Lymphangioleiomyomatosis or LAM is a rare lung disease that affects primarily women. In this disease, cysts or abnormal air spaces replace the normal lung and progressively impair lung function. LAM can occur alone or as part of another disease called tuberous sclerosis (TS) that is characterized by tumors in different parts of the body such as the brain, skin, and kidneys. Tumors arising in the kidneys are called angiomyolipomas or AML. Importantly, both diseases share the same type of genetic error, which results in increased activity of a protein called mTOR that allows cells to have uncontrolled growth as seen in tumors. Sirolimus or rapamycin regulates the growth of these LAM cells, but cannot induce death of these tumor cells. Recent studies suggest that sirolimus controls lung function decline and tumor size in LAM and TSC patients. However, sirolimus needs to be taken continuously, since tumor growth and lung function decline resume after the medication is stopped.

Cancer cells can use autophagy (self-eating), a process where a cell breaks down and reuses parts of itself to survive, which may explain why LAM cells continue to grow after sirolimus treatment is stopped. Hydroxychloroquine has been shown to block autophagy and in combination with sirolimus has better effects than sirolimus alone in reducing tumors in animals. We therefore believe that using the combination of sirolimus and hydroxychloroquine will lead to tumor cell death and an improved outcome in patients with LAM or TS.

Based on these findings, we propose a study to examine the safety and tolerability of combining hydroxychloroquine and sirolimus in patients with LAM. All patients will receive sirolimus at effective doses. The first three to six patients enrolled will receive hydroxychloroquine at 200 mg daily. If this dose is well tolerated, the next three to six subjects recruited will receive hydroxychloroquine 400 mg daily. Once safety of that dose has been established, 6-12 more patients will be enrolled to further examine the effects of the combination therapy. In addition to safety, we will examine the effects of the combination therapy on lung function, exercise capacity, kidney tumor size, and quality of life.

In summary, this study aims to establish the safety of the combination of sirolimus and hydroxychloroquine in patients with LAM and TS, with the future goal of performing larger clinical trials to demonstrate efficacy.