Elizabeth (Lisa) Henske seeks a cure for LAM.

In 1999, Elizabeth (Lisa) Henske, MD, met about a dozen patients who would help to shape her research path and, ultimately, lead to breakthroughs in a little-known disease at the time. Henske was attending a conference sponsored by the LAM Foundation and encountered patients who had been diagnosed with lymphangioleiomyomatosis (LAM), a rare, destructive lung disease that usually strikes women during their childbearing years. Inspired by these women, Henske turned the primary focus of her research toward understanding and treating this disease.

When Henske, who is now the director of the Center for LAM Research and Clinical Care at BWH, began working on LAM, the genetic mutations that caused the disease were unknown. Henske helped change that: her discovery of the genetic mutations that cause one form of LAM accelerated the field. The pace of discovery since then has been rapid. In the course of a decade, the field advanced from pinpointing genetic mutations to treatment, with the results of a recent clinical trial suggesting that a drug known as rapamycin may be able to help keep LAM in check. But Henske has her eyes on the end goal: a cure for LAM.

“Our team can achieve breakthroughs,” said Henske, who works closely with Lung Research Center collaborators David Kwiatkowski, MD PhD, Souheil Y. El-Chemaly, MD, MPH, and Carmen Priolo MD, PhD. “We’re not interested in incremental advances. We want to bring additional breakthroughs forward, not in a ten year timeframe, but in a five year timeframe or even sooner.”

LAM occurs almost exclusively in women and can appear “sporadically” – in otherwise healthy women – or in women with another disease known as tuberous sclerosis complex (TSC). TSC, which is caused by mutations in either the TSC1 or TSC2 genes, causes noncancerous growths in various parts of the body and is often diagnosed in childhood or infancy. Up to 80 percent of girls diagnosed with TSC will go on to develop evidence of lung destruction from LAM as adults.

This May, Henske received a $5 million gift from Gregg and Molly Engles to establish the Lucy Engles TSC/LAM Medical Research Program at BWH, which will focus on TSC and LAM research. The new program is named after the Engles’s 3-year-old daughter.

According to Henske, the gift comes at a pivotal moment as she and her colleagues look toward translating biological discoveries about TSC and LAM into therapy.

“With this gift, we will take the very strong foundation of knowledge about the functions of the TSC genes and use that knowledge to develop more effective treatments, including treatments that can essentially eliminate LAM,” said Henske.

In patients with LAM, smooth muscle cells grow abnormally, invading the lungs, blood and lymph vessels. These cells have the ability to grow uncontrollably in the lungs. As they do, they destroy the delicate alveoli (air sacs) of the normal lung, which can lead to lung collapse, shortness of breath and even death.

In many women, LAM progresses slowly, but in some cases it can progress at a much more rapid rate – and currently, there aren’t any diagnostic tools available to determine which patients will progress rapidly. Henske and her team are working to develop biomarkers – molecular readouts – that may help predict an individual’s rate of progression.

“We want to develop better biomarkers of disease to understand in which women the disease will become severe and in which women it will remain mild,” said Henske. “These biomarkers will allow us to do faster, more efficient clinical trials.”

Although Henske’s main focus is on LAM and TSC, her team’s research has the potential to accelerate the pace of discovery in other diseases. The mTOR pathway, which is upregulated in LAM, is also dysregulated in many human diseases, including obesity and most forms of cancer. In addition, understanding how LAM destroys the lungs may lead to new insights into lung destruction in other cystic lung diseases such as emphysema; understanding how LAM cells metastasize to the lungs could shed new light on how cancer cells spread.

Henske is optimistic about what the new gift from the Engles family will allow her team to accomplish.

“We’re uniquely positioned at the Brigham, especially with our new Lung Research Center. We have a strong research base in LAM and TSC and a very well-established Clinical LAM Center. We are poised to translate basic discoveries into better treatments and a cure for LAM,” said Henske. “We have lots of questions to pursue, but also tremendous optimism and the right team to advance this field.”