Current LAM Research

It is amazing how far LAM research has come in such a short period of time, thanks especially to the many researchers who have helped to make this disease a research priority. LAM and TSC researchers have identified a wealth of potential molecular targets and experimental therapies that may be appropriate for testing in clinical trials. Many of these drugs are FDA-approved or in development for other indications.

The majority of the $10.7 million raised by The LAM Foundation has supported 79 peer-reviewed research projects for the study of lymphangioleiomyomatosis (LAM). LAM Foundation scientists reported three breakthroughs, resulting in the first-ever LAM treatment trial to test a drug called sirolimus, or rapamycin. Clinical trials are underway as LAM Foundation researchers continue to work with urgency in search of an effective treatment.

$425,000 Additional Funds are Committed to LAM Research in 2008!
Thanks to John and Vi Adler, the Adler Foundation, the Tante Mela Foundation, the American Thoracic Society (ATS), and the many LAM patients, families, and friends who have raised funds for LAM research, $425,000 has been committed to LAM research! Four scientists were selected from the Fall 2007 applicants to receive LAM awards in 2008. Take a look at our new recipients!

Young Lisa R. Young, MD, Assistant Professor of Pediatrics and Medicine at Cincinnati Children's Hospital Medical Center and The University of Cincinnati, has been awarded a one-year Pilot Award to determine the clinical utility of serum VEGF-D levels in LAM. Vascular endothelial growth factor (VEGF) is a factor that promotes the growth of blood vessels and lymphatic vessels. VEGF-D is known to be significantly elevated in blood samples from patients with LAM. This research project will determine if VEGF-D levels can be used to distinguish LAM from other disorders like lymphangiomatosis, pulmonary Langerhans cell histiocytosis, and emphysema. The study will also investigate whether VEGF-D levels predict the presence or absence of LAM in women with Tuberous Sclerosis Complex (TSC), and whether levels of VEGF-D decreases after treatment with Sirolimus and other agents. The VEGF-D project is supported by the Tante Mela Foundation.

Young Ray Yeung, MD, a surgical oncologist and researcher at the University of Washington, received a three-year Established Investigator's Award to explore a novel function of the TSC proteins in the regulation of movement of molecules through the cell, as well as the movement of the cell through space. In this study, Dr. Yeung will characterize the molecular components of the pathway, which may lead to new targets for potential therapeutic intervention. He hypothesizes that the trafficking defect in TSC protein deficient cells may cause mislocalization of estrogen receptors, resulting in aberrant estrogen signaling. His studies promise to advance our understanding of the remarkable gender restriction in LAM. Dr. Yeung's Award is jointly funded by the Adler Foundation.

Elena Goncharova, PhD, Research Associate at the University of Pennsylvania School of Medicine, was awarded a two-year Research Award to determine the role of small GTPase, RhoA, in abnormal cell proliferation in Lymphangioleiomyomatosis (LAM). Dr. Goncharova will investigate the benefits of the combined treatment of TSC deficient cells and tumors with mTOR inhibitor rapamycin and Rho GTPase inhibitors, statins. This study will provide a better understanding of the cellular and molecular mechanisms of LAM pathobiology and will provide insights into the potential combinatorial therapeutic targets that may inhibit tumor growth in LAM. Dr. Goncharova's research will be co-funded by the American Thoracic Society (ATS).

Henske Elizabeth Henske, MD, a Tenured, Senior Member of Fox Chase Cancer Center in Philadelphia was awarded a three-year Established Investigator Award to study the role of autophagy in the pathogenesis and treatment of LAM. Autophagy ("to eat one's self") is a process in which the cell sequesters a portion of cytoplasm, delivers it to a degradative organelle and recycles the content. Autophagy has multiple normal physiologic and developmental functions. When cells encounter bioenergetic stress such as nutrient deprivation, induction of autophagy can sustain metabolism and delay cell death. Autophagy is also believed to play an important role in tumor development and response to therapy. Mutations in either TSC1 or TSC2 result in activation of the mTOR pathway, preventing the normal regulation of cell metabolism, protein synthesis and cell growth. As mTOR is a key inhibitor of autophagy, one would predict that LAM cells would have constitutively low autophagy. Dr. Henske's entral hypothesis is that TSC2-null and LAM-derived cells are bioenergetically compromised, in part due to low autophagy. She will determine the impact of autophagy on the growth and survival of TSC-null and LAM-derived cells in vitro, determine whether TSC-null cells have enhanced sensitivity to autophagy inhibition in vivo, and utilize a proteomics-based strategy to delineate estrogen-associated protein events that promote the progression of LAM. Dr. Henske's research project is jointly funded with the Adler Foundation.

The LAM Foundation 2006/Spring 2007 Awards for the Study of LAM

Primal de Lanerolle, PhD
Dr. de Lanerolle is a Professor of Physiology and Biophysics and Medicine at the University of Illinois at Chicago. He received a Pilot Award to focus on how various signaling processes, including some that have been implicated in cancer and metastasis, interact in LAM cells to regulate cytoskeletal dynamics, cell motility, and proliferation. By relating signaling networks in LAM cells to other diseases, these studies may provide the foundation for using existing therapeutic agents to treat LAM.

Caroline Le Poole, PhD, MS
Caronline Le Poole Dr. Le Poole is an Associate Professor of Pathology at Loyola University Chicago. She is interested in tweaking immune responses to tumor cells as a means to treat patients with melanoma. Pigment cells and their malignant counterparts, melanoma cells, are relatively ‘easy to spot' for the immune system. These same molecules are also found in LAM cells, meaning some vaccines under development to treat melanoma may be useful to treat LAM. Dr. Le Poole's Pilot Award will allow her to test whether antibodies and T cells to melanoma cells can also interact with LAM cells.

Seong Woo Anthony Kang, PhD
Dr. Kang is a Postdoctoral Fellow in the laboratory of Dr. David Sabatini at the Whitehead Institute for Biomedical Research. He has been awarded Special Project Award to characterize the structures of mTORC1 and its catalytic domain. This study will analyze mTOR and its interacting proteins via various biological imaging techniques with a goal of elucidating the atomic structure of the mTOR protein. Since inhibition of mTOR signaling is thought to be a promising strategy for anti-cancer therapeutics, this study will provide vital information for the development of novel mTOR inhibitors with enhanced specificity and efficacy.

Gregory Hoffman, PhD
Dr. Hoffman is a postdoctoral fellow in the laboratory of Dr. John Blenis at Harvard Medical School. He received a three-year Fellowship Award to conduct biochemical- and RNAi-based studies on the mechanism(s) by which amino acids regulate the mTOR signaling network. Amino acid deprivation has been shown to block mTOR signaling in TSC2 null cells and the mechanistic understanding of the amino acid signaling network provided by this work may identify novel therapeutic avenues for the treatment of LAM.

Cheryl Walker, PhD
Dr. Walker is the Ruth and Walter Sterling Professor of Carcinogenesis at the University of Texas MD Anderson Cancer Center. She has been awarded a three-year Fellowship Award to study the consequences of mislocalization of p27 in the cytoplasm of LAM cells. These studies will investigate the contribution of aberrant p27 localization to the hormone-responsiveness of LAM cells and explore potential therapeutic agents that can reverse the adverse effects of loss of p27 from the nucleus.

Dan Noonan, PhD
Noonan Dr. Noonan is a Professor of Biochemistry at the University of Kentucky Chandler Medical Center. He has been awarded a three-year Established Investigator Award to study the biochemical mechanism(s) that relegate LAM disease primarily to lung smooth muscle cells of women. These studies will define how loss of a functional tuberous sclerosis gene facilitates the anomalous expression of the intracellular receptor for the female sex hormone estrogen. These studies will significantly advance our understanding of why LAM is a female and lung smooth muscle-specific disease, and may provide a novel mechanism for the development of LAM-specific therapeutic approaches.

Nicholas Vlahakis, MD
Dr. Vlahakis is an Assistant Professor, Rochester Mayo Clinic College of Medicine, was awarded a three-year Fellowship Award to determine the molecular mechanisms of vascular endothelial cell growth factor (VEGF)-induced LAM cell proliferation and the modulatory role of LAM-endothelial cell crosstalk in this proliferative response. These studies will help to determine the cause of LAM and provide novel pharmacotherapeutic targets for its treatment.

Hui Zhang, PhD
Zhang Dr. Zhang is a research assistant in the laboratory of Dr. Brendan Manning at the Harvard University, School of Public Health. She has been awarded a Pilot Award to determine the molecular and cellular mechanisms by which adipose tissue mass aberrantly develops and its potential role in the progression and pathogenesis of AMLs. The study will be carried out using a combination of cell-culture models, novel animal models, and available human AML tissue.

Aristotelis Astrinidis, PhD
Dr. Astrinidis is a staff scientist in the laboratory of Dr. Elizabeth Henske at Fox Chase Cancer Center. He has been awarded a three-year Fellowship Award to study the role of the molecular interaction between hamartin and Plk1 in the pathogenesis of LAM, utilizing biochemical, cell culture, and laboratory animal techniques. This study aims to identify new molecular pathways relevant to LAM, and new targets suitable for pharmacological intervention.

Geraldine Finlay, MD
Dr. Finlay is an Assistant Professor at the Tufts-New England Medical Center in Boston. She was awarded a three-year Fellowship Award to determine the role of statins as potential inhibitors of tuberin null cell growth and the mechanism that underlies the statin response. These studies will help to identify the mechanisms that drive proliferation in TSC and LAM and to aid the development of pharmacotherapeutic targets for their treatment.

NHLBI Intramural Research on LAM and LAM Patient Protocol

LAM research is being conducted through the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH).

LAM patients may be eligible to participate in clinical and basic research studies at the Mark O. Hatfield Clinical Research Center of the National Institutes of Health in Bethesda, Maryland. Participants must meet specific LAM patient protocol requirements.

The protocol includes an initial three- or four-day admission for inpatient studies involving a general medical evaluation, as well as routine pulmonary function testing. LAM patients are asked to return if they qualify for clinical trials or research studies. Any part(s) of the testing may declined by the patient.

Any LAM patient who participates in this study will continue to remain under the care of the patient's own physician. If requested by the patient, a summary of the clinical findings will be sent to the LAM patient's physician. There is no charge for the evaluation. In addition, under most circumstances, transportation expenses will be paid for patients with LAM living in the United States and Canada. LAM patients in other countries may participate if they are willing to pay their own expenses for travel to the United States (U.S.)

The LAM Foundation encourages women with LAM and physicians who have patients with LAM to participate in this worthwhile study. Studies such as this are important in understanding this devastating disease and we are fortunate that the NHLBI is conducting a LAM protocol aimed at understanding the pathogenesis of LAM. Success of the program depends on their ability to recruit LAM patients. If you are interested in further information or have any questions, you may contact the LAM Foundation at (513) 777-6989.

The following information is requested for the intramural LAM protocol:

Referral letter from your physician
Medical history, including medications and surgeries
Copy of most recent PFTs
Lung biopsy slides and biopsy specimens from other sites (e.g., abdominal tumors) with pathology report and, if available, paraffin tissue blocks
Copies and reports of the most recent chest X-ray and CT films of the chest, abdomen and pelvis

If you have questions, you may call the clinical research office toll-free at 1-877-NIH-LUNG (option # 3).

Information and inquiries may be directed to:

Joel Moss, M.D., Ph.D.
National Institutes of Health
Bldg.10, Room 6D03, MSC 1590
Bethesda, MD 20892-1590

Intramural Research on LAM

LAM research is being conducted presently through the Intramural Research Program at the National Heart, Lung, and Blood Institute (NHLBI) at the National Institutes of Health (NIH). The program is headed by Dr. Joel Moss.

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