No Time to Waste: Frontier Program Advancing Precision Medicine in Cancer Care

By Lauren Ingeno

Theodore Laetsch, MD, a pediatric oncologist with the Cancer Center at Children's Hospital of Philadelphia, remembers the first patient he successfully treated with one of the initial “precision medicines” approved by the U.S. Food and Drug Administration.

The medication, larotrectinib (Vitrakvi®, Bayer), was approved in 2018 for a wide range of cancers that shared a genetic mutation — an NTRK gene fusion — rather than a tumor’s location in the body.

At the time, Dr. Laetsch was a clinician at the University of Texas Southwestern Medical Center, where he was leading a clinical trial testing the safety and efficacy of the drug. Witnessing his young patient recover from her disease was “remarkable,” he said.

“She had a refractory sarcoma that we identified as having an NTRK gene fusion. We gave her the TRK-inhibitor, and her cancer rapidly disappeared,” Dr. Laetsch said. “She’s now been in remission for more than six years, and she was on hospice when she entered the trial.”

As coordinating principal investigator of the Center for Precision Medicine for High-risk Pediatric Cancer — a CHOP Frontier Program — Dr. Laetsch is hoping to replicate the success of that clinical trial for more patients.

Broadly defined, precision medicine tailors medical treatment to the specific vulnerabilities in an individual’s tumor, such as the tumor’s genetic makeup. The Center for Precision Medicine for High-risk Pediatric Cancer Frontier Program will build upon ongoing precision medicine efforts across many CHOP departments, with the goal of defining and expanding patients’ treatment options.

“I believe there will be a world in which precision medicine could benefit the majority of high-risk cancer patients, which is not where we are today,” Dr. Laetsch said.

Expanding Clinical Trials

At CHOP, Dr. Laetsch is continuing to lead clinical trials that build on the TRK inhibitor studies to evaluate whether these drugs can completely replace chemotherapy for children whose tumors have NTRK gene fusions.

Simultaneously, he is collaborating with Andrew Bauer, MD, medical director of CHOP’s Pediatric Thyroid Center, and Aime Franco, PhD, director of the Pediatric Translational Thyroid Cancer Laboratory, on a clinical trial funded by the U.S. Department of Defense. This trial is evaluating whether targeted therapies, including TRK inhibitors, could be combined with radioactive iodine therapy to increase the efficacy in treating pediatric patients who have thyroid cancer.

“There is some data that TRK inhibitors may make thyroid tumors more sensitive to radioiodine,” Dr. Laetsch said. “Radioiodine is the current standard of care, but it is not very effective at completely eliminating tumors when the cancer has spread to the lungs.”

Patrick Grohar, MD, PhD, a pediatric oncologist with CHOP’s Cancer Center and director for Translational Research at CHOP’ Center for Childhood Cancer Research, is collaborating with Dr. Laetsch and the Frontier Program team to conduct two new clinical trials that will investigate whether the drugs trabectedin and lurbinectedin can block the genetic change that drives Ewing sarcoma. These studies are being conducted in partnership with the Sarcoma Alliance for Research through Collaboration and Stand Up to Cancer.

“There are many different diseases and many different targets, but these studies are all in the same vein of understanding the genetics of the cancer and then directly targeting those genetic changes, rather than giving generic therapy that just kills fast-growing cells,” Dr. Laetsch said.

Using Single Cell Analysis to Understand Therapy Resistance

Each cancer patient who comes to CHOP is offered genetic testing to identify the unique biomarkers that could potentially be targeted with therapy; however, even with that information available, barriers persist. Part of the challenge is that standard profiling of tumors doesn’t always detect cancer heterogeneity, or the differences between cancer cells within a single tumor. 

As part of the Frontier Program, co-principal investigators Marilyn Li, MD, vice chief of the CHOP’s Division of Genomic Diagnostics, and Kai Tan, PhD, director of the Center for Single Cell Biology, are expanding on their cancer genomic research to map the molecular and cellular changes in tumor tissue after therapy. This expansion includes adding single-cell analysis and DNA methylation methods to their genetic testing toolbox.

“Part of the reason this hasn’t been done before is that the layers of data generation technologies have dramatically expanded over the last five years,” said Adam Resnick, PhD, director of the Center for Data-Driven Discovery in Biomedicine (D3b) and a co-principal investigator of the Frontier Program.

Using single cell analysis — a rapidly evolving approach to characterize molecular information at the individual cell level — Dr. Tan can better understand the granular composition of tumors, and why certain tumors might be resistant to certain therapies.

“You might imagine that patient A has a different combination of different cell types compared to patient B — maybe some rare, therapy-resistant population,” Dr. Tan said. “Using traditional bulk analysis, we can’t get that kind of information. But with new technologies we can analyze cells at the individual level, and we can see which genes are turned on or off within that population.”

Having that kind of information, Dr. Laetsch said, can be as useful in suggesting a therapy as recommending against one. In addition to defining new therapeutic targets, precision medicine can help refine prognosis. 

“Many patients today are likely overtreated with very toxic therapies, because we can’t determine which tumors are likely to be cured by less intense therapy,” Dr. Laetsch said. “If we could understand that your tumor was very likely to be cured with surgery, then you could forgo chemotherapy.”

Building the Largest Dataset in Pediatric Cancer

The final piece of the Frontier Program that will help researchers and clinicians throughout CHOP come together to discover treatment options for patients with high-risk cancers is the development of the largest dataset in pediatric cancer. In partnership with the D3b Center led by Dr. Resnick, the database will combine information on the patient, tumor, multi-omics, epigenetics, clinical outcomes, and multi-omic tumor profiling.

This Frontier group is focused on obtaining living samples of individual patients’ tumors, which are rare in current biorepositories. Having those samples will enable researchers like Dr. Li and Dr. Tan to perform detailed, novel sequencing analysis to better understand these cancers and test new therapies. 

Building the database, Dr. Resnick said, will help bring bench findings to the bedside more quickly than ever before.

“In the past, we could collect tumors, but that might be very separate from what’s taking place in the clinic. Now, the infrastructure of data analysis can be integrated into the clinic in real time,” Dr. Resnick said.

For instance, if a patient comes to CHOP with a type of cancer for which there is no existing standard of care or clinical trial available, “maybe we can identify a new target and potential clinical trial in a much more rapid fashion than we could otherwise,” Dr. Resnick said.

The database will not only help inform care for CHOP patients, but it also will be available to help inform clinicians at clinics and health systems across the world.

“With cancer, time is a variable that you have to optimize for. That’s both a challenge and opportunity,” Dr. Resnick said. “We have a unique opportunity to rethink the way research is leveraged, so that there isn’t a 15- or even 10-year timeline of discovery. We’re trying to shorten that process.”