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SCIENTIFIC RESEARCH:

The efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis
August 2013

Background
Lymphangioleiomyomatosis (LAM) is a rare disease caused by dysregulated activation of the mammalian target of rapamycin (mTOR). Sirolimus, an inhibitor of mTOR, has been reported to decrease the size of angiomyolipomas and stabilize pulmonary function in patients with LAM. However, the optimal dose for the treatment of LAM remains unclear.

Methods
We conducted a retrospective, observational study of 15 patients with LAM who underwent sirolimus therapy for more than 6 months. The efficacy was evaluated by reviewing the patients' clinical courses, pulmonary function and chest radiologic findings before and after the initiation of sirolimus treatment.

Results
All patients had blood trough levels of sirolimus lower than 5ng/mL. Sirolimus treatment improved the annual rates of change in FVC and FEV1 in the 9 patients who were free from chylous effusion (FVC, ?101.0 vs. +190.0mL/y, p=0.046 and FEV1, ?115.4 vs. +127.8mL/y, p=0.015). The remaining 7 patients had chylous effusion at the start of sirolimus treatment; the chylothorax resolved completely within 1?5 months of treatment in 6 of these cases. These results resembled those of previous studies in which blood trough levels of sirolimus ranged from 5 to 15ng/mL.

Conclusions
Low-dose sirolimus (trough level, 5ng/mL or less) performed as well as the higher doses used previously for improving pulmonary function and decreasing chylous effusion in patients with LAM.
Ando K, et al. The ef?cacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis. Respiratory Investigation (2013)

> Click here to view this paper.


Stunning Breakthrough from TSC and LAM Research!
February 2013

LAM Foundation-funded scientists, Drs. Issam Ben-Sahra and Brendan Manning, today reported in the Science journal that mTOR, the cellular growth switch that is stuck 'on' in LAM, also directly controls the synthesis of nucleotides, the building blocks for RNA and DNA. This newly-discovered mTOR function explains how cells are able to create the additional genetic material required for cellular replication and tumor growth. This finding joins the ranks of 'classic principles in biology', one of several that have emerged from the study of TSC and LAM, and will suggest new targets for the treatment of LAM, TSC, and other neoplastic and cancerous processes.

The LAM Foundation congratulates Drs. Ben-Sahra and Manning for this remarkable discovery. This work was funded in part by a LAM Foundation Fellowship Award to Dr. Ben-Sahra. Dr. Manning is a member of The LAM Foundation Scientific Board.


Clinical paper published holds exciting news for LAM patients
3 October 2012

Publication of the collaboration between Professor Merv Merrilees of the University of Auckland and Professor Vera Krymskaya et al of the University of Pennsylvania.

The LAM Trust is proud to announce publication in the prestigious Science Translational Medicine of the paper titled "Model of Pulmonary Lymphangioleiomyomatosis (LAM): Prevention of Alveolar Destruction and Airspace Enlargement in a Mouse".

This collaboration and publication of this research heralds new and exciting opportunities for clinical trials in LAM patients.

> Click here to read this paper


Self-Renewal Properties of LAM cells
Final Research Report for the LAM Trust of NZ – JW Baty and M Berridge, Malaghan Institute of Medical Research
July 2012

LAM cells invade lung tissue forming nodules and causing cystic destruction and remodeling of the lung interstitium as well as obstructing airways and pulmonary lymphatics, and leading to the development of cystic structures...

> read full document


Use of variability in national and regional data to estimate the prevalence of lymphangioleiomyomatosis
Q J Med

Published by Oxford University Press on behalf of the Association of Physicians.

> open document


Room to Breathe
North South magazine
August 2011

For a small group of New Zealand women with a rare but fatal lung condition, Mervyn Merrilees' pioneering research on heart disease offers an unexpected glimmer of hope.

Day by day, Imeleta Maddox's lungs are running out of space. You can almost feel the effort of each laboured breath - the fight to draw in air and the suffocating sensation of never quite getting enough.

> read full article


MILES Trial Results Published
The LAM Foundation, USA
16 March 2011

The LAM Foundation is extremely pleased and proud to share some outstanding news. The MILES Trial final analysis has taken place and the trial results are reported in today’s on-line version of the New England Journal of Medicine (NEJM). In addition to the trial results, the NEJM also published an editorial which highlights the trial and the role of The LAM Foundation in research advancements

The MILES Trial was the first randomized, controlled study designed to develop a therapy for LAM. The primary endpoint was met. Treatment with sirolimus, also known as rapamycin, for one year resulted in a small but significant improvement in FEV1. Frank McCormack, MD, Director of the Pulmonary, Critical Care and Sleep Medicine Division at the University of Cincinnati, was the lead investigator on the study. Dr. McCormack also serves as the Scientific Director of The LAM Foundation, which played an integral role in the success of the trial. In addition to providing supplemental funding, which covered the costs of data monitoring and patient travel reimbursement, the Foundation worked together with the investigators on the education and recruitment of LAM patients.

The LAM Foundation would like to take this opportunity to thank the LAM patients in the United States, Japan and Canada who were involved in the MILES Trial. Because of their hope for a treatment and ultimately a cure, they chose to become involved. Trials are not for everyone for a variety of reasons, but for the 111 LAM patients who consented, and the 89 who completed this trial, all LAM patients and their families thank you. Without your courage, a treatment would have been missed. Our gratitude is extended to the generous sponsors who provided the funding. The LAM Foundation would also like to thank Dr. McCormack and all of the professionals and institutions involved in the MILES Trial.

Please click here to go to The LAM Foundation’s website for the links to the full New England Journal of Medicine article, the editorial, a press release from the University of Cincinnati and also FAQs about the Trial results.

links:
New England Journal of Medicine (NEJM) Publishes MILES Trial Results


The Power of Patient and Family Pays Off
16 March 2011
New England Journal of Medicine

There are an estimated five women per million in the United States who suffer from lymphangioleiomyomatosis (LAM), a rare and devastating disease that almost exclusively strikes young women.1-3 These patients have progressive loss of lung function, and many die from respiratory failure. Until recently, a diagnosis of LAM was a medical anomaly, and a woman who received this diagnosis had little cause for hope. The disease was likely to be managed symptomatically by physicians unfamiliar with the disease. > read more


New LAM Research
November 2009

A contract has been signed and work begins this month at the Malaghan Institute for Medical Research in Wellington.

The Agreement to fund a one year pilot programme of new LAM Research is between the Malaghan Institute's Cancer Cell and Molecular Biology Group and The New Zealand LAM Trust in collaboration with LAM Australasia Research Alliance (LARA).

Malagan's Dr James Baty & Prof Mike BerridgeThe Wellington based work which is part of a proposed three year study will be undertaken by Professor Mike Berridge and his team at the Institute, in collaboration with Dr Lyn Moir from Professor Judy Black's lab at the University of Sydney.

The Project will investigate the cancer-like properties of LAM cells; in particular, whether LAM cells can grow in culture, under conditions that support the growth of self-renewing cancer cells. The team will investigate whether LAM cells grown in these conditions, express self renewal genes typical of cancer stem cells.This work is designed to be part of a larger study that will explore the feasibility of treating LAM, using the immunological therapies currently being developed for treating cancer.

Both the Australian and New Zealand LAM patient organisations which have raised the money for this project wish to thank supporters for their donations that have made this work possible and we wish the research teams well in the first year of this exciting programme.


Feasibility of Immunotherapy for Lymphangioleiomyomatosis
published in The American Journal of Pathology

November 2009
From the Department of Pathology and the Cancer Research Center, University of Hawaii, Honolulu, Hawaii

LAM strikes women during their reproductive years and leaves patients with a much reduced life expectancy at diagnosis. Patients with LAM present with recurrent pneumothoraces, hemoptysis, pleural effusions, and dyspnea on exertion. There is no truly effective treatment available beyond lung transplantation. LAM is definitively diagnosed by detecting expression of the glycoprotein recognized by the antibody HMB45. Differential diagnosis is otherwise difficult, and patients with sporadic LAM typically remain undiagnosed for several years. > more


Melanoma–Associated Antigen Expression in Lymphangioleiomyomatosis Renders Tumor Cells Susceptible to Cytotoxic T Cells
published in The American Journal of Pathology

November 2009
From the Departments of Pathology, Microbiology and Immunology/Oncology Institute,* and Department of Surgery,† Loyola University, Chicago, Illinois; Illinois Math and Science Academy,‡ Aurora, Illinois; Department of Medicine,§ Loyola University, Chicago, Illinois; Department of Surgery,¶ University of Chicago, Chicago, Illinois; Department of Dermatology, University of Cincinnati, Cincinnati, Ohio; and Department of Surgery,** Medical University of South Carolina, Charleston, South Carolina

Following the identification of underlying mutations responsible for the symptoms incurred in LAM and intracellular signaling pathways affected by TSC1/TSC2 through the mammalian target of rapamycin complex, proposed disease treatments have been aimed at the hyperproliferative responses observed in mutant cells. The mammalian target of rapamycin inhibitor rapamycin has been tested in phase 1 trials with mixed results. > more


Molecular Pathogenisis of LAM
published in American Journal of Respiratory, Cell and Molecular Biology

December 2007

Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials. > more


Collaborative Programme of Scientific Investigation into LAM

As a result of three years of work by The New Zealand LAM Trust, the team of New Zealand and Australian researchers (pictured right) are working against the clock as part of an international collaborative effort to uncover answers to the causes of this rare and cruel disease.

Dr Lyn Moir began her work at The University of Pennsylvania in the lab of Dr Vera Krymskaya in June 2007. Dr Moir will return to The University of Sydney in 2008, and it is hoped that funds will be raised to enable her to continue her cell signalling work there.

A presentation abstract on the work completed in Philadelphia will be made at the American Thoracic Society's annual meeting in Toronto in 2008 and at the Australasian Thoracic meeting in Melbourne in May 2008.


Lymphangioleiomyomatosis
by Francis McCormack, MD

Lymphangioleiomyomatosis (LAM) is a rare, progressive, cystic lung disease that occurs almost exclusively in females, usually between menarche and menopause. The hallmarks of LAM are diffuse infiltration of the pulmonary parenchyma with atypical smooth muscle cells, airflow obstruction, pneumothorax and chylothorax, and progressive respiratory failure... > more


Australian Scientific Investigation

In June 2004 the prestigious UK Journal of Pathology published a Paper from Professor Mervyn J Merrilees, principal investigator,University of Auckland in conjunction with Professor Judith L. Black, University of Sydney. The paper is titled "Matrix Proteoglycans and remodelling of interstial lung tissue in Lymphangioleiomyomatosis (LAM)".

This Paper can be seen on line in Wylie InterScience (www.interscience.wiley.com) and is published in J Pathol 2004; no 203: 653-660.

Currently, NZ LAM Trust funded LAM science investigation continues at the University of Auckland.

Professor Merrilees and his team's recent studies (UK Journal of Path) have shown that LAM is characterised not only by the growth of defective smooth muscle cells, but also by significant amounts of interstitial tissue that contain normal fibroblasts and large amounts of space occupying matrix proteoglycans.

Of particular interest is the finding that areas rich in proteoglycans are depleted in elastic fibres which are essential to the proper functioning of the lung during breathing.

Prof Merrilees and the team have been working with the drug rapamycin which has been found to be a very effective inhibiter of cell migration.

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