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 105 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 Awards for the Study of LAM

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

 

Past 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.

 

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