Wells A. Messersmith, MD, has spent more than a decade running clinical trials that attempt to match gastrointestinal cancer patients with new therapies targeting the genetic causes of their conditions. On October 2, 2018 he was invited to share what he’s learned, as recipient of the Michaele C. Christian Oncology Development Award and Lecture, presented at the National Cancer Institute (NCI) Cancer Therapy Evaluation Program Early Drug Development Meeting at the National Institutes of Health in Rockville, Maryland. The honor is given annually to an outstanding researcher in the field of drug development and testing.
“It’s funny, they surprise you with the award a few days before the meeting. So my first reaction to learning about the award was, Oh gosh, I have to put together a lecture in two days!” says Messersmith, who was recently named Associate Director for Translational Research at University of Colorado Cancer Center.
The time period he would be speaking about saw a paradigm shift in the way doctors and researchers design and run clinical trials, from the time of toxic chemotherapy agents used somewhat indiscriminately against cancers defined by where they occur in the body, to the modern era of treatments targeting cancers defined by their genetics.
“It was an opportunity to look back on the projects I’ve worked on, some of which failed and some of which inched the field along. Sometimes when you’re making incremental progress, it’s hard to see the forest for the trees. This award made me realize how far the field has come. When you look back over your work, you realize, Hey, we did a few things that are important,” he says.
Of course, many of these “important things” have been specific drugs that Messersmith and his team have helped to shepherd from first-in-human trials to FDA approval. As an example, Messersmith points to the drug trametinib. The drug targets cancers that depend on improper activation of the gene MEK. After helping to run the first-in-human clinical trials of trametinib, it became clear that it worked better against a common subtype melanoma than it did against colorectal or pancreatic cancer with certain gene mutations. Because Messersmith’s team collaborates closely with the CU Cancer Center skin cancer team, the university’s melanoma researchers we able to take over the project and helped to lead phase III clinical trials leading to FDA approval.
“The collaborative design of our phase I program helped us move the project along where it belonged, and our eye researchers on campus even helped figure out an ocular toxicity from the drug,” Messersmith says.
In addition to specific drugs, Messersmith spoke about the process of redefining the mechanics of clinical trials in order to test genetically-targeted treatments.
“One of the biggest hurdles we’ve been able to solve is feasibility,” he says. “Throughout much of my early career, there was doubt as to whether biomarker-driven trials could be done. A lot of issues had to be worked out.”
Instead of simply noticing a cancer in, say, the colon, and then treating all colon cancer patients as part of a clinical trial with a new chemotherapy, biomarker-driven trials commonly require sampling a patient’s tumor, sending the sample for genetic analysis, and then delivering treatment based on the tumor’s specific genetic characteristics. Patient consent, acquiring usable tissue samples, genetic testing, predicting based on test results which patients are likely to benefit from a drug, and then delivering targeted treatment are all recent steps in the clinical trial process.
“Now it’s fairly standard to do broad molecular testing,” Messersmith says. “But still, in many of these studies, we’re looking at novel biomarkers that aren’t tested for yet, initially using laboratory-based tumor models to work out the details.”
In an increasingly specialized world of full-time clinicians and full-time benchtop researchers, Messersmith also discussed the value of having faculty who can “speak the language” of both the laboratory and the clinic.
“Understanding the clinical context of benchtop discoveries, and how they can be developed in clinical trials—as well as studying blood and tumor samples from the clinical trial, back in the laboratory—are important aspects of cancer drug development that require faculty comfortable in both settings,” he says.
“Importantly, we have also put a lot of effort into programs to educate the next generation of cancer researchers, to continue to accelerate the process of finding cancer cures,” Messersmith says.
The Michaele C. Christian Oncology Development Award and Lecture, named for a highly respected researcher who retired after a long career at the NCI, was an opportunity to recognize these efforts that helped usher in a new era of cancer clinical trials and treatment, while also describing next steps in biomarker-driven clinical trials. For example, “We were one of the first teams to do a clinical trial in pancreatic cancer based on the inherited genetics of the drug targets, using a blood test to identify the patients most likely to benefit,” Messersmith says.
“From my standpoint, I see it as a team honor,” Messersmith says. “As a group we’ve been able to bring a lot of agents through the drug development process and look for novel biomarkers. But without support from CU Cancer Center’s researchers and clinical trials teams, it wouldn’t have been possible. This award highlights more than a decade of work that has gone on in Colorado across the continuum of science and translational research.”