Naveed Saleh, MD, MS, for MDLinx | December 10, 2019
Researchers have discovered a much-needed drug target for small cell lung cancer (SCLC), as evidenced by a recent preclinical study published in Science Transitional Medicine. Even better, drugs that target this pathway already exist.
A research team at Massachusetts Institute of Technology (MIT) harnessed CRISPR to identify a metabolic weakness in SCLC. The weakness involves an enzyme, dihydroorotate dehydrogenase (DHODH), that is responsible for pyrimidine biosynthesis. More so than other types of cancer cells, SCLC cells are particularly dependent on pyrimidine. Fortunately, well-established drugs that block DHODH, such as brequinar, are already available.
“The new findings show the promise of gene-editing technology as a research tool for uncovering elusive cancer targets. Such hard-fought discoveries will help to advance precise approaches to the treatment of even the most aggressive cancer types. And that should come as encouraging news to all those who are hoping to find new answers for hard-to-treat cancers,” according to Francis S. Collins, MD, PhD, in his NIH Director’s Blog.
In the study, co-lead authors Leanne Li, MD, PhD, and Sheng Rong Ng, PhD, David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA used a CRISPR-based screening method to target about 5,000 genes considered to encode “druggable” proteins. They performed loss-of-function genetic screens in cell lines from genetically engineered mouse models of SCLC, lung adenocarcinoma, and pancreatic ductal adenocarcinoma.
On cross-cancer analyses, the investigators identified SCLC-selective vulnerabilities—the disruption of the pyrimidine biosynthesis pathway, in particular. Not only did blocking DHODH decrease survival of SCLC cells in vitro, but it also suppressed growth in human patient-derived xenograft (PDX) models and in an autochthonous mouse model.
(“Autochthonous” refers to spontaneously occurring tumors and chemical, viral, or physical carcinogen-induced tumors, which are thought to model human tumors with higher fidelity than transplanted tumors. In other words, the researchers engineered mouse models to harbor the same genetic mutations found in human cancers.)
In SCLC mouse models, the researchers found that mice treated with brequinar lived about 40 days longer than controls. Moreover, when combined with other cancer drugs, the benefit was even greater, and two of four human-derived tumors shrunk in brequinar-treated mice.
Brequinar is already approved for use as an immunosuppressant, and some preclinical research has shown that brequinar and other DHODH inhibitors may be effective for other types of cancers.
“Despite decades of research, the combination of platinum and etoposide remains the backbone of SCLC therapy. Although initial response rates are high, patients almost invariably relapse,” the authors wrote. “In contrast to the growing number of options for treating non-small cell lung cancer (NSCLC), no new therapies have demonstrated efficacy in SCLC patients, highlighting a great need for additional treatments.”
While the outlook for patients with NSCLC has improved over the past 30 years due to targetable mutations—including EGFR, ALK, and ROS1—SCLC has few, if any, targetable mutations, and is marked by inactivating mutations. Furthermore, even though adding atezolizumab to carboplatin/etoposide lengthens overall survival, clinical outcomes are still poor in patients with SCLC, with median survival a bit more than 1 year.
The authors concluded, “We have only tested the efficacy of brequinar in the classic subtype of SCLC; whether the variant subtype is sensitive to DHODH inhibition has not been assessed. Therefore, it would be of interest in the future to expand the treatment cohort to a larger panel of human PDX models, including both classic and variant subtypes of SCLC, as well as samples with a wide spectrum of DCTD expression.”
The authors also pointed out that it will be important to analyze the efficacy of brequinar or other DHODH inhibitors at different dosing schedules, and as combined with the current standard of care.