Patrick Ma: Undaunted by Two Pandemics

Back in 2003, Patrick Ma, MD, MSc, a young cancer researcher, was looking forward with excitement to his moment in the spotlight at the AACR Annual Meeting in Toronto, where he had attended medical school and had his internship. He was scheduled to step on the stage in front of fellow scientists and receive the AACR-AstraZeneca-Cancer Research and Prevention Foundation fellowship in translational lung cancer research that would allow him to pursue a promising new avenue in lung cancer treatment.

Instead, the meeting was canceled, a victim of the SARS pandemic. Ma had to wait three months to receive his fellowship at home via courier delivery, and the meeting was rescheduled in Washington, D.C.

Nothing daunted, he launched his project and says the bumpy start simply reminded him of the need to be flexible.

“We all have to learn how to adapt and modify our plans according to external pressure,” says Ma, now a professor of medicine, associate director of translational research, and leader of the multidisciplinary thoracic oncology disease team at the Penn State Cancer Institute, Penn State College of Medicine, Penn State University in Hershey, Pennsylvania.

Ma says the grant, which he calls a “vote of confidence and a validation,” helped “lay a strong foundation” for his research career. The grant allowed him to pursue research investigations into the various c-Met (also called MET) mutations, the functional implications of these mutations in lung cancer, and the therapeutic potential of targeting c-Met.

Working with his mentor, Ravi Salgia, MD, PhD, and others, Ma discovered that c-Met is “overexpressed, activated, and sometimes mutated” in non-small cell lung cancer (NSCLC), which is by far the greatest cancer killer in the United States. They published for the first time then the discovery of MET exon 14 skipping mutations in both small cell lung cancer (SCLC) and NSCLC, and demonstrated that genomic alterations impacting the exon 14 encoded juxtamembrane domain of the c-Met receptor tyrosine kinase (RTK) are oncogenic and potentially targetable. They also showed that a known c-Met prototype inhibitor called SU11274 could inhibit the viability of NSCLC cells.

“These results indicate that c-Met inhibition will be an important therapeutic strategy against NSCLC to improve its clinical outcome,” Ma and his colleagues wrote in a paper published by AACR’s Cancer Research in 2005.

His research helped lay the basis for the body of research on the importance of the c-Met exon 14 skipping mutations that reached a climax last year with the U.S. FDA approval of a new agent, capmatinib, as a targeted therapy for metastatic non-small cell lung cancer patients with that mutation. FDA has subsequently also approved tepotinib as a therapy aimed at c-Met exon 14.

Seventeen years elapsed from his landmark 2005 study to the FDA approval.

”It actually came as a great lesson for me and many trainees, in the sense that therapeutic drug development targeting c-Met in cancer therapy turned out to be a marathon race, rather than a 100-meter dash,” he says.

“A great lesson for all to learn,” he adds, “is for us to have endurance, dedication, and perseverance in whatever we choose to pursue. The key is to choose to do the right thing, and walk the right path regardless of what the immediate trends surround you. These are indispensable in our cancer research success over the long term.”

Having an early bump in the road provided by an epidemic, Ma is alert to the effects of the current COVID pandemic.

“We’re all shadowed quite badly by the pandemic over the past year or two, in the sense that we are becoming more siloed; we only see each other on video camera and not in person,” he says. “But we have to overcome that barrier and be able to communicate, even digitally, in order to exchange ideas and science.”

The biggest unmet need in lung cancer therapy, he thinks, is to solve the problem of resistance to immunotherapy, and resistance to targeted therapies, not only in c-Met but also in other targets as well, such as EGFR (epidermal growth factor receptor) mutations.

Ma’s continuing research included a combinational targeting approach to preemptively prevent the emergence of drug-persisting tumor cells and to ultimately overcome acquired drug resistance. He and colleagues published in Cancer Research in 2011 a study on identification and characterization of early-onset adaptive drug persister tumor cells in EGFR-mutated NSCLC.

“Specifically, we provided the first proof-of-concept in-vivo study validation that the drug persister cells emerged as early as day 9 after drug initiation in the drug-sensitive tumor cell system. These could be a secondary ‘Achilles’ heel’ that could be therapeutically inhibited through targeting the mitochondrial pro-survival priming mechanisms using BH3 mimetics,” he recalls.

Ma says that cancer science today is irrefutably team science — “we build on one another’s scientific discoveries” – and he is Penn State’s representative on the Big Ten Cancer Research Consortium steering committee.

“To fully unleash the power of these novel cancer therapeutics that have been shown to improve cancer outcomes already, particularly in lung cancer,” he says. “I look forward to participating in active collaboration, as a member of the steering committee and the thoracic disease team, to come up with novel, investigator-initiated trials to try to bring bedside benefits to our patients.”

He also believes strongly in mentoring and is mentor to a junior PhD faculty member at Penn State College of Medicine within the Junior Faculty Development Program (JFDP), working with her to provide translational expertise to her work in studying the role of translesion DNA synthesis (TLS) polymerase kappa in lung cancer and in chemotherapy resistance.

Mentorship can hardly escape a sports analogy on a Big Ten campus.

“A mentor is like your coach,” he chuckles, “and just like an athlete won’t be totally successful without a great coach, so a mentor can coach you in many ways, not just scientifically but emotionally, and help you overcome the low points in your career, such as rejections on funding application or other obstacles that you almost inevitably encounter going forward.”