A New Role for Folliculin in Cancer Prevention

We are excited to be sharing with you a recently published paper by Woodford et al., exploring the reason why the loss of folliculin (FLCN), the gene mutated in Birt-Hogg-Dubé syndrome (BHD), drives tumour development.

Cancer cells have characteristics that allow them to grow and replicate uncontrollably. One of these is the deregulation of cellular metabolism, in other words, cancer cells can change how they get their energy. To produce energy cells normally break up glucose to produce pyruvate which then interacts with oxygen and releases carbon dioxide (CO2). If there is limited or no oxygen pyruvate is converted to lactate instead. However, cancer cells will rapidly take up glucose and convert pyruvate into lactate, even in the presence of oxygen, which is beneficial for the cancer cell. This shift in cellular metabolism is known as the Warburg effect and is driven by Lactate Dehydrogenase A (LDHA), the enzyme which converts pyruvate into lactate. Interestingly, loss of FLCN has previously been shown to increase LDHA activity. Woodford et al., examined this relationship further and investigated whether LDHA could be targeted to treat Kidney cancer.

Several different experiments were undertaken to characterise the relationship between FLCN and LDHA. Detailed examination of the FLCN protein in a kidney cell line showed that FLCN interacted with 114 different proteins including LDHA and that high FLCN expression reduced LDHA activity. To determine how FLCN reduced LDHA activity the relationship between LDHA and its cofactor (a small molecule needed for LDHA activity) was examined. High levels of FLCN reduced the binding between LDHA and its cofactor likely through alteration of LDHA’s structure thereby reducing the activity of LDHA. Taken together these results demonstrate a new role for folliculin as a binding partner and inhibitor of LDHA.  

Next Woodford et al., examined the significance of this finding in cancer cells. 13 cell lines, including a kidney cell line, showed a metabolic shift and hyperactivity of LDHA. 11 of these cell lines also showed a dissociation between FLCN and LDHA suggesting that the inhibitory effects of FLCN are lost in many cancer cell lines.

The creation of targeted therapies against LDHA has always been an appealing area of investigation for cancer treatments, however creating a target that is specific to LDHA has been challenging because there are other similar proteins. The discovery of FLCN as an inhibitor of LDHA creates a new opportunity for such therapies. Firstly, Woodford et al, showed that FLCN binds specifically to LDHA and none of its similar proteins. They then identified the specific region of the FLCN protein which binds to LDHA.  They produced a series of peptides (a chain of amino acids which is the building blocks of proteins) derived from FLCN to target LDHA based on their findings of how FLCN binds to LDHA. These peptides were tested in normal kidney cells in vitro and those that were taken up by the cells and reduced LDHA activity were selected for further tests. They then examined the response to the peptides in a kidney cancer cell line. One of the peptides named FLCN-10 was able to bind to LHDA and this resulted in cancer cell death. Next tissue samples from a kidney cancer of a BHD patient were treated with FLCN-10. FLCN effectively reduced LDHA activity in the kidney cancer cells.  

Altogether Woodford et al., have demonstrated a new role of FLCN as an inhibitor of LDHA. It binds to LDHA and regulates its activity. Therefore, in BHD, loss of FLCN results in LDHA hyperactivity resulting in the Warburg effect which is beneficial for cancer cells.  An understanding of this interaction between FLCN and LDHA meant Woodford et al., were able to create a folliculin derived peptide which bound to LDHA and inhibited its activity. This discovery could pave the way for a new LDHA targeted cancer treatment not only for BHD patients but other cancer patients as well.

We are sorry that the paper is currently not freely available. Please message us if you have any further questions at contact@bhdsyndrome.org.

References

1. Woodford MR, Baker-Williams AJ, Sager RA , Backe SJ , Blanden AR, Hashmi F, et al. The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect. Nat Struct Mol Biol [Internet]. 2021 Aug 1 [cited 2021 Sep 3];28(8):662–70. Available from: https://pubmed.ncbi.nlm.nih.gov/34381247/

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.

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/


Rare Disease Study Day

Rare Disease Study Day

Sheffield Institute for Translational Neuroscience.

7th September 2017.

The Sheffield Institute for Translational Neuroscience will be hosting a day of informative talks about Rare diseases and will include a presentation by Dr Derek Lim, consultant in clinical genetics and BHD expert at Birmingham Women’s Hospital.

Clinicians and rare disease families welcome!

Travel and accommodation can be paid for thanks to the support from the Galton Institute and the Genetics Society.

To attend email: a.mcneill@sheffield.ac.uk