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 $13 million raised by The LAM Foundation has supported 83 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.
Click here to read recent article by LAM Foundation scientist Nicholas Vlahakis.
$275,000 Additional Funds are Committed to LAM Research!
Three scientists were selected from the Fall 2009 applicants to receive LAM awards for projects beginning in January 2010. Take a look at our latest recipients!
John Blenis, PhD Harvard Medical School, Dr. John Blenis is Professor of Cell Biology at Harvard Medical School. He has been awarded a three-year Established Investigator Award to study the role of glutamine metabolism in LAM and TSC. One goal of this research effort is to determine how glutamine provides cells exhibiting inappropriately activated mTOR signaling, with an alternative source of energy and TCA cycle replenishment needed to promote their survival. Another goal is to investigate if inhibition of glutamine metabolism can be utilized as a therapeutic option for TSC and LAM.
Lawrence Quilliam, PhD Indiana University, Dr. Lawrence Quilliam is Professor of Biochemistry and Molecular Biology at Indiana University School of Medicine. He was awarded a two-year Established Investigator Award to determine if drugs that prevent the clearance of unfolded proteins from the endoplasmic reticulum (ER), that arise as a result of TSC1/2 loss in angiomyolipoma and LAM cells, will selectively promote ER stress and death of these cells. Since this approach, in contrast to rapalog treatment, is designed to selectively kill TSC/LAM cells rather than just halt their growth, it could have a longer-lasting impact following completion of therapy.
Stephen Hammes, MD, PhD University of Rochester, Dr. Stephen Hammes is Chief of the Division of Endocrinology at the university of Rochester Medical Center. He has been awarded a Pilot Award to create a mouse model for Lymphangioleiomyomatosis (LAM). Despite intese investigation, it is still not known why LAM is seen almost exclusively in women. Dr. Hammes postulates that LAM lung lesions are specific to women because they share similar features and possibly origins to uterine tumors. Pathologic and physiologic evidence reveal remarkable similarities between LAM lesions and uterine myometrial tumors. For example, all express markers consistent with a smooth muscle origin. Furthermore, like uterine tissue and uterine-derived tumors, LAM tumors grow in response to estradiol. Importantly, the majority of LAM tumors have mutations in TSC genes. The Hammes Lab believes that LAM lesions may have similar origins to adenomas derived from the uterine from the uterine myometrium; however, mutations in TSC genes provide the "additional hit" to promote tumor growth. Therefore, they are creating a mouse strain with a uterine-specific loss of TSC-2 expression, with hopes that they will form LAM-like tumors in mice that can be used as a working model for LAM.
The LAM Foundation 2008 & 2009 Awards for the Study of LAM
Dr. Roberto Zoncu, Whitehead Institute, Dr. Roberto Zoncu works in the laboratory of Dr. David Sabatini at the Whitehead Institute in Cambridge, Massachusetts. Dr. Zoncu is using advanced live microscopy to understand the spatial and temporal properties of the mammalian Target of Rapamycin (mTOR), a master regulator of cellular growth and proliferation. Mutations of the mTOR pathway are increasingly viewed as key players in the pathogenesis of LAM Dr. Zoncu will investigate whether the cellular location and dynamic behavior of mTOR proteins is altered in cellular models of LAM, with the ultimate goal of identifying novel cellular and molecular processes that may be targeted in the therapy of this disease.
Dr. Elena Lesma University of Milan, Dr. Elena Lesma performs her research in the laboratory of Dr. Alfredo Gorio at the University of Milan in Milano, Italy. Dr. Lesma's research award will allow her to focus on developing a LAM model by inoculating TSC2 smooth muscle cells in nude mice. This animal model may help to determine how pathological cells migrate and metastasize and to design and evaluate tha development of pharmacological strategies. Dr. Lesma's grant is jointly funded with the American Thoracic Society (ATS).
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.
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, PhoA, 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 potentila combinatorial therapeutic targets that may inhibit tumor growth in LAM. Dr. Goncharova's research will be co-funded by the American Thoracic Society (ATS).
Elizabeth Henske, MD, Director, Center for LAM Research & Clinical Care at Brigham & Women's Hospital, Harvard Medical School 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.
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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