Current LAM Research

It is amazing how far LAM research has come in such a short period of time. Many researchers who have received funding from The LAM Foundation 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 LAM Foundation has committed over $10 million to LAM research to support 102 peer-reviewed grants and other research projects for the study of lymphangioleiomyomatosis (LAM). LAM Foundation funded scientists reported numerous breakthroughs, resulting in the first-ever LAM treatment trial to test a drug called sirolimus, or rapamycin, which proved to be an effective treatment for LAM (results published in the April 2011 issue of the New England Journal of Medicine (NEJM). Additional clinical trials are underway as LAM Foundation-funded researchers continue to work with urgency in search of more safe and effective treatments.

The LAM Foundation Announces Its Annual Awards for the Study of LAM

$350,000 Additional Funds are Committed to LAM Research! Take a Look at Our Fall 2012 Grant Recipients.

Dr. Hammes

Stephen Hammes, MD, PhD
Dr. Stephen Hammes is a Professor and Chief of Endocrinology and Metabolism at the University of Rochester Medical Center. He has received a three-year Established Investigator Award to further develop a mouse model of uterine-specific knockout in Tsc-2. Dr. Hammes proposes that LAM tumors are basically uterus leiomyomas that have been made more aggressive through inactivation of the TSC gene. As proof of this hypothesis, Tsc signaling was shut off exclusively in the uterus of a mouse. These mice developed uterine tumors that resemble leiomyomas, and some developed lung lesions that resemble LAM.  Dr. Hammes plans to use these mice as a model to develop novel strategies to both detect and treat LAM.

Dr. Kristof

Arnold Kristof, MD
Dr. Arnold Kristof is an Associate Professor of Medicine at McGill University in Montreal, Canada. He has received a three-year Established Investigator Award to further his study of the role of urotensin, a growth-promoting neuropeptide, in the tumors that arise in LAM. His work is based on the observation that urotensin-II and its receptor are increased in the LAM nodules that cause progressive destruction of the lung. The main goal of this work is to understand the effect of urotensin-II on the growth and destructive properties of cells lacking the TSC2 gene. Dr. Kristof will also test whether a drug that blocks urotensin-II activity prevents the appearance of cells lacking the TSC2 gene in the lungs of mice. Targeting the urotensin receptor may prevent the progression of disease in patients with LAM. Funding for this project is jointly provided by The LAM Foundation and the LAM Canada Fund at Tides Canada.

Dr. Handin

Robert Handin, MD

Dr. Robert Handin is a Senior Physician at Brigham & Women’s Hospital and Professor of Medicine at Harvard Medical School. He has received a one-year Pilot Award to evaluate the use of a zebrafish system to study angiogenesis and lymphangiogenesis in LAM. Dr. Handin has developed a technique to study angiogenesis (development of blood vessels) in other cancers by injecting tumor cells into developing zebrafish embryos. His goal is to determine whether using this technique with cultured LAM cell lines will induce blood vessel development, as well as lymphatic development (lymphangiogenesis), and whether blocking lymphatic or blood vessel production prevents LAM tumor growth.



Dr. Holz

Marina Holz, PhD
Dr. Marina Holz is an Assistant Professor at the Stern College for Women and the Albert Einstein College of Medicine of Yeshiva University. She has received a one-year Pilot Award to study mTORC1 and S6K1 signaling in LAM. Dr. Holz proposes that S6K1 may be an attractive target for LAM treatment since it is an important regulator of cell growth, proliferation and autophagy. She hypothesizes that inhibiting specific components of S6K1 signaling downstream of the mTORC1 pathway may prove to be a more effective and less toxic treatment than current rapalog therapies. She also will study the connections between the S6K1 and estrogen functions in LAM cells as a basis to develop combination therapy approaches for treatment.

Dr. Lo

Pechin Lo, PhD

Dr. Pechin Lo is a Postdoctoral Researcher at UCLA’s Center for Computer Vision and Biomarker Imaging. He has received a one-year Pilot Award to evaluate whether a computer-aided CT imaging biomarker might provide valuable outcome measurements for LAM clinical trials. Current radiologist methods that involve visual assessment give only coarse evaluation of the extent of LAM in a chest CT.  Computer-based approaches developed in recent years provide the level of destruction in lung tissue, but are not sufficient to analyze the changes and progression of complicated diseases such as LAM. Dr. Lo seeks to develop and evaluate a quantifiable and sensitive CT imaging biomarker for early detection of treatment effects of LAM. The goal of the imaging biomarker is to reduce both duration and population size of drug trials, thus lowering the cost and time required to develop safe and effective treatments for LAM.

 

Past Grant Recipients

Dr. Krymskaya

Vera Krymskaya, PhD
Dr. Vera Krymskaya is an Associate Professor of Medicine in the Pulmonary, Allergy and Critical Care Division of the Department of Medicine at The University of Pennsylvania.  She has received a three-year Established Investigator Award to study the role of TSC2 in airspace enlargement in LAM.   Dr. Krymskaya’s preliminary data provides evidence that airspace enlargement occurs specifically due to growth of cells deficient for TSC2, thus establishing a direct link between loss of TSC2 function, abnormal growth of TSC2-null cells and lung destruction. Her study will identify cellular mechanisms of airspace enlargement induced by TSC2-null tumor growth, will provide insights about novel molecular targets, and will provide pre-clinical evidence for treatment of LAM.
Dr. Ben-Sahra

Issam Ben-Sahra, PhD
Dr. Issam Ben-Sahra is a Postdoctoral Research Fellow in the laboratory of Dr. Brendan Manning in the Department of Genetics and Complex Diseases at the Harvard School of Public Health.  He has received a three-year Fellowship Award to study the molecular consequences of TSC2 loss, with a focus on cellular metabolism. It is well known that the way cancer cells metabolize nutrients to rapidly grow is quite distinct from their tissue of origin. Dr. Ben-Sahra hypothesizes that LAM cells also have a unique form of metabolism that they depend on for their unique characteristics. Importantly, this difference between LAM cells and normal cells, by definition, provides a therapeutic opportunity to selectively eradicate LAM cells. This study will define the metabolism of cells lacking TSC2, establish molecular mechanisms underlying the metabolic reprogramming of these cells, and identify points of vulnerability that can be exploited for LAM therapy.
Dr. Kim

Carla Kim, PhD
Dr. Carla Kim is an Assistant Professor in the Department of Genetics at Harvard Medical School and the Stem Cell Program at Children's Hospital Boston.  She has received a one-year Pilot Award to test the possible uterine origin of LAM.   Dr. Kim will be examining whether additional LAM lesions express the same molecules as uterine tissues and also work to model the disease in mice by inducing a LAM-specific mutation directly within the uterus. Dr. Kim believes that the proposed studies will not only clarify the origins of LAM, but will aid in the development of novel therapeutic avenues.

Dr. Gan

Boyi Gan, PhD

Dr. Boyi Gan is an Assistant Professor in the Department of Experimental Radiation Oncology at The University of Texas M.D. Anderson Cancer Center.  He has received a one-year Pilot Award to study the role of a protein called FoxO in the molecular pathogenesis of LAM.  FoxO serves as a transcription factor which can regulate the expression of many gene targets and functions as an important component in PI3K pathway, which is a heavily studied target in current cancer drug development pipelines. Given the critical role of FoxO in PI3K signaling, Dr. Gan hopes to expand drug development opportunities for LAM and/or identify a FoxO biomarker which may provide a pharmacodynamic marker for monitoring the impact of anti-PI3K drugs in LAM clinical trials.

Dr. Gu

Xiaoxiao Gu, PhD

Dr. Xiaoxiao Gu is a Postdoctoral Fellow in the laboratory of Dr. John Blenis at Harvard Medical School. She received a three-year LAM Foundation Fellowship Award to study the role of the Ras/Raf/MEK/ERK pathway in regulating LAM cell migration. Preliminary data has confirmed that estrogen stimulates the TSC2-null LAM cell migration and that blocking MEK1/2 significantly blocks LAM cell migration. Migration significantly increases upon RSK inhibition at the same time ERK1/2 is activated. The hypothesis is that signaling through the Ras/Raf/MEK/ERK pathway diverges at the level of ERK1/2 to ERK-DEF motif subset signaling and regulates Fra1 and ZEB2 expressions, which may be connected to the mTORC1 pathway in regulating migration, invasion and survival of LAM cells. The objective of this project is to elucidate the role of the Ras/Raf/MEK/ERK pathway in regulating LAM cell migration in the presence and absence of estrogen, and elucidate the molecular details of how this pathway contributes to the LAM phenotype. The clinical goal is to optimize the current rapamycin treatment regimens by combining them with inhibition of the ERK-DEF motif signaling pathway. Long-term goals are to define and validate the proposed studies and develop small molecule screens to find inhibitors of ERK-DEF signaling, with anticipation that such small molecules will be effective therapies for LAM and other ER-sensitive cancers.

Dr. Csibi

Alfredo Csibi, PhD

Dr. Alfredo Csibi is a Postdoctoral Fellow in the laboratory of Dr. John Blenis at Harvard Medical School. He received a three-year LAM Foundation Fellowship Award to focus on finding a treatment for LAM by exploiting the metabolic properties of LAM and TSC cells. Recent work from this laboratory has demonstrated that these cells have high metabolic demand, requiring glutamine as a critical source for survival during energetic stress. Moreover, recent data suggest that the activation of the mTORC1 signaling pathway stimulates glutaminolysis by regulating the expression of glutaminase. The goal of Dr. Csibi’s project is to elucidate the mechanisms involved in the mTORC1-dependent control of glutamine metabolism and to evaluate whether the estrogen receptor signaling promotes glutaminolysis as well as its consequences on the survival of LAM and TSC cells. This project will also examine alternative metabolic drugable targets and screen for small molecules that target glutamine metabolism to efficiently kill TSC-null cells, providing new therapeutic avenues for the treatment of LAM and TSC.
Dr. Henske

Elizabeth Henske, MD
Dr. Elizabeth Henske is the Director at the Center for LAM Research and Clinical Care at Brigham and Women's Hospital. She is completing an Established Investigator Study of 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) 777-6889.

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