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 109 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 Annual Grant Awards for the Study of LAM

$367,000 Additional Funds are Committed to LAM Research! Take a Look at Our Fall 2014 Grant Recipients.


Andrey Parkhitko, PhD
Fellowship Award
Harvard Medical School

A Cross-Species Approach to the Discovery of Genes Accelerating TSC/LAM Tumor Growth

The goal of this research project is to test the relevance of the additional transcriptional alterations in Tuberous sclerosis complex (TSC) tumors to its pathogenesis. TSC, a tumor syndrome associated with various tissues that include the brain, skin, kidneys, heart, and lungs, affects an estimated 1 in 6,000 to 10,000 births. In addition, varied neurological and cognitive deficits are very common and represent the most severe features of TSC. Currently, clinical trials of mTORC1 inhibitors (Sirolimus, Everolimus) are effective at reducing the size of SEGA and renal AMLs, as well as stabilizing lung function in women with LAM. After withdrawal, however, renal AMLs regrow and lung function decline resumes. Our research will allow the identification of additional pathways that synergize with mTORC1 and provide new strategies for the cure of TSC diseases.


Raymond Yeung, MD
Pilot Award
University of Washington

Serum Metabolites in LAM

The diagnosis of LAM is often delayed and requires invasive biopsy. Blood tests such as VEGF-D level may one day simplify this process. Biomarkers are also useful in detecting disease burden and may indicate response to therapy. Hence, biomarkers may enable one to determine if a certain treatment is likely to produce a response or not, and if not, to seek alternatives and to lessen undue toxicities. In this proposal, we seek to discover novel biomarkers using state-of-the-art techniques in detecting changes in metabolite levels in the blood. This pilot award will enable us to screen a limited number of samples and come up with a handful of candidate metabolites that will form the basis of larger validation studies in the future.

Lisa Young, MD
Established Investigator Award
Vanderbilt University
Lymphangiogenesis and Estrogenic Milieu as LAM Biomarkers

Lymphangioleiomyomatosis (LAM) is a progressive lung disease that occurs essentially only in women. Vascular endothelial growth factors (VEGF) promote the growth of blood/lymphatic vessels. Serum VEGF-D is a protein that is elevated in the blood of ~70% of women with LAM and can be used for LAM diagnosis. In addition, higher VEGF-D levels are associated with more severe lung disease, and blood levels correlate with response to sirolimus therapy. However, VEGF-D levels are normal in ~30% of LAM patients, and there remains significant unmet need for additional biomarkers to aid in diagnosis, prognosis, and assessment of treatment response. Further, the reason why LAM occurs only in women remains uncertain, as well as the factors that lead to onset of LAM in women with Tuberous Sclerosis Complex (TSC). This research project is designed to determine whether VEGF-D levels are elevated in women with TSC who are at risk for LAM, and to examine whether other related markers are elevated in the blood of women who have normal VEGF-D levels. These studies will also examine measures of estrogen activity, to understand whether estrogen-related compounds are additional biomarkers for LAM that may relate to disease onset and progression. Overall, these studies will improve understanding of the early contributors to LAM onset and disease progression, and identify additional biomarkers that can be used to diagnose, predict prognosis, and monitor patients with LAM.

Debbie Clements, PhD
Pilot Award
University of Nottingham
United Kingdom
Investigating the Cross Talk Between LAM Cells and recruited Stromal Fibroblasts

LAM cells grow in the lungs and cause the lung tissue to break down, resulting in respiratory failure, but we do not know what causes this to happen. Our hypothesis is that the nodules that form in the lungs of patients with LAM contain different cell types, some of which have a mutation in TSC2, and some of which do not. We think the cells which do not carry the mutation are a normal cell type called a fibroblast.  We believe that it is the interaction between these cells that is so destructive to the lungs, because high levels of damaging proteases are generated.

We would like to test our hypothesis by looking very closely at changes that occur in fibroblasts after they have been in contact with LAM cells. The cells may become more migratory, grow faster, or produce more proteases. We are able to look at changes in the expression of all the genes of the fibroblasts at once using a microarray. We can then see which pathways are most affected by the interaction between the cells and identify underlying mechanisms that will be targets for new and effective therapies.

Once we have identified altered pathways we can investigate them in a model of LAM, including both fibroblasts and cells with a mutation in TSC2, which we can grow in a tissue culture dish. We can target these pathways using existing drugs and determine whether this disrupts the formation or survival of our co-culture LAM nodules, and in this way test many drugs which may prove to be novel therapies for LAM.

http://www.thelamfoundation.org/images/khalid-almoosa.jpg

Khalid Almoosa, MD
Special Project Award
University of Texas
Health Science Center
Does Variability of Care Exist Among LAM Specialty Clinics?

Variability in healthcare is a common problem that can affect the quality of care provided to patients with complex diseases. Lymphangioleiomyomatosis (LAM) is a rare and complex lung disease that affects women and results in significant limitations in their health and life activities. The LAM Foundation has helped establish specialty clinics for LAM patients whose goal is to provide the best and most state-of-the-art care possible. The objective of this application is to determine the presence of unwarranted variability in the LAM clinics that is not due to patients needs or preferences and reduce it, so that the optimal quality of care is provided to these patients at all times. The successful completion of this project will further our understanding of how these growing LAM clinics operate, including their strengths, challenges, and patient experiences.

 

 


 

2013 Grant Recipients


Gina Lee, PhD
Fellowship Award
Harvard Medical School

 

MECHANISM OF TUMORIGENSIS BY mTOR1-MEDIATED mRNA ALTERNATIVE SPLICING

Cells can make different types of proteins from a single gene by cutting, removing, and rejoining part of the gene. This process, called alternative splicing, normally occurs to make specific protein types required for each organ and developmental time. Cancer research has mostly focused on investigating gene expression or protein quality control. However, recent large-scale screen technologies have found that alternative splicing is remarkably changed in tumors. For example, cancer cells express an embryonic type of a certain metabolic protein to provide growth advantage. In breast cancer patients resistant to chemotherapy, aberrantly spliced oncogene was identified to confer drug resistance. I discovered that alternative splicing of specific genes is changed in LAM cells. Moreover, I found that the activity of splicing regulating factors is also dysregulated in LAM cells. I will perform in-depth mechanistic studies to identify signaling processes controlling alternative splicing and investigate the effect of altered splicing in LAM pathogenesis. Successful completion of the proposed work will demonstrate that the alternative splicing process is likely to be a rich source of novel drug targets and diagnostic markers, which will lead to development of more selective and effective therapeutic interventions for LAM.



Chenggang Li, PhD
Fellowship Award
Brigham and Women's Hospital

Estradiol and mTORC2 Orchestrate to Enchance Prostaglandin Biosynthesis and Tumorgenesis in LAM

Lymphangioleiomyomatosis (LAM), the pulmonary manifestation of tuberous sclerosis complex (TSC), is a devastating disease affecting women, often leading to end-stage lung disease during or soon after pregnancy. The pathogenesis of LAM is very unusual: LAM cells are histologically-benign smooth muscle cells carrying TSC2 mutations that are believed to transfer or metastasize to the lungs, where they cause lung degeneration. The only proven treatment for LAM is lung transplantation, which carries significant one-year mortality and after which LAM can recur in the transplanted lungs. The reasons that LAM affects women almost exclusively are not yet clearly defined, and animal models that mimic the metastatic behavior of LAM cells have not been previously developed. Our animal model provides in vivo evidence that estrogen promotes the survival and metastasis of Tsc2-null cells and increased expression of COX-2, which allows us to investigate the possibility that targeting COX-2 pathways may have a major role in the treatment of TSC and LAM. In addition, this model will allow other novel agents and/or combinations of existing agents to be tested in preclinical stage. This will further facilitate the eventual development of effective therapies for TSC and LAM, which are urgently needed.

Hilaire Lam, PhD
Fellowship Award
Brigham and Women's Hospital

 

MicroRNA in LAM:  Therapeutic Targets and Biomarkers

Lymphagioleiomyomatosis (LAM) is a devastating disease of women that is associated with lung destruction and progressive lung function decline. LAM is caused by mutations in TSC1 and 2, resulting in hyperactive mammalian Target of Rapamycin (mTORC1), which leads to excessive cell growth and proliferation. Rapamycin and related “rapalogs” inhibit mTORC1 and promote tumor regression; however, tumors regrow upon treatment cessation suggesting that rapalogs prevent LAM cell proliferation, but do not induce specific LAM cell death. To identify novel therapies that promote cell death in TSC-deficient cells, we sought to determine whether dysregulated expression of microRNA (miRNA or miR) contributes to TSC pathogenesis and rapamycin-resistance. miRNA are small molecules that can target multiple mRNA transcripts, negatively regulating the formation of proteins from genes. In recently published experiments using TSC2-deficient cells we identified rapamycin-dependent miRNA “Rapa-miRs”. Amongst the most highly expressed Rapa-miRs we identified pro-tumorigenic miRNA, “onco-miRs,” including miR-21, miR-221 and miR-29b. We hypothesize that targeting these pro-survival miRNAs will enhance rapamycin effectiveness. To explore this hypothesis we will investigate the regulation of miRNA by rapamycin, identify target genes regulated by rapa-miRs, determine the in vitro and in vivo effects of rapa-miR knockdown, and measure TSCLAM miRNA biomarkers in patient plasma versus healthy patient controls. These studies will identify novel therapeutics and potential biomarkers, which may have a profound impact on the clinical diagnosis and treatment of LAM patients.

 

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