Although the FDA’s approval of sirolimus for lymphangioleiomyomatosis was a major breakthrough in treating the disease, the drug does not work for all LAM patients. In the following blog, Dr. Sang-Oh Yoon, recipient of a pilot grant from The LAM Foundation, describes how he is working on new ways to stop LAM cells from evading sirolimus and other mTOR inhibitors. His team is currently progressing to mouse studies to develop new therapeutic remedies for LAM.
Lymphangioleiomyomatosis (LAM) is caused by mutations in tuberous sclerosis complex (TSC) genes, which highly activate a key player of protein production, the mechanistic target of rapamycin (mTOR). Proteins are essential parts of organisms that participate in virtually every cellular process, including the structural/mechanical maintenance of cells, metabolism, immune response, muscle maintenance, and cell growth. Therefore, making proteins is one of the most critical processes in all living organisms and is tightly controlled. Uncontrolled protein synthesis by hyperactive mTOR due to a TSC mutation is one of the core reasons for LAM-associated tumor growth, and thus, an FDA-approved first-generation mTOR-targeting drug is recommended as a first-line treatment for LAM.
Although mTOR-targeting drugs make tumors stop growing or even shrink, they do not make them go away altogether, which causes tumors to regrow upon the stop of treatment. Moreover, some patients’ tumors do not respond well to these drugs. One of the reasons is that mTOR-targeting drugs do not reduce protein production significantly, even though mTOR is regarded as a master regulator of protein synthesis.
For a comprehensive picture of the effects of mTOR targeting drugs on protein production, our lab used different mTOR inhibitors (from first-generation to third-generation mTOR inhibitors). Extensive analysis of data from global levels of proteins/RNAs and further confirmation with cellular results has revealed that even though these drugs stop mTOR from making many proteins involved in tumor growth, the tumors develop an alternative protein production system to make selective proteins involved in tumor survival.
This study helps us understand why mTOR-targeting drugs do not always work in LAM-associated tumors and gives us clues about how tumors develop new ways to survive. Based on these findings, we are now looking into new treatment strategies that use different drug combinations with mTOR-targeting drugs.