapsed blood vessels and allows circulating drugs to get to the tumor cells. What I really like about the studies with this drug is that in early studies they asked if it worked for all patients or if you had to have a certain level of hyaluronic acid in your tumor before breaking down hyaluronic acid makes a difference. It turns out that not 100% of tumors have a lot of hyaluronic acid. Others have stromal involvement, but involving other proteins. I think the phase II results were very promising; it’s a molecularly driven approach, and patients are being selected on the basis of whether they are likely to respond.
What are the most significant challenges and hurdles to effective new treatments for pancreatic cancer?
The challenges include getting more patients with pancreatic cancer on clinical trials so we can test new approaches and see if they work, learning which patients are most likely to respond to what therapies, and getting all physicians across the United States to use best practices in treatment and supportive care so all patients get state-of-theart care.
PanCAN’s Patient Central, Clinical Trial Finder, and Know Your Tumor initiatives are designed to help accomplish the goal of improving clinical trial enrollment. Patient Central, our Patient Registry, and research publications contribute to education efforts. We coordinate efforts so we can use the information from patients with pancreatic cancer most effectively and efficiently to figure out the best treatments for future patients.