A team of researchers at UT Southwestern Medical Center identified the protein ASCL1 as critical for the development of small cell lung cancer (SCLC); the team also found that the absence of ASCL1 in the lungs of mice inhibits cancer formation.
The findings were published in the journal Cell Reports in an article titled “ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs.”
The new findings identify ASCL1 as an important therapeutic target for SCLC.
“We used a genetically engineered mouse model that develops human-like small cell lung cancer and identified two regulatory pathways that in turn revealed vulnerabilities in this cancer,” said the study’s senior author, Dr. Jane E. Johnson, professor of neuroscience and pharmacology and a member of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, in a recent UT Southwestern news release.
SCLC is a type of highly malignant cancer that forms within the lung. Compared to non-small cell carcinoma, SCLC has a shorter doubling time, higher growth fraction, and earlier development of metastases.
For people with SCLC, regardless of stage, chemotherapy is an essential part of the treatment. Radiation treatment may be used as well, depending on the stage of the cancer. Patients with SCLC generally have few available treatment options, a fact that underscores the importance of the finding.
“Small cell lung cancer is a devastating disease that is diagnosed in 30,000 people a year in the U.S. and accounts for roughly 15 percent of lung cancer cases,” said Dr. John D. Minna, professor and director of the Hamon Center for Therapeutic Oncology Research. “Most patients survive one year or less and therapy has not changed significantly in 30 years. Our work shows the possibility of developing entirely new types of targeted therapies for small cell lung cancer by focusing on ASCL1.”
The research team determined that the Achaete-scute homolog 1, a protein that in humans is encoded by the ASCL1 gene, is found in most SCLC tumors and is required for the development of the disease. In their experiments, the team used mice with SCLC and deleted the expression of ASCL1 in the lungs. The researchers found that this loss prevented development of the cancer.
In addition, the researchers were able to distinguish between the tumor-promoting function of ASCL1 and a related protein, NEUROD1 in SCLC. Specifically, they found that while some SCLC tumors expressed ASCL1, others expressed another protein called NEUROD1. While ASCL1 and NEUROD1 regulate different cells processes, both seem to control genes that are essential for the development of lung cancer.
For many years, Johnson, who holds the Shirley and William S. McIntyre Distinguished Chair in Neuroscience, has been examining the roles of ASCL1 in the developing nervous system. Now, using UT Southwestern’s Genomics and Microarray Core facility, he was able to identify new roles for the protein in SCLC.