In a report that appears in the journal Nature as an advanced online publication, the researchers describe one of the first studies to demonstrate the value of “co-clinical” trials, in which drugs targeting cancers with specific genetic mutations are tested simultaneously in patients and in lab animals with the same type of tumor.
The arrangement enables investigators to use information from the animal studies to predict how specific patients will respond to the drugs, and to design follow-up trials in which the drugs undergo more extensive testing in patients.
The Nature paper focused on non-small cell lung cancers that carry a mutation in the gene Kras. By conducting a mouse study that paralleled a human clinical trial, researchers found that a two-drug therapy shrank lung cancer tumors in mice with one set of mutations but not another. The findings may help scientists understand why some human patients respond to the drugs while others don’t.
“The animal studies complement the human studies,” said senior author Kwok-Kin Wong, MD, PhD, of Dana-Farber. “By running them concurrently, we can gain insights from the animal tests that indicate, in real time, what might be happening in the human trials. The goal is to improve our ability to identify patients who might be helped by a particular therapy, and better understand how patients can eventually become resistant to that therapy.”
The notion of co-clinical trials was first presented in a paper last year by Beth Israel Deaconess Medical Center researchers who also co-authored the new Nature study. It was conceived as a way of overcoming the procedural and bureaucratic obstacles that often slow the application of animal study results to human clinical trials.
Under the standard approach, therapies that target genetic abnormalities in cancer are first tested in mice whose tumors carry a specific set of mutated genes. If a therapy proves successful in these preclinical studies, it is then tested in patients whose tumors have the same mutations.
While this preclinical-to-clinical model has led to the development of several therapies, it doesn’t operate as quickly or smoothly as it might, many scientists believe. For one, clinical trials don’t begin until the corresponding animal studies are completed and the findings published. For another, some pharmaceutical companies remain skeptical that studies involving genetically engineered mouse models of human cancer are useful for predicting drugs’ effectiveness in patients.
Co-clinical trials offer a way of speeding this process up and zeroing in on patients who are likely to have the best response to new therapies, Wong asserted.
“It’s not unusual for a clinical trial to find that some patients with mutation X respond to a particular therapy, while others with the same mutation don’t,” he said. “With animal studies that mimic human trials, we can explore which additional mutations might influence patient response. We can then take that information and apply it to the next stage of clinical trials.”
For the Nature paper, investigators conducted a mouse study that mirrored an ongoing human trial of a potential treatment for non-small cell lung cancer.
Patients in the clinical trial had a form of the disease that carries a mutation in the gene Kras. They received either standard chemotherapy or a combination of chemotherapy and selumetinib, a drug that inhibits a specific kinase in cells.
In the parallel study, mice with Kras-mutant non-small cell lung cancer also received either chemo alone or chemo and selumetinib. But the mice were further subdivided based on the genetic makeup of their tumors: some had mutations only in Kras, some had mutations in both Kras and the gene p53, and some had mutations in Kras and the gene Lkb1.
The researchers found that that the chemo and selumetinib tandem produced a substantial improvement in mice whose cancer contained mutations in Kras alone and in Kras and p53, but not in those with Kras and Lkb1 mutations.
“Our work identified mutated p53 and Lkb1 as potential biomarkers of the effectiveness of combination chemotherapy and selumetinib in this group of patients,” said Wong. “Analysis of tumor samples from patients in the clinical trial can show whether human non-small cell lung cancer shows the same pattern of responsiveness to this therapy. If so, the next stage of clinical trials can focus on patients who are most likely to benefit from this combination of therapies.”
He added that the co-clinical trial technique can generate useful information for trials of a wide range of targeted cancer therapies.
Funding for the study was provided by the National Institutes of Health, the United Against Lung Cancer Foundation, the American Lung Association, and the Susan Spooner Research Fund.
The lead author of the study is Zhao Chen, PhD, of Dana-Farber. Co-authors include Katherine Cheng, Zandra Walton, Yan Liu, PhD, Tanya Tupper, NMT, Jing Ouyang, PhD, Peng Gao, Michele Woo, Chunxiao Xu, PhD, Masahiko Yanagita, MD, PhD, Abigail Altabel, Yanping Sun, PhD, Yoko Franchetti, PhD, Catherine Yao, Amy Saur, Mohit Butaney, David Jackman, MD, George Demetri, MD, Pasi Janne, MD, PhD, and Andrew Kung, MD, PhD, of Dana-Farber; Yuchuan Wang, PhD, and Mizuki Nishino, MD, of Dana-Farber and Brigham and Women’s Hospital; Hiromichi Ebi, MD, PhD, Nabeel Bardeesy, PhD, and Jeffrey Engelman, MD, PhD, of Massachusetts General Hospital; Takeshi Shimamura, PhD, of Loyola University; Jie Li of Iowa State University; Shumei Wang, Lucian Chirieac, MD, and Charles Lee, PhD, of Brigham and Women’s Hospital; Yuji Nakada, PhD, Christopher Pena, and Diego Castrillon, MD, PhD, of University of Texas Southwestern Medical Center; Michael Cameron, PhD, of the Scripps Research Institute; D. Neil Hayes, MD, MPH, Matthew Wilkerson, PhD, Patrick Roberts, PharmD, PhD, Carrie Lee, MD, MPH, and Norman Sharpless, MD, of the University of North Carolina, Chapel Hill; Daniel Costa, MD, PhD, Pier Paolo Pandolfi, MD, PhD, and Lewis Cantley, PhD, of Beth Israel Deaconess Medical Center.