Current LAM Research

It is amazing how far LAM research has come in such a short period of time. Thanks to the many researchers who have received funding from The LAM Foundation for helping 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 raised over $14 million, much of which has supported 87 peer-reviewed research projects for the study of lymphangioleiomyomatosis (LAM). LAM Foundation- funded scientists reported three 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 March 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.

Click here to read about Dr. Frank McCormack's & Dr. Lisa Young's VEGF-D project.

Click here to read a recent article by LAM Foundation funded scientist Nicholas Vlahakis.

The LAM Foundation 2010 Scientific Awardees for the Study of LAM

$350,000 Additional Funds are Committed to LAM Research!

	Xiaoxiao Gu, PhD, Harvard Medical School, Dr. Xiaoxiao Gu is a Postdoctoral Fellow in the laboratory of Dr. John Blenis at Harvard Medical School. She has 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.
	Alfredo Csibi, PhD, Harvard Medical School, Dr. Alfredo Csibi is a Postdoctoral Fellow in the laboratory of Dr. John Blenis at Harvard Medical School. He has 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.
	Arnold Kristof, MD, McGill University, Dr. Arnold Kristof is an Associate Professor of Medicine at McGill University in Montreal, Canada. He has received a LAM Foundation Pilot Award to study 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 why urotensin-II and its receptor are increased in cells lacking the TSC2 gene, and to understand how activation or blockade of the urotensin receptor might affect their growth and survival. Targeting the urotensin receptor may help kill, or halt the proliferation of, LAM cells and LAM-related tumors.
	Caroline Le Poole, PhD, Loyola University, Dr. Caroline Le Poole, is an Associate Professor of Pathology, Microbiology and Immunology at Loyola University Chicago. She has received a LAM Foundation Pilot Award to study a new protein on the surface of the LAM cell as a therapeutic target. Dr. Le Poole proposes that consistent expression of ganglioside D3 in LAM can be exploited to drive therapeutic immune responses to developing lung tumors. A major expression increase in GD3 is associated with tumor development in LAM. The same molecule has been targeted in clinical trials by antibodies to treat non-small cell lung tumors in the past, showing that targeting GD3 expression within the lung is safe. Besides assessing existing immune responses in patients, Dr. Le Poole wants to prepare a vaccine based on a novel means to target GD3.

These 2008 & 2009 award recipients have received continued funding for the second and third year of their grant projects:

	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. This project is currently supported by the Dawn Kleps Memorial Award and The LAM Foundation Board of Directors/Advisory Board Award.
	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) 777-6889.

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

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.