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!


 

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/


Meet a BHD expert

Following the success of our last Meet the Experts session, we are excited to announce that we are hosting another Meet the Experts virtual event on Wednesday 23rd June at 7:30 pm BST (British Summer Time). Stefan Marciniak is a Professor of Respiratory Science at the University of Cambridge and Honorary Consultant at Addenbrooke’s and Papworth Hospitals and has a particular interest in the genetics of pneumothorax. Stefan will be sharing his insight and answering your questions about one of the main symptoms of BHD, pneumothorax!

Sign up now for the event: https://www.eventbrite.co.uk/e/meet-the-experts-pneumothorax-tickets-156227433459

If you are unable to attend the event, we will be recording it and posting it on our webpage.

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.

April Newsletter

The April 2021 BHD newsletter is out! We discuss the highlights from this month, including our first Meet the Experts event, the European International Kidney Conference 2021, the latest research and the patients’ perspective of being diagnosed with Birt-Hogg-Dubé syndrome.

Read it now

If you would like to receive future newsletters please email contact@bhdsyndrome.org with the subject line “Subscribe to Newsletter”.

Is Kidney Cancer Curable?

We attended The European International Kidney Cancer 2021 virtual meeting in April, providing insights into clinical developments in renal cancer. The meeting was fascinating, and of note was the remarkable pace of research yielding new insights into treatments.

The keynote address was given by Dr David McDermott, Chief, Division of Medical Oncology at the Beth Israel Deaconess Medical Center. Dr McDermott challenged the audience to think about advanced renal cancer as a curable neoplasm.

To move into an era where we think in this way, Dr McDermott suggested that we need to treat patients who are predicted to respond well to therapy in a more aggressive manner. This will require new ways of predicting response to treatment, the discovery of new biomarkers and targets as well as new trials. We will also need to explore the end of point of trials in a more nuanced manner, and start thinking about “treatment free survival” as an output. This final point is key for patients – the difference between a continuous therapy with all the associated side effects versus a treatment that ends and provides a treatment free survival benefit is huge.

We are in a period where the potential of immunotherapies and combined treatments are close to being realised, and it was incredible to witness the change in approach and the grand challenge of curing kidney cancers and supporting patients to live treatment-free lives addressed.