White Paper
The LAM Treatment Alliance: Fast-Tracking Treatment Research
A rare, untreatable neoplastic disease called LAM offers researchers an opportunity to help patients with severe unmet medical needs while uncovering new treatment possibilities for more common life-threatening illnesses such as diabetes, atherosclerosis, certain cancers and neurologic disorders. In a very short period, the LAM Treatment Alliance has enlisted some of the finest scientific minds studying the LAM disease pathway to collaborate in a process aimed at finding a treatment for this less common disease and in doing so benefiting current understanding of ways to approach treatment of "bigger" diseases. Funds are urgently needed to fast-track expert-directed, multidisciplinary translational research.
Lymphangioleiomyomatosis (commonly known as LAM) is an uncommon, fatal lung disease that affects women in their childbearing years. In LAM, abnormal smooth muscle-like cells proliferate in the lungs, pulmonary airway, parenchyma, lymphatics, and blood vessels, ultimately leading to respiratory failure.1
Approximately 30,000 to 50,000 women worldwide are estimated to have LAM. Women of all races are affected. There are approximately 250,000 estimated women worldwide with both Tuberous Sclerosis Complex as well as sporadic LAM. 2
Currently there are no effective treatments for LAM. A lung transplant is sometimes an option of last resort (once one becomes dependent on supplemental oxygen), if a matched donor can be found. There is a critical shortage of lungs for transplant. Current estimated survival rates for lung transplants irrespective of underlying disease are up to 80% at 1 year and 60% at 4 years.7 However, since transplantation does not treat the underlying cause of LAM, and LAM is understood to be metastatic with an origin outside of the lung, LAM is known to recur in the transplanted lungs. Transplant recipients also must take immunosuppressive (anti-rejection) medications indefinitely. These drugs lower immunity to prevent rejection, but also increase the risk of infection and other serious diseases. 3
LAM cells are very similar to cells found in the lungs of patients with a genetic disorder called tuberous sclerosis complex (TSC). 1 As many as 39 percent of women with TSC also have LAM.4 In TSC, usually benign tumors grow in the brain, kidneys, heart, eyes, lungs, skin and elsewhere. When it is not accompanied by LAM, TSC is usually treatable and disease varies from mild to severe. TSC can have serious effects including seizures, autism, developmental delays, and kidney disease.5
TSC and LAM seem to be affected by mutations in one of two tumor suppressor genes, TSC1 (which encodes a protein called hamartin) and TSC2 (encoding a protein called tuberin). One of the major functions of the tuberin-hamartin protein complex is to inhibit protein synthesis and limit the growth and proliferation of cells. Growth factors such as insulin activate an enzyme called Akt, which inhibits tuberin-hamartin function and thus increases protein synthesis. The tuberin-hamartin complex is also regulated by another enzyme called AMPK, which inhibits protein synthesis when energy levels in cells drop.6
The tuberin-hamartin complex - in combination with Akt, AMPK and a third protein, Rheb - plays a role in a key regulator of cell growth and proliferation, called mTOR.7
Targets and Regulators
Rapamycin (also known as sirolimus) is an immunosuppressive drug commonly given to transplant patients to avoid organ rejection.8 Rapamycin binds to and inhibits a key regulatory protein called the target of rapamycin (TOR). In animals ranging from fruit flies to humans, the TOR pathway (mTOR in mammals) plays a fundamental role in cell growth via the regulation of protein synthesis.9
The mTOR pathway regulates cell growth and survival in response to changes in levels of nutrients, energy sources, and growth factors.6 Several clinical trials are investigating inhibition of the mTOR pathway as a potential treatment approach for solid tumors such as those of the breast, prostate, and kidney, as well as certain hematologic malignancies. The mTOR disease pathway has also been implicated in type 1 and 2 diabetes,11 atherosclerosis,12 fibrosis,13 and several neurological disorders beyond TSC including Huntington disease 14 and epilepsy.15
The mTOR pathway comes in two flavors, because the mTOR protein is part of two distinct multiprotein complexes that contain mTOR and different interacting proteins. One complex, called mTORC1, is defined by the protein raptor. mTORC1 is likely to be directly activated by rheb. The second complex, called mTORC2, is defined by the protein rictor. mTORC2 activates the Akt kinase, which regulates tuberin-hamartin.16 The potential role of tuberin-hamartin and rheb in regulating mTORC2 is unknown.
Despite the evidence that the tuberin-harmartin regulates mTOR, there are increasing clues that this complex and rheb have other targets besides mTOR. Certain features of neurons that have lost tuberin-hamartin function are not affected when cells are treated with an mTOR inhibitor.17
Recently, scientists have found that mTORC1 suppresses signaling by the PI3 kinase pathway that is the key activator of Akt. Therefore, inhibition of mTORC1 can lead to activation of Akt and activated Akt is thought to promote tumorigenesis. Because loss of tuberin-hamartin (as occurs in LAM) activates mTORC1 it also suppresses Akt.18 Therefore, inhibition or activation of mTORC1 with drugs like Rapamycin (or its analogues) or genetic mutations will also have effects on Akt signaling. The implications for LAM and TSC of these effects on Akt are currently unknown.
Scientists looking for new drugs to inhibit the action of the mTOR pathway are intensely interested in tuberin, hamartin, and Rheb. Compounds that modify the function of those proteins and regulate mTOR activity could be studied as possible treatments for a large array of diseases, many of them life-threatening. It is important to keep in mind that mTOR inhibition is unlikely to affect other potential targets of tuberin-hamartin and that Rheb may have a role in the pathophysiology of LAM and other diseases. LAM provides a unique opportunity for research. Although rare, LAM is well understood at a molecular and cellular level, and lies at the intersection of pathways involved in several more common diseases, including sporadic cancers and diabetes.
A Multidisciplinary, Systems Biology Approach to Research
Discovering a treatment for LAM requires a multidisciplinary, systems biology approach, bringing together laboratory and clinical researchers interested in cell signaling, estrogen biology, pulmonary pathophysiology, vascular biology, and cancer, among other disciplines. Such an approach is directly in keeping with the multidisciplinary perspective outlined by the U.S. National Institutes of Health (NIH) Roadmap for Medical Research as a guiding principal for research funding and support.19,20 It is also the approach of the LAM Treatment Alliance.
This approach is compatible with a research thrust focused on translating basic science into clinically relevant interventions - i.e. translational research. One of our focus areas is working with institutions, corporations and scientists interested in translational research who increasingly look to diseases like LAM that are fairly well defined and in which the molecular pathway leading to the disease state is fairly clear for opportunities to show proof of concept. The idea here is to test compounds known to inhibit a specific target on a particular disease pathway for clinical efficacy, first in the laboratory and then in a small clinical trial. If the proof of concept is successful in the rare prototype disease (e.g. LAM), it can then be tested in more common diseases that share the same pathway.21
The proof of concept trial can become a win-win-win situation: Patients with the rare prototype disease benefit from early access to a promising treatment, scientists learn more about the underlying disease pathway, and the proof of concept can be applied to ongoing research for "bigger" diseases associated with the same pathway.
As a first step toward implementing a multidisciplinary, translational approach to research toward a treatment for LAM, the LAM Treatment Alliance has assembled leading scientists for a half-day summit at Harvard Medical School on December 3, 2005. These scientists and clinicians - already immersed in relevant research - have been moved by the human toll of LAM to take up the challenge of cracking this disease. By bringing together these hand-picked thought leaders (participants may rotate during future bi-annual summits) to pool their knowledge, define a set of research projects, prioritize and revisit them regularly, we believe we can significantly improve the chances of finding a treatment to LAM in the shortest time possible and point the way for research in other relevant diseases.
In a complementary stream of work, the Boston LAM/TSC Seminar Series (http://www.bostonlamtscresearch.org/) provides a forum for researchers who are working separately on problems related to LAM and TSC to share existing information; to identify gaps in research that might impact future work on LAM and TSC; and to foster interdisciplinary collaboration at clinical and basic science levels within the research community in Boston, and throughout the United States and internationally (through invitations to researchers beyond the Boston area and future dissemination of presentation outlines, with presenter permission). The response to these seminars has been positive. Attendance by senior as well as a new cohort of junior researchers has been strong across disciplines and across the basic science to clinical spectrum.
Unparalleled expertise relevant to LAM/TSC research and potential therapies is accessible within the Boston-Cambridge medical research community. Harvard Medical School, Brigham and Women's Hospital and Dana-Farber Cancer Center are situated side-by-side and within reach of the most advanced biotech corridor in the United States, at the center of a $310 billion dollar industry and with the largest share of NIH funding in the country.22
Making Progress Possible
A third, critical stream of work involves mobilizing the vital resources to fund the research projects that will be most likely to yield a treatment for LAM in the shortest time possible. The opportunity to have highest-caliber scientists apply their minds to LAM is priceless, but fast-tracking this research process also requires funds - an estimated $150,000 per project to support work in a single lab or in collaboration between labs and institutions under the guidance of established leaders in fields relevant to LAM and/or an established LAM expert in a laboratory using the latest technology for preclinical research.
Given our strategic successes in enlisting support from the best and the brightest, and in light of the challenges ahead, our immediate remaining challenge is funding. We have mapped out a timeline for research. The Boston-Cambridge business community has donated expertise in strategic planning, nonprofit start-up, management and development. Now, with funds, we can accelerate the pace of research in LAM and related diseases through expert-directed, multidisciplinary translational research.
Footnotes:
1 Finlay G. The LAM cell: what is it, where does it come from, and why does it grow? Am J Physiol Lung Cell Mol Physiol. 2004 Apr;286(4):L690-3. [PubMed]
2 McCormack FX, Young L. Advances in Lymphangioleiomyomatosis. Pulmonary and Critical Care Update. American College of Chest Physicians. Vol 18, Lesson 9. Dec 2005. http://www.chestnet.org/education/online/pccu/vol18/lessons09_10/lesson09.php Accessed: 17 Jan 2006
3 U.S. National Library of Medicine. MedlinePlus Medical Dictionary. Lung Transplant. Accessed 27 Nov 2005: http://www.nlm.nih.gov/medlineplus/ency/article/003010.htm. Updated 5 June 2004.
4 McCormack F et al. Pulmonary cysts consistent with lymphangioleiomyomatosis are common in women with tuberous sclerosis: genetic and radiographic analysis. Chest. 2002 Mar;121(3 Suppl):61S [PubMed]
5 US National Institutes of Health. National Institute of Neurological Disorders and Stroke. Tuberous Sclerosis Fact Sheet. Accessed 3 Nov 2005: http://www.ninds.nih.gov/disorders/tuberous_sclerosis/detail_tuberous_sclerosis.htm. Updated 13 Oct 2005.
6 Multi-Disciplinary Tuberous Sclerosis Program. Research Update. Accessed: 17 Jan 2006: http://www.tsclinic.org/research_update.php. No date.
7 Li Y et al. TSC2: filling the GAP in the mTOR signaling pathway. Trends Biochem Sci. 2004 Jan;29(1):32-8. [PubMed]
8 Wyeth Pharmaceticals, Inc. Approved labeling and patient information for Rapamune® (sirolimus). Accessed 3 Nov 2005: http://www.fda.gov/cder/foi/label/2004/21083s017,21110s020lbl.pdf Updated 13 July 2004.
9 Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004 Aug 15;18(16):1926-45. [PubMed]
10 Boulay A et al. Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 2004;64:252-261. [PubMed]
11 McDaniel ML et al. Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic beta-cells. Diabetes. 2002 Oct;51(10):2877-85. [PubMed]
12 Martin KA et al. The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol. 2004 Mar;286(3):C507-17. [PubMed]
13 Shegogue D. Mammalian target of rapamycin positively regulates collagen type I production via a phosphatidylinositol 3-kinase-independent pathway. J Biol Chem. 2004 May 28;279(22):23166-75. [PubMed]
14 Ravikumar B et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease." Nature Genetics 2004 Jun;36(6):585-95. [PubMed]
15 National Institute of Neurological Disorders and Stroke. New Perspectives In Tuberous Sclerosis Complex Conference Summary. September 19-22, 2002. Accessed 16 Nov 2005: http://www.ninds.nih.gov/news_and_events/proceedings/2002_tsc_conference.htm. Updated 9 February 2005.
16 Tavazoie SF et al. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. 2005 Dec;8(12):1727-34. [PubMed]
17 Sarbassov DD et al. Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR complex. Science. 2005. 307:1098-1101. [PubMed]
18 Manning BD et al. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 2005 Aug 1;19(15):1773-8. [PubMed]
19 Zerhouni E. Medicine. The NIH Roadmap. Science. 2003 Oct 3;302(5642):63-72. [PubMed]
20 Zerhouni EA. Translational and clinical science--time for a new vision. N Engl J Med. 2005 Oct 13;353(15):1621-3. [PubMed]
21 Fishman MC, Porter JA. Pharmaceuticals: a new grammar for drug discovery.
Nature. 2005 Sep 22;437(7058):491-3. [PubMed]
22 Pierce CP. Boston's biotech moment. The Boston Globe. 14 December 2003.
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