Worldwide LAM Awareness Month

June is Worldwide LAM Awareness Month which aims to raise awareness and educate people about Lymphangioleiomyomatosis (LAM). LAM is a rare disease caused by mutations in the tuberous sclerosis genes. It affects the lungs, kidneys and lymphatic system and almost exclusively affects women. Recognising the symptoms of LAM is important in order for patients to access the treatment they need early. The most common presenting symptom of LAM is worsening shortness of breath and a history of recurrent pneumothoraces. Additionally, patients can experience bloating due to fluid around their lungs and stomach (from the disruption of their lymphatic system) and angiomyolipomas, which are a type of benign tumour that can cause pain and bleeding. Although there is no cure for LAM, the progression of the disease can be slowed by a drug called Sirolimus (Rapamycin).  

Due to its similarities with BHD, researchers often study both conditions. We talked to Professor Elizabeth (Lisa) Henske, Director of the Center for LAM Research and Clinical Care, Brigham and Women’s Hospital, about her work in LAM and how this translates to the BHD community. Her lab’s discovery of Tuberous Sclerosis Complex 2 (TSC2) resulted in the first FDA approved drug for LAM.

Could you tell me about your discovery of the TSC2 mutation and what that meant for patients? 

LAM occurs in two forms:  in women with tuberous sclerosis complex (TSC) and in women who do not have TSC (referred to as sporadic LAM).  The Henske Lab discovered that sporadic LAM is caused by mutations in the TSC2 gene.  A few years later, it was discovered that the TSC proteins inhibit the mTOR pathway (a pathway involved in cell growth), and Dr. Vera Krymskaya demonstrated that the mTOR pathway is hyperactive in LAM cells.   Together, these discoveries paved the way for a pivotal clinical trial led by Dr. Frank McCormack, which was published in the New England Journal of Medicine in 2011.  This trial proved that treatment with sirolimus (Rapamycin), an oral inhibitor of the mTOR pathway, stabilizes lung function in women with LAM.  In my own clinical practice, I can see the tremendous benefit of sirolimus in so many women with LAM, allowing them to work, care for their families, travel, exercise, and live a life that is close to “normal.” 

What research is currently being done into LAM? 

Some of our most urgent research questions include:

1) why does LAM affect almost exclusively women?
2) can we use treatments that block estrogen’s actions to treat LAM? 
3) how does the immune system promote the growth of LAM cells?
4) why do LAM cells cause cystic destruction of the lungs? 

We are excited to be working with Dr. Wei Shi, a leading developmental biologist at Los Angeles Children’s Hospital, to understand how both LAM and BHD lead to cystic lung disease. 

What difficulties have you come across in researching LAM? 

With any rare disease, access to tissue samples (for example, lung and kidney samples) is absolutely essential to progress.  We have been very fortunate that The LAM Foundation (based on Cincinnati OH) has helped make samples available for research.  We are also lucky to have an exceptionally collaborative and connected LAM research community, including many dedicated scientists and physicians who are committed to curing LAM.  Dr. Joel Moss, who leads the LAM program at the National Institutes of Health, has had an especially positive impact on these collaborative efforts.

From your experience what are the main differences/similarities between the symptoms of BHD and LAM? 

There are important similarities and also important differences between BHD and LAM.  The similarities include the risk of lung collapse (pneumothorax) and the risk of kidney tumors (renal cell carcinoma in BHD and angiomyolipomas in LAM).  One important difference is that in BHD, it is unusual for shortness of breath to develop.  In LAM, many women develop shortness of breath, and some become dependent on oxygen therapy, especially if the LAM is not treated early in the disease.  Another difference is that LAM affects almost exclusively women, while cystic lung disease in BHD occurs in both men and women.

What can the BHD community learn from the research into LAM? 

LAM research has brought together a highly collaborative group of clinicians and scientists.  The scientists are diverse in their background and approaches, including biochemists, developmental biologists, cancer biologists, cell biologists, geneticists, and more.  This allows LAM to be studied from many different angles.  Regular scientific and clinical meetings allowing new data to be discussed and ideas to be shared have propelled LAM research breakthroughs. 

What can we do to raise awareness about rare conditions such as LAM and BHD?

One of the best ways to raise awareness is to make clinically relevant discoveries.  In LAM and TSC, breakthroughs have consistently boosted awareness among both scientists and clinicians.  This has a “positive feedback” effect, with more awareness leading to even more progress. 

The BHD Foundation sincerely thanks Professor Elizabeth (Lisa) Henske for taking part in this interview and sharing her insights on LAM and BHD. If you a researcher working on BHD we would love to hear about your research. Please contact us at contacts@bhdfoundation.org

To find out how you can get involved with LAM awareness month visit the LAM Foundations webpage. The LAM Foundation is a wonderful resource for both clinicians and members of the LAM community and they have several useful resources for raising awareness about LAM. Their centres of clinical excellence also support BHD patients.

World Kidney Cancer Day

Today is World Kidney Cancer day and the theme is ‘We need to talk about how we are feeling’. A patient survey revealed that 96% of kidney cancer patients experience psychosocial problem but less than half talk about it. It is not always easy to discuss how you are feeling but research shows that it does improve wellbeing.  World kidney day is striving to make this easier.  They have produced a personalised psychosocial wellbeing report for you to complete with recommendations on how to improve your mental wellbeing. The report is available here.

The BHD Foundation is talking about kidney cancer and wellbeing because up to 30% of patients with BHD develop kidney cancer and we want you to know you are not alone. In addition to initiatives such a world cancer day there is a welcoming patient lead BHD Facebook group who are always happy to answer questions and share their stories. Earlier this year we also interviewed a member of the BHD community about her experience being diagnosed with kidney cancer and it is available to read here. The BHD Foundation can help connect you with others who have been diagnosed with BHD.

I ♥ Small Charities Day

The BHD Foundation is taking part in #SmallCharityWeek. The aim of this week is to raise awareness of the UK small charity sector making a difference across the world. As a small charity, the BHD Foundation (run by the Myrovlytis Trust) is getting involved in this event and we would love the BHD community to get involved too!  
 
Monday 14th June is “I ♥ Small Charities Day”. The team at the BHD foundation will be posting a picture of themselves on Twitter and Facebook holding a poster saying how much we love our charity and why. We think this is a great way to connect with the BHD community so you get to see some of our faces behind the scenes! We would also really love to see some of you too – we would be nothing without the strong community we have.  
 
We have provided a link to a downloadable poster for you to adapt and we would love to see them across social media using the hashtags #ILoveSmallCharities  #SmallCharityWeek #BHDsyndrome #SCWeek2021. 

Alternatively, you can share the poster without a photo on social media with the same hashtags – or even just share your feelings in a FB post or tweet!  

We will be gathering all the responses and putting them together.
 
The poster is available here!


 

Loss of folliculin causes cellular dysfunction of pleural mesothelial cells

People with Birt-Hogg-Dubé syndrome (BHD) have a 25% chance of developing at least one spontaneous pneumothorax (collapsed lung) in their lifetime and many people will have several. A pneumothorax occurs when air enters the lining of the lung (known as the pleural cavity) causing the lung to be compressed. The size of the pneumothorax usually determines the clinical presentation and required intervention ranging from a conservative watch and wait approach to surgery. Pneumothoraces in BHD patients are primarily thought to be caused by the lung cysts (which are seen in 80% of BHD patients) bursting. However, it has been suggested that this is not the only cause (1).  Okamoto et al., conducted the first study assessing the effect of folliculin haploinsufficiency (one mutated folliculin gene) on pleural mesothelial cells (PMCs) (2). PMCs are a single layer of cells that blanket the lung and chest wall acting as a protective barrier. If this layer is disrupted it can result in a pneumothorax.  Studying these cells increases our understanding of how BHD causes pneumothoraces and potential drug targets to prevent them.    

Okamoto et al., collected PMCs from 32 patients who developed spontaneous pneumothoraces: 12 BHD patients and 20 other patients who had no underlying lung conditions (control group). The purpose was to compare the cells in both cohorts to see if there were any differences. The cells were examined under a microscope and they found that PMCs in BHD patients were cuboidal in shape compared with the cobblestone appearance of the control group.

Next, Okamoto et al., looked at the expression of genes involved in cell adhesion (binding of cells together). The expression of E-cadherin, which is involved in cell adhesion was reduced in BHD PMCs. To investigate the effects of reduced E-cadherin on BHD PMCs they assessed cell adhesion in Petri dishes. A significantly greater number of cells detached in the BHD PMCs compared to the control and then underwent anoikis (programmed cell death due to loss of attachment to other cells). In addition to reduced cell adhesion and anoikis, Okamoto et al., demonstrated delayed cell growth and reduced migration in BHD PMCs compared with the control group.  PMCs are involved in maintaining the health of the lining of the lung and repairing any disruption, so need to be able to move and grow. Altogether this suggests that folliculin haploinsufficiency causes PMCs to be disrupted through loss of adhesion and cell death and the repair process hindered resulting in pneumothoraces.  Okamoto et al., suggest these changes to PMCs function may be due to reduced activation of the E-Cadherin-LKb1- AMPK pathway which is a known pathway affected by folliculin loss (3).

Altogether Okamoto et al, found that folliculin haploinsufficiency causes changes in the shape of PMCs in BHD patients and impairs the function of the cells, potentially through the E-Cadherin-LKb1- AMPK pathway. This is important as the disruption of PMCs may be a cause of pneumothoraces in BHD. Further research is required to determine how exactly PMC disruption causes pneumothoraces and whether the pathways affected could be targeted to prevent them.

References

1.            Ohata M, Suzuki H. Pathogenesis of spontaneous pneumothorax. With special reference to the ultrastructure of emphysematous bullae. Chest [Internet]. 1980 Jun 1 [cited 2021 Jun 8];77(6):771–6. Available from: http://journal.chestnet.org/article/S0012369215456168/fulltext

2.            Okamoto S, Ebana H, Kurihara M, Mitani K, Kobayashi E, Hayashi T, et al. Folliculin haploinsufficiency causes cellular dysfunction of pleural mesothelial cells. Sci Rep [Internet]. 2021 Dec 24 [cited 2021 Jun 8];11(1):10814. Available from: http://www.nature.com/articles/s41598-021-90184-9

3.            Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, et al. Folliculin Controls Lung Alveolar Enlargement and Epithelial Cell Survival through E-Cadherin, LKB1, and AMPK. Cell Rep [Internet]. 2014 Apr 24 [cited 2021 Jun 8];7(2):412–23. Available from: https://pubmed.ncbi.nlm.nih.gov/24726356/

Drug Repurposing for Rare Diseases

This June we will be attending the annual drug repurposing conference organised by Findacure, a charity dedicated to bringing the rare disease community together. There are over 7000 rare diseases but currently, only 400 have licenced treatments. It is paramount that we increase the available medication for rare disease and drug repurposing is one way we can do this. Repurposing involves taking a known licensed drug and finding new therapeutic uses for it; It is usually quicker and cheaper than drug discovery. The conference will be discussing drug repurposing for rare disease.

The event is open to everyone in the rare disease community and will be held virtually from 15th -16th June 2021. You can register for free here.

We will be attending the event and updating you with the latest developments in drug repurposing for rare diseases.

European International Kidney Cancer Symposium Report

In April we attended the European International Kidney Cancer Symposium (EIKCS). Many of the discussions focused on future therapeutic approaches and the use of immunotherapies to treat kidney cancer. Immunotherapies are drugs that harness the body’s immune system and help it to destroy cancer cells. Here we share with you some of the highlights of the symposium. 

Keynote

The Keynote address was given Dr David McDermott, Chief, Division of Medical Oncology at the Beth Israel Deaconess Medical Center. Dr McDermott discussed the importance of identifying novel biomarkers and using combination therapy to treat kidney cancer. He also emphasized the importance of not only aiming to treat cancer but to strive for patients to live treatment-free lives.

Clinical Trials

Dr Hans Hammers, Associate Professor of Internal Medicine at UT Southwestern Medical Center, discussed some of the novel therapeutics being trialed in kidney cancer patients. A phase 3 clinical trial with 1069 patients found that the combination of Lenvatinib and pembrolizumab, immunotherapy drugs, was associated with longer progression-free survival than sunitinib, which is a protein kinase inhibitor currently used in kidney cancer (1). He also referenced a phase 2 clinical trial testing belzutifan (an inhibitor of HIF-2α) on patients with Von Hippel-Lindau disease (VHL). Similar to Birt-Hogg-Dubé syndrome, VHL patients develop multiple tumors in their kidneys. Preliminary results show that belzutifan is both well tolerated by patients and reduces tumor size (2). To find out more about clinical trials including current research into BHD visit our Clinical Trials webpage

Biomarkers

A biomarker is a molecule that is naturally present in or on specific cells and can therefore be targeted for treatment of a disease. Medical oncologist Dr Yann-Alexandre Vano from Georges Pompidou European Hospital discussed his research looking for specific biomarkers (gene signatures) in tumors and targeting them with specific therapies. The BIONIKK trial was the first to investigate tailoring treatment options in metastatic kidney cancer to patient’s tumor characteristics and showed an improved patient response (3). Dr Yann-Alexandre Vano discussed the importance of collaboration between different centers and countries to help facilitate the discovery of novel biomarkers and improve patient outcomes.

The Microbiome

The microbiome is the collection of microorganisms that live on and in the human body and are essential for the body to function normally. Everyone’s microbiome is unique and dynamic, changing in response to environmental and genetic factors. It is suspected that the microbiome may affect responses to cancer therapy. Dr Lisa DeRosa researcher at the Gustave Roussy Hospital investigated how a patient’s microbiome may affect their response to checkpoint inhibitors, a type of immunotherapy. She compared the response to therapy in patients who had required antibiotics, which are known to disrupt the microbiome, with those who had not. Patients who had been treated with antibiotics had a reduced response to checkpoint inhibitors (4). Therefore, she hypothesized that altering those patient’s microbiome may improve their response to immunotherapy. This idea is supported by a recent study where melanoma patients, who were given fecal transplants to change their microbiome, had an improved response to checkpoint inhibitors (5). Further research is required to identify the specific microorganisms responsible for these changes in response. 

EIKCS demonstrated the extent of innovative research being conducted into kidney cancer. The Myrovlytis trust/ BHD Foundation will be keeping up to date with the latest research and funding studies looking at kidney cancer treatments with an initial focus on Birt-Hogg-Dubé syndrome.

Interested to find out more? You can now watch all the talks from the conference here.

References

1.          Motzer R, Alekseev B, Rha S-Y, Porta C, Eto M, Powles T, et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med [Internet]. 2021 Apr 8 [cited 2021 May 28];384(14):1289–300. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2035716

2.          Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan V, Maughan BL, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020 May 20;38(15_suppl):5003–5003.

3.          Epaillard N, Simonaggio A, Elaidi R, Azzouz F, Braychenko E, Thibault C, et al. BIONIKK: A phase 2 biomarker driven trial with nivolumab and ipilimumab or VEGFR tyrosine kinase inhibitor (TKI) in naïve metastatic kidney cancer. Bull Cancer [Internet]. 2020 Jun 1 [cited 2021 May 28];107(5):eS22–7. Available from: https://pubmed.ncbi.nlm.nih.gov/32620212/

4.          Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol [Internet]. 2018 Jun 1 [cited 2021 May 28];29(6):1437–44. Available from: https://pubmed.ncbi.nlm.nih.gov/29617710/

5.          Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science (80- ) [Internet]. 2021 Feb 5 [cited 2021 May 28];371(6529):595–602. Available from: https://pubmed.ncbi.nlm.nih.gov/33542131/


Folliculin prevents phagocyte activation and accumulation of glycogen.

Guest Blog by Neil Pearson

Birt-Hogg-Dubé syndrome (also known as BHD) is a dominant hereditary condition caused by variants (mutations) in the Folliculin (FLCN) gene that results in a loss of function causing skin lesions, lung cysts, collapsed lungs, and kidney cancer. As researchers uncover how FLCN achieves these functions we will understand, and hopefully find ways to treat, BHD.

A collaborative project involving researchers in the USA, Japan and Singapore showed there was an increase in activated phagocytes in FLCN mutant mice that mimic human BHD(1). Phagocytes are cells in our bodies that “eat” substances like bacteria, damaged or infected cells and protect the body from infection and damage. Phagocytes contain structures called lysosomes which store acids and chemicals that destroy the substances “eaten” by the macrophage. Lysosomes are also important in sensing and responding to low nutrient and energy levels in the cell by recycling material inside the cells for energy and repair. Loss of FLCN results in increased lysosome function, glycogen accumulating in the cytoplasm and phagocytes no longer functioning properly. The accumulation of glycogen has also been observed in cancer cells taken from the kidneys of BHD patients suggesting a potential link between accumulation of glycogen in phagocytes and cancer in BHD.

How this causes damage to organs and contributes to cancer in BHD is not yet known but there are two likely possibilities. One is that glycogen is required for generating fats and oils, too much of which can damage cells and tissues. The other possibility is that cells which can survive in the absence of accurate nutrient sensing are more likely to become cancerous. Both scenarios could potentially explain the high frequency of kidney cancer in BHD patients. More research is required to investigate these possible scenarios, but it could be an important development in understanding FLCN function and BHD.

Another exciting finding in this paper was that deleting TFE3 in FLCN deficient mice reduced the accumulation of glycogen in phagocytes. TFE3 is a transcription factor meaning it controls the expression of other genes. FLCN is known to prevent TFE3 from entering the nucleus where it controls expression(2). The researchers showed that TFE3 increases the expression of two genes that are involved in making glycogen, Gys1 and Gyg. TFE3, Gys1 and Gyg are potential drug targets for treating BHD as reducing their amount or activity could have therapeutic benefits. Although there needs to be further confirmation that the observed lysosomal effects are actively contributing to BHD symptoms in patients and mouse models, these initial findings are very promising and provide more evidence that FLCN is a key player in regulating nutrient sensing and lysosomal function.

References

1.       Endoh M, Baba M, Endoh T, Schmidt LS, Linehan WM, Suda T. A FLCN-TFE3 Feedback Loop Prevents Excessive Glycogenesis and Phagocyte Activation by Regulating Lysosome Activity. CellReports [Internet]. 2020 [cited 2021 May 27];30:1823-1834.e5. Available from: https://doi.org/10.1016/j.celrep.2020.01.042

2.       Hong SB, Oh H Bin, Valera VA, Baba M, Schmidt LS, Linehan WM. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS One [Internet]. 2010 [cited 2021 May 27];5(12). Available from: https://pubmed.ncbi.nlm.nih.gov/21209915/
Read our blog to find out more about FLCN and TFE3

The clinical characteristics of East Asian patients with Birt-Hogg-Dubé syndrome

The symptoms of Birt-Hogg-Dubé syndrome (BHD) have been widely described in Europe and the United States (USA) with approximately 90% of individuals developing skin lesions, 30% developing kidney cancer, 80% developing lung cysts and 25% developing pneumothoraces. However, studies looking at BHD in the East Asian population suggest a difference in prevalence of these characteristics. Guo et al., published a study to provide further information about the clinical characteristics of BHD in the East Asian population to aid diagnosis and ensure early intervention (1).

Guo et al., reviewed the current literature on BHD in Japan, China and Korea and enrolled 166 patients from these papers for their study. In addition, they gathered data from 10 BHD patients from Xiangya Hospital in China. The patients’ age, sex, BHD symptoms, genetics and family history were recorded and analysed. They found that skin lesions were less common in the East Asian BHD population with only 36.7% patients recorded to have them, though the most common lesions were fibrofolliculomas and trichodiscomas as seen in the European/USA population. Prevalence of kidney cancer were also lower with 7.2% of patents developing kidney cancer. However, there were more incidences of lung cysts (87.3%) and pneumothoraces (74.7%) in the East Asian BHD population.

The reason for these differences in characteristics is not clear. Interestingly Guo et al., found no significant difference in folliculin mutations found in the East Asian BHD population compared with other countries.  This supports research by Schmidt et al., which found no link between folliculin mutations and BHD characteristics and suggests difference in characteristics may be the result of other genetic or environmental factors(2). Guo et al., also suggest that the reduced incidences of skin lesions could be due to misdiagnosis, highlighting that there are differences in medical habits in different countries which could contribute to the difference in BHD characteristics being diagnosed.

Altogether this study suggests BHD will present differently in the East Asian population, with the biggest difference seen in prevalence of pneumothoraces (25% of cases in the Europe/USA population compared with 74.7% in the East Asian population).  This is important as a pneumothorax is more likely to be the only characteristic of BHD in the East Asian population and therefore it is essential that clinicians consider the diagnosis of BHD in patients who have spontaneous pneumothoraces in the absence of any other BHD characteristics.    

1.          Guo T, Shen Q, Ouyang R, Song M, Zong D, Shi Z, et al. The clinical characteristics of East Asian patients with Birt-Hogg-Dubé syndrome. Ann Transl Med [Internet]. 2020 Nov [cited 2021 May 12];8(21):1436–1436. Available from: http://dx.doi.org/10.21037/atm-20-1129

2.          Schmidt LS, Nickerson ML, Warren MB, Glenn GM, Toro JR, Merino MJ, et al. Germline BHD-Mutation Spectrum and Phenotype Analysis of a Large Cohort of Families with Birt-Hogg-Dubé Syndrome. Vol. 76, Am. J. Hum. Genet. 2005.


Announcing the 2021 BHD Symposium

The Myrovlytis Trust/ BHD Foundation is delighted to announce the relaunch of our annual BHD Symposium, bringing together researchers and clinicians worldwide to discuss the latest developments in the BHD world. Although the event is aimed at researchers and clinicians, we welcome everyone from the BHD community and will also be holding a patient and family-focused session. Details and registration for the patient/family-focused event to be announced soon.

The 2021 Symposium will take place on October 21st– 22nd, and will be held virtually. We anticipate returning to in-person symposia from 2022. Visit the Myrovlytis Trust webpage for more information about the event and how you can get involved.

Register to secure your attendance at the 2021 BHD Research Symposium here.