Small cell lung cancer (SCLC) is an aggressive type that can be fatal; there are few treatments for the disease and it has an abysmal five-year survival rate of only five percent. Now scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) have identified a vulnerability in SCLC that can be exploited as a target - with existing drugs. This work has been reported in Cell Metabolism and is outlined in the following video.
Cells that are cancerous have aberrations in their metabolism that enables them to rapidly grow and spread in the body. Some of those malignant cells become extremely dependent, practically addicted, to those altered metabolic pathways. They also offer researchers a pathway to new treatments.
"SCLC metabolism has not previously been studied in-depth," said Dr. Ralph DeBerardinis, Professor at CRI and Director of CRI's Genetic and Metabolic Disease Program. "If we identify the metabolic pathways SCLC uses to grow and spread, then maybe we can find drugs to inhibit them. This could effectively cut off the fuel supply to these tumors."
For this work, the scientists assessed metabolic and genetic data from cells taken from human SCLC patients. That research revealed that there are two groups of SCLC, which are defined by the expression levels of two genes that are related to the formation and proliferation of cancer - MYC and ASCL1.
The researchers found that lung cancer connected to MYC can promote the production of molecules called purines. They are critical to the production of RNA and DNA, two vital kinds of genetic material that are necessary for the growth and division of cells. One particular kind of purine, guanosine, is especially important to cells that express the MYC gene.
"We were excited to discover that purine synthesis was so important for this subset of SCLC cells. There are already safe and effective inhibitors of guanosine synthesis used in patients for other diseases besides cancer. Our findings suggested that mice with MYC-expressing SCLC might benefit from treatment with drugs that inhibit purine synthesis," explained the first author of this work, Dr. Fang Huang, a visiting scholar at CRI.
Various mouse models of SCLC was used to investigate that hypothesis. The researchers exposed the mice to a drug called mizoribine, which can halt the synthesis of purine. Exposed mice that were expressing the MYC gene in SCLC had an extended lifespan after drug treatment and tumor growth was suppressed in those animals.
"Our findings suggest purine synthesis inhibitors could be effective in SCLC patients whose tumors have high levels of MYC. If we are right, this could quickly provide a new treatment for this disease, which has few options at present," concluded Dr. DeBerardinis.