2006 Virginia Northwood Memorial LAM Science Symposium

Fairmont Resort, Blue Mountains, Australia

Symposium Report by Jen Shieff – Trustee, NZ LAM Trust

The 2006 Virginia Northwood Memorial LAM Science Symposium was hosted by the Australia and New Zealand LAM Trusts and held at the Fairmont Resort in the Blue Mountains west of Sydney. This was the third Symposium and the first to be held in Australia. Previously the meetings were in Auckland – first on Waiheke Island and then at Hotel du Vin south of Auckland.

There were some basic facts about LAM that I was already very familiar with before I went to the Blue Mountains:

• Lymphangioleiomyomatosis (LAM) is a rare lung disease that affects almost exclusively women. It was first described in the medical literature by von Stossel in 1937. The disease is characterised by an unusual type of muscle cell that invades the tissue of the lungs, including the airways, and blood and lymph vessels. Over time, these muscle cells form into bundles and grow into the walls of the airways, and blood and lymph vessels, causing them to become obstructed
• Although these cells are not considered cancerous, they grow without the usual controls within the lungs. Over time, the muscle cells block the flow of air, blood, and lymph vessels to and from the lungs, preventing the lungs from providing oxygen to the rest of the body
• An unusual, frequently asymptomatic, kidney tumour called an angiomyolipoma (AML) is found in up to 60% of patients with LAM
• About 2.5% of patients with Tuberous Sclerosis, a genetic disorder, develop a lung disease that is identical to that which occurs in LAM. These patients often have AMLs of the kidneys as well
• Although patients with LAM do not develop the central nervous system and skin changes of Tuberous Sclerosis, the similarities in the lung and kidney manifestations of the two diseases have led some investigators to postulate that they may have common causes

Although I had heard many of the speakers previously, they all had sparkling new material to present. There are LAM-related discoveries every few months that change the ways in which scientists think about LAM. All the speakers filled me with hope that progress is being made rapidly and that a cure will be found for LAM.

I am always grateful to the speakers for their efforts to make their work intelligible to lay people like me, and it is a great privilege to sit, feeling almost like an equal, with eminent scientists and researchers, hearing them speak and being there while they pose questions to each other, challenging each other to do more and more thinking about LAM. And they do it in an atmosphere of trust and calm enquiry, leaving their egos outside the door.

I won’t name all the speakers, but I will put their ideas together in a summary as well as I can. Professor Frank McCormack from the University of Cincinnati opened proceedings after dinner on the first night with a history and update on LAM research. From him and Professor David Franz (also from the University of Cincinnati) from Sarah Boustany (University of Sydney), and from Dr Merv Merrilees (University of Auckland) and Dr Vera Krymskaya (University of Pennsylvania) I have gained my updated LAM understandings and vocabulary. It never ceases to amaze me how my unscientific mind has been opened to a huge range of issues in science which seem clear to me because of the LAM context and because of the clarity of the speakers.

This year I learned a bit more about cellular and molecular remodelling in LAM as compared with asthma, and in particular the increase in smooth muscle transforming growth factors in LAM. I learned about a kind of support network (my term) for bad behaviour amongst uneducated cells – cells which exhibit the enhanced growth, proliferation, motility and invasiveness typical of LAM. The support comes from several delinquents – from an absent protein called Tuberin, also known as tumour suppressor TSC2 (Tuberous Sclerosis Complex 2), which when present is known to shrink cancer tumours; from Actin-negative tissue which is abnormally proliferated and is even more of a problem than smooth muscle cell proliferation; from hyper-active Versican, a space occupying matrix Proteoglycan which promotes the breakdown of Elastin; from absent Tumstatin, a cleavage fragment of Collagen IV, which functions as a tumour suppressor; and from suppressors of the molecular switch RAC, leading to the activation of another switch RHO and hence to an abundance of stress fibres.

I also learned that TSC2 is mutated in LAM and fails to suppress the activity of protein S6 Kinase (S6K1) which leads to constant protein synthesis and abnormal LAM tumour cell growth. LAM cells destroy normal lung interstitia and until recently, only a lung transplant could prolong a LAM patient’s life.

Dr Vera Krymskaya reported on her finding that that TSC2 negatively regulates S6K1. She identified S6K1 as a molecular target to treat LAM and found that an FDA approved antibiotic drug called Rapamycin (Sirolimus) specifically and directly inhibits S6K1 and therefore is a drug that can be used to treat LAM.

There was discussion of Rapamycin, which is about to be trialled in the Multicenter International LAM Efficacy of Sirolimus Trial.

The scientific evidence on which the trial is based is, as Professor Frank McCormack has stated for the US LAM Foundation website:

• Dr Elizabeth Henske found that LAM is caused by a loss of the protein Tuberin
• Fruit fly biologists, Drs Ito and Rubin, found that Tuberin controls cell size and growth
• Dr Vera Krymskaya found that Tuberin plays very similar roles in LAM cells as it does in fly cells, and that Rapamycin can mimic the function of Tuberin in LAM cells
• Drs Yeung and Kwiatkowski have found that Rapamycin can shrink tumors in Tuberous Sclerosis animal models
• Rapamycin is known to inhibit the proliferation of smooth muscle cells that contribute to recurrent blockage of coronary arteries after stent placement
• Rapamycin for Tuberous Sclerosis and LAM is an elegant example of molecular therapy targeted at the precise cellular defect that causes disease.

International multicentre clinical trials using Rapamycin are already going on in the USA, UK, Canada and Germany. Professors McCormack and Franz have found that treating LAM with Rapamycin has had promising results.

At the Symposium I sat beside a woman in her late 50s who had been diagnosed only recently, despite a five year history of AMLs. She listened quietly, rather stunned, as we heard from two other women with LAM, both diagnosed several years ago. Everyone present was deeply saddened by many of their experiences. One had been abandoned by her partner and was fearful about the reaction of her employer to her illness, the other had been fearful that her new partner would leave her when he heard about LAM. These stories demonstrated the typical LAM diagnosis pattern of protracted process and disbelief, of wanting to carry on regardless because there appeared to be so few symptoms. Both had felt singled out.

The Symposium ended on a very upbeat, enthusiastic note, with fresh hope being given by pharmaceutical research scientist, Dr Jilly Evans. Always inspired and inspiring, this time she seemed even more brilliant than usual. She talked of chance favouring the prepared mind and described how she took a giant leap into the abyss of chance to find a female hormone, Prolactin, that could just possibly be driving LAM cell proliferation in angiomyolipomas.

Messages, codes, signals, hormones, switches, stimulators and suppressors: it’s as if all the pieces are falling in place and we are extremely close to finding the answer to this enormously complex puzzle. Although LAM is thought to affect only three or four women in a million, the discovery of how to treat it has tremendous implications for many other more prevalent diseases.