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Conversations in Pulmonary, Critical Care and Sleep Medicine by the American Thoracic Society
Ugo: Welcome back to ATS Now, live from ATS 2026. I'm your host, Ugo Ezeama. We're returning to a question we opened with Dr. Tisha Wang: Are we entering an era of disease-modifying therapy for rare lung diseases? We used autoimmune pulmonary alveolar proteinosis as the first lens. Now we're using a second, lymphangioleiomyomatosis, or LAM.
LAM is a rare cystic lung disease that almost exclusively affects women in their reproductive years, driven by TSC1 or TSC2. These mutations cause progressive cystic destruction, and for decades all we could offer was supportive care and [00:01:00] transplant. Then in 2011, the MILES trial showed sirolimus stabilized lung function.
But sirolimus is cytostatic. It slows LAM, it doesn't cure it. Come off it, and the disease returns. So the question for 2026 isn't, do we have a disease-modifying therapy? It's, are we ready to move from suppressing the disease to eliminating it? My guest is one of the people best positioned to answer that question, Dr.
Gregory Downey of National Jewish Health, co-author of the ATS/JRS LAM guidelines, and an investigator of the long-term sirolimus work. Dr. Downey, welcome to the show.
Gregory: Thank you very much, Ugo.
Ugo: I really appreciate- My pleasure ... I, I really appreciate you coming by. Um, before the MILES, uh, study in 2011, what was the conversation like when we're talking to a newly diagnosed LAM patient, and how much of that has changed, uh, in 2026?
Gregory: Right. So it, it's an excellent question to [00:02:00] begin, and I will just say that it is a watershed difference between the conversations we had to have with people before the MILES trial and after. But even before the MILES trial itself, one of the benefits to rare lung diseases is a coalition of investigators, clinicians who are interested in the same area.
And one of the seminal events was actually the collection of longitudinal data- Mm-hmm ... on these rare diseases, and that was enabled by the University of Cincinnati and the people at the NIH, where we combined all of our data sets with longitudinal follow-up. So we already had a sense before the MILES trial that, as opposed to the conversation that we had in the, let's say, the '80s and the '90s, that this was a disease we didn't really know the cause, there was no treatment, and probably the life expectancy was about 10 years.
Mm-hmm. We already knew that 10 years was [00:03:00] way too short. Women were living 15, even longer years, in at least the early phases of, of that data collection. But of course, then the MILES trial came along, and again, that was you know, not quite fortuitous, but there were developments in the field of TS, so tuberous sclerosis complex, uh, and all the signaling pathways.
And it was discovered by Vera Krimskya and Lisa Hensky that the same mutations that were present in tuberous sclerosis were present in the cells in the lung that we thought were the cells that were causal for the cystic lung disease, so-called LAM cells. And we knew in those cells there was this aberrant signaling pathway, and drugs like sirolimus or sirolimus, uh, temsirolimus, uh, everolimus inhibited that pathway.
So it was A logical next step to try the therapy which [00:04:00] had been in place, for example, for immunosuppression for transplant was sirolimus or everolimus to apply that to the LAM patient population. And that really led to the trial, the Miles trial. That was, uh, Frank McCormick who, who really spearheaded that trial.
The trial showed that sirolimus, and at least for that trial, when taken over a year, significantly attenuated the decline in lung function. Mm-hmm. But also importantly, as you indicated, when the drug was stopped for the second half of the trial, the decline in lung function returned to the p- prior to the treatment levels.
Mm-hmm. So this was your point about this was a cytostatic therapy as opposed to a cytotoxic or permanently disease-modifying therapy. Mm-hmm. But I don't wanna underestimate the importance of that to the field because it has radically changed [00:05:00] the outlook for women who have LAM. And we have many patients who are now in their s- 70s and even 80s who would never have survived that long without sirolimus.
There's a couple of other factors, though. We also know that hormonal influences are important in the progression of LAM, and that became apparent when we looked at women who were premenopausal versus postmenopausal. And when women become postmenopausal, the rate of decline of lung function decreases.
Ugo: Mm-hmm.
Gregory: S- And those are very different populations of people, and we have to take that into account. And one of the big areas of interest right now is can we use some type of, I'll use the broad term, hormonal antagonism. We're really talking about estrogen antagonism because that is thought to drive [00:06:00] the disease, and one of the reasons we think that the disease progresses more rapidly in premenopausal women as opposed to postmenopausal women.
So to wrap up, the conversation that we have today with women newly diagnosed with LAM is very different than that very difficult conversation we had before the seminal Miles trial.
Ugo: Of, of all of the, the newer therapies being investigated now, you mentioned hormonal, uh, therapy. There's VEGF, VE- VEGF-D.
Right ... um, uh, looking into VEGF-D and its role and how that could be therapeutic as well. Right. And immunotherapy as well. Um- Which one of those, you highlighted the hormonal influence, which one of those do you think is the most promising and which one might be able to work more in a cytocidal space as opposed to the cytostatic- Yeah
um, space where we understand sirolimus is working?
Gregory: Right. So [00:07:00] let me take each of those in turn.
Ugo: Mm-hmm.
Gregory: Because they're slightly different Uh, concepts and approaches. Let me talk first about biomarkers. And the biomarker that we are all most familiar with is VEGF-D. Mm-hmm. And it is true when you look at a population that the women who have the highest levels of VEGF-D tend to progress more rapidly, but they also tend to have the best responses to sirolimus.
Ugo: Hmm.
Gregory: The problem is that's on a population, and on individual levels sometimes it's not quite so clear. So the first thing I will say is that we desperately need a better biomarker approach. And now I'm talking about a prognostic biomarker or a therapeutic biomarker because what happens frequently is that there are some women who are not gonna respond to sirolimus.
It takes [00:08:00] nearly a year for us to really know if that therapy's going to work. Mm-hmm. And if there were a way to identify that patient population with a higher degree of certainty to begin with, if the biomarker or the biomarker panel predicted sirolimus response, we would put them on that at the beginning.
But if the biomarker panel suggested that they wouldn't respond to sirolimus, then we would choose an alternate therapy. So we are working on that right now, and through the LAM Foundation, we are well on our way to, uh, conducting another comprehensive biomarker study. It's gonna involve about 160 patients.
Uh, and one of the key things is getting appropriate controls, and that's sometimes it seems simple, but it's not so easy in practice because you have to have age and sex math- Mm-hmm ... controls for women who have non-LAM cystic lung disease because you really need to be able to distinguish those from a [00:09:00] diagnostic perspective.
But also we need a marker, uh, biomarkers that will help predict their course. So that is, I think, really important and something that we're working on hard now. So in terms of disease-modifying or curative therapy, we, we have data in a very early clinical trial, uh, with, um, with hydroxychloroquine, but that was really just a phase one trial.
There's lots of theoretical reasons why that could work, but we need a definitive phase two trial to at least know whether we're gonna be able to modify the course of disease. Um, there's, uh, resveratrol that has also been shown, so that's a compound that's present in red wine. Mm-hmm. Uh, but it can be purified and, and that's also been shown, at least in a phase one trial, to be well-tolerated and to have some [00:10:00] potential effect on disease progression.
But I think, in my own mind, we need much better cytocidal drugs, cytotoxic drugs, that are gonna halt the progression of the disease and hopefully kill the LAM cells, uh, so that when we stop the drug, they won't continue to proliferate. It's very much like oncology was 20 or 30 years ago. You know, they initially started with single-drug approaches, but now most of the chemotherapy in, for example, lymphoma, can be four or five drugs.
Uh, I think that is one of the logical, um, pathways that we can pursue. The second way is because we know a lot more about this mTOR signaling pathway- Mm-hmm ... and they're... I- it's no longer considered to be one pathway. There's mTORC1 and mTORC2 parts of the pathway. A lot of the attention in the field has [00:11:00] been trying to see what happens if we selectively inhibit one or the other arm of that pathway.
And although it's still early days, the mTORC1 pathway, the selective inhibitors of that seem to have promise to stop the progression of the disease, but lower some of the l- side effects that are very prominent in women who are on sirolimus, so glucose intolerance, hyperlipidemia, oral ulcers, which make quality of life a big issue when s- a drug is being taken for years or the rest of the life.
So I think that is another area to pay very close attention to. And you mentioned immunotherapy, and it's very clear that the LAM cells produce probably a variety of soluble mediators or disguise some of the ligands on their s- on their own surface so that the immune system cannot recognize them [00:12:00] as foreign or neoplastic, and they don't kill them.
They also subvert the i- the response of the surrounding cells in the tissue, so they're... There's a concept, tumor-associated fibroblasts or cancer-associated fibroblasts. It's very much the same situation in LAM, where the LAM cells secrete something, the fibroblasts that are surround them become activated and lay down excess connective tissue.
So in addition to the cystic component of LAM disease, there's a proliferation of fibrous tissue as well. So it's a complex situation but has lots of opportunities for us to intervene therapeutically.
Ugo: L- LAM is a rare disease predominantly affecting women, and pulmonologists will probably see just a handful of them in their entire career.
Surlaimus is FDA approved, but there's [00:13:00] still a diagnostic delay, and part of that is because it takes so long to, to actually get to that diagnosis by the various means that we, we try and get and do so. How can we bridge that gap? What workflow changes can we make to bridge that gap so that our patients, seeing that it does make a significant improvement and does prolong their lives, um, what can we do with our workflows for a community pulmonologist to get to that diagnosis and to get our patients on Surlaimus?
Gregory: Right. A very important point. So I will say that it is better now than it was 20 years ago. Part of that has been from patient-centered foundations and other not-for-profit organizations who try to represent that patient voice. But also part of their approach is education, not only of patients and their families, [00:14:00] but of healthcare providers.
And the other part that these organizations have brought is an organization, and I'll just give you an example of the LAM Clinic Network, which now I think has Probably 80 or 90 centers around the world, not just in the US, but around the world. And we have monthly or bi-monthly Zoom sessions where clinic directors and their members from all over the world participate.
They can present new studies, present difficult cases, and so it's an educational process. And many institutions like the one I'm in have rare lung disease clinics, and we have a very large group of pulmonologists, over 100 in our center, but many centers are way smaller, right? Mm-hmm. And so our goal is to try and get out the educational materials and the experience to smaller centers in particular so that they know the [00:15:00] resources that are available to them.
The other part of this is outreach. So many women with LAM present for a first time with a collapsed lung- Mm-hmm ... pneumothorax. Mm-hmm. And we've done an outreach education to emergency departments around the country and around the world that if a woman in their, you know, childbearing years presents with a s- what appears to be a spontaneous pneumothorax, look for an underlying cause.
Progress to that high-resolution chest CT to see if they have cystic lung disease. The other area that we're working on is the area of women who present with renal tumors, angiomyolipomas. They are actually pretty common in the general population, but it is a... 50% of women with LAM, approximately sporadic LAM, have angiomyolipomas.
So if someone presents with renal symptoms, hematuria, pain, and they're found to have a angiomyolipoma, [00:16:00] think about systemic diseases like LAM, like tuberous sclerosis, that can tie everything together. It's Occam's razor. Mm-hmm. Sometimes the simplest explanation or the singular explanation is the right one.
You just have to think about it
Ugo: What does the future look like in the next five years, um, for rare lung diseases at large and, but certainly with our patients that has LAM?
Gregory: Right. So I think the future is very promising. I think we have the strong foundation of the LAM Clinic Network. I'll also bring in the Rare Lung Disease Network, something that is being supported now by the American Thoracic Society, uh, but al- by other organizations as well, and that is a, represents a group of clinicians and researchers who have a specific interest in rare diseases, rare lung diseases.
S- some of that is cystic lung diseases, but there are also other rare diseases in that [00:17:00] network. But what this brings, again, is a coalition of, coalition of people with knowledge, with interest to, to band together to try and create this network. That network is going to be critical for rapid adoption of protocols for clinical trials.
And with, uh, groups at the University of Cincinnati, uh, NHLBI, Brigham and Women's, and National Jewish Health to, to begin, um, we have really, uh, injected new energy into that. I'm, we're hoping that we will be able to get some federal funding to help support that. But again, it brings together minds from across the country, across the world, for a common purpose and a common infrastructure to help raise awareness, but also to facilitate new developments and clinical trials.
Ugo: Dr. Downey, thank you so much for coming to share on your expertise and, uh, your care and passion for our [00:18:00] patients with LAM, and looking forward to the, to the future and to the work that you're coming out with.
Gregory: My pleasure. Thank you for having me.
Ugo: That was Dr. Greg Downey from National Jewish Health, one of the people who has spent a career writing the standard of care for a disease that a generation ago didn't have one.
What I'll take away from this conversation, and from this series, The Rare Lung Disease Story, is increasingly a story about communities organizing themselves first. For instance, we take into consideration our patients with autoimmune pulmonary alveolar proteinosis. They have a foundation, dedicated investigators, and a mechanistic target.
In LAM, LAM has the same. The diseases that followed that template now have therapies. The ones that didn't are still waiting. That's not a scientific accident. It's an ecosystem decision. The next disease-modifying therapy in rare lung disease will probably come from a community that looks a lot like LAM's, or it won't come [00:19:00] at all.
You've been watching ATS Now, live from ATS 2026. I'm your host, Ugo Ezema, and we'll see you at the next session