How One Scientist Is Tackling a Woman-Predominant Disease
For decades, a rare lung disease called LAM progressed with few treatment options, primarily affecting women and often leading to oxygen dependence. This is the story of Dr. Elizabeth Henske, whose work is illuminating the genetic shadows of this disease.
Lymphangioleiomyomatosis (LAM) is a rare and progressive lung disease that almost exclusively affects women. In LAM, abnormal, smooth muscle-like cells invade the lungs, leading to the destruction of healthy lung tissue and the formation of cysts4 .
This process can progressively impair lung function, causing symptoms like shortness of breath, chest pain, and, for many, eventual oxygen dependency4 .
What makes LAM particularly intriguing to scientists is its genetic origin. It can occur sporadically in women with no family history, or in women who have a genetic condition called Tuberous Sclerosis Complex (TSC). Both forms are linked to mutations in the same genes—TSC1 or TSC2—which act as powerful "brakes" on cell growth4 .
At the heart of this research is Dr. Elizabeth P. Henske, the Director of the Center for LAM Research and Clinical Care and a Professor of Medicine at Harvard Medical School4 . For years, her laboratory has been dedicated to unraveling the complex cell biology of TSC and LAM.
The central player in this story is a critical cellular pathway known as mTORC1. Under normal conditions, the proteins produced by the TSC1 and TSC2 genes (hamartin and tuberin) work together to keep the mTORC1 pathway in check4 .
TSC1/TSC2 proteins inhibit mTORC1, preventing excessive cell growth.
When either gene is mutated, this regulatory complex fails, causing mTORC1 to be constantly active.
Hyperactive mTORC1 drives excessive cell growth and proliferation, fueling LAM progression4 .
While LAM is a lung disease, the same TSC2 gene mutations can also lead to a rare type of kidney cancer called chromophobe renal cell carcinoma (ChRCC). Research into this cancer has yielded a critical discovery with major implications for LAM5 .
A pivotal study highlighted a unique vulnerability in ChRCC cells that also applies to TSC2-deficient cells found in LAM: a hypersensitivity to a specific type of cell death called ferroptosis5 .
| Reagent / Tool | Function in Research |
|---|---|
| Bi-steric mTORC1 Inhibitors (e.g., RMC-5552) | A new class of investigational drugs designed to selectively and potently inhibit hyperactive mTORC1 signaling, inducing tumor cell death4 . |
| Solute Carrier Family 7 Member 11 (SLC7A11) | A critical protein studied to understand cystine import and its role in making TSC2-deficient cells vulnerable to ferroptosis4 . |
| IL-15 Based Immunotherapy | An emerging immunotherapy approach that shows promise for "cold" tumors like ChRCC (and potentially LAM) by engaging different immune cells than standard PD-1 inhibitors5 . |
Researchers hypothesized that TSC2-deficient cells, which have rewired metabolism, might depend on specific nutrients to survive.
The team used laboratory models of TSC2-deficient cells and employed specific chemical inhibitors to block cystine import.
This discovery is revolutionary because it identifies a direct, targetable weakness in the cancer cells associated with TSC and LAM, opening a door to potential new therapies that force these harmful cells to self-destruct.
The translation of basic science into clinical hope is already underway. Dr. Henske's team continues to publish groundbreaking work, including a November 2024 paper on how new bi-steric mTORC1 inhibitors can reduce mTORC1 signaling and growth in LAM4 .
Next-generation mTOR inhibitors are designed to be more potent and selective, offering improved treatment options.
Researchers are now actively investigating drugs that can safely induce ferroptosis in patients, offering combination therapy potential.
For a disease that was once a mystery, the future is looking brighter, with multiple therapeutic strategies now on the horizon. Dr. Henske's work exemplifies how decades of persistent focus on a rare genetic condition can unravel fundamental biological principles, revealing unexpected vulnerabilities and forging a path toward a cure.
Director, Center for LAM Research and Clinical Care
Professor of Medicine, Harvard Medical School
Initial identification of LAM as a distinct disease entity
Discovery of TSC gene mutations in LAM patients
mTOR inhibitors approved for LAM treatment
Ferroptosis vulnerability discovered in TSC2-deficient cells