For William Whalen II, MD, MS, combating idiopathic pulmonary fibrosis (IPF) means understanding individual patients’ treatment responses on a molecular level.
“We need to investigate the idea that there are genetic differences that matter and traits that may respond to particular treatment,” said Dr. Whalen, whose work was supported by a 2023 CHEST Research Grant in Pulmonary Fibrosis. The grant gave him the opportunity to drill down into preexisting clinical trial data, extracting secondary findings from previously gathered research.
Two previous randomized clinical trials, EME-TIPAC published in 2020 and CleanUP-IPF published in 2021, explored whether antimicrobial therapy—with trimethoprim-sulfamethoxazole and doxycycline—could enhance treatment and improve outcomes in patients with IPF.
While those studies concluded that the addition of those antibiotics did not improve composite outcomes overall, the authors of the CleanUP-IPF study wanted to get the most out of the data they had collected from nearly 500 patients over two years.
Bacterial load, which is often elevated in patients with IPF, correlates with a decline in lung function and increased mortality. Toll-interacting protein (TOLLIP), encoded by the TOLLIP gene, produces an innate immune response that can decrease inflammation in IPF. The authors sought to investigate whether that response could mediate the effect that antibiotics may have on hospitalization, death, or the need for a lung transplant.
“There’s a concept called heterogeneity of treatment, where perhaps you have negative clinical studies because you’re not enriching your study with the most representative population or with the population of patients who could benefit,” Dr. Whalen explained. “They wanted to see whether there were single nucleotide polymorphisms within the patient population that was associated with more favorable responses to treatment.”
Following a “grand rounds” presentation at NewYork-Presbyterian/Weill Cornell Medical Center in New York City, Dr. Whalen joined a conversation with two of the CleanUP-IPF authors, Fernando Martinez, MD, MS, and Imre Noth, MD. “Dr. Noth mentioned that they had found genotypes associated with treatment effects and that one of the planned secondary analyses was to look for genotype effects in the CleanUP-IPF cohorts,” Dr. Whalen explained. “He said, ‘You know, I think this is a good project for a junior faculty member. Are you interested?’”
That’s where Dr. Whalen’s CHEST Research Grant project came in. He and his team hypothesized that there may be a pharmacogenomic interaction between TOLLIP polymorphisms and antimicrobial drugs.
“This was the first grant that I successfully applied to, and it has proven to be a huge steppingstone in my career as a clinician-researcher in the field of pulmonary fibrosis,” Dr. Whalen said. “It was the first research project that I helped devise and run, and I was involved in all phases, like writing the institutional review application, organizing the manuscript, helping with the analysis, [and] writing the paper.”
Because his project was a secondary study—which meant that the biological samples were already available—the one-year CHEST grant provided the perfect amount of protected study time and laboratory funding that Dr. Whalen needed to carry out his specific analyses.
Dr. Whalen’s team found that patients with IPF with the TOLLIP TT genotype who received doxycycline demonstrated slower rates toward hospitalization, lung transplant, or death when compared with other patients.
“Our results further the hypothesis that pharmacogenomic treatment interactions exist in patients with IPF. They support the idea that there is heterogeneity, at least at the molecular level, in patients with IPF, and that needs to be delved into further,” Dr. Whalen said.
He added, “A secondary analysis such as this one is valuable because it shows that negative clinical trials may actually be positive when genotype is taken into account.”
Dr. Whalen’s project enriches the literature on the genomic implications of IPF, and it paves the way for large-scale clinical trials that explore new therapeutic options.
It also bolsters his options for continued research. He plans to shift his focus toward ensuring that clinical trials for lung disease are truly representative of the populations who can benefit from personalized treatment.
Patients from racial minority groups are historically underrepresented in clinical trials of interstitial lung disease (ILD). Black patients tend to experience an earlier onset of disease, hospitalization, and death—and they are less likely to be prescribed medications with proven benefit—compared with their White counterparts. Dr. Whalen’s team aims to identify barriers that may contribute to disproportionate health-related quality of life metrics and to examine factors—including patient beliefs, perceptions about the health care system, and treatment options—that contribute to lower enrollment of racial minority groups in ILD research studies.
“Through the support of the CHEST grant, I was able to apply not only my clinical knowledge of IPF but also my knowledge of biostatistics and data analytics,” said Dr. Whalen, who also holds a master’s degree in biostatistics and data science. “This grant also provided me the opportunity to network with other physician-scientists throughout the world.”
Those opportunities influenced his professional status as well, he said. On July 1, 2024, he was promoted to Assistant Professor at Weill Cornell Medicine.
“Junior researchers spend so much time with their noses down, working hard and meeting walls of resistance that are hard to break through,” Dr. Whalen reflected. “With a grant like the CHEST Research Grant, aside from the scientific impact, the networking impact really can’t be overestimated. It helps to get you in the door.”
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