Danielle Stevenson

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BHD Research Blog
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  • November 20, 2015
  • 08:37 AM

Summary of recent kidney cancer clinical trials

by Danielle Stevenson in BHD Research Blog

Kidney tumours, if detected early enough, can often be removed surgically without the need for further drug treatments. However, if the primary tumour metastasises traditional chemotherapies and radiotherapies become ineffective and patient survival is limited. In recent years there have been great advances in treatments for metastatic renal cell carcinoma (mRCC) with several targeted treatments now available. However, these targeted treatments show variable response rates and efficacy. This blog summarises recent results from clinical trials assessing new treatments.... Read more »

Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER.... (2015) Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. The New England journal of medicine, 373(19), 1803-13. PMID: 26406148  

  • November 13, 2015
  • 06:07 AM

FLCN modifies the cytoplasmic translocation and aggregation of TDP-43

by Danielle Stevenson in BHD Research Blog

TDP-43 is a DNA/RNA binding protein whose cytoplasmic aggregation is associated with neuronal death in ALS and frontotemporal lobar degeneration (FTLD). TDP-43 has multiple cellular functions and shuttles between the nucleus and cytoplasm. However, in ALS and FTLD nuclear clearance of TDP-43 results in increased cytoplasmic localisation – a precursor to TDP-43 aggregation and stress granule formation. The mechanisms that regulate TDP-43 transport are not well understood but new research from Xia et al. (2015) has uncovered a role for FLCN in its nuclear export and the formation of stress granules.... Read more »

  • November 6, 2015
  • 05:25 AM

In response to amino acids yeast FLCN-FNIP orthologues Lst7-Lst4 stimulate TORC1 activity

by Danielle Stevenson in BHD Research Blog

In eukaryotic cells TORC1 signalling has a key role in controlling cell growth in response to nutritional status. Folliculin (FLCN) and the FNIP proteins regulate mTORC signalling via interactions with Rag family GTPases (Petit et al., 2013, Tsun et al., 2012). Recently Péli-Gulli et al. (2015) reported that the yeast orthologues of FLCN and FNIP, Lst7 and Lst4, form a heterodimer that acts as a GTPase Activating Protein (GAP) for yeast Rag family GTPase Gtr2 . Lst4-Lst7 is the first GAP identified for Gtr2.... Read more »

  • October 30, 2015
  • 09:00 AM

Pleural covering as an alternative treatment for recurrent pneumothorax

by Danielle Stevenson in BHD Research Blog

Most BHD patients develop pulmonary cysts and although only 30-35% will suffer a pneumothorax the recurrence rate is very high (Toro et al., 2008). The standard treatment for recurrent pneumothorax is pleurodesis, sometimes accompanied with pleurectomy, which attaches the lung surface to the chest wall thereby reducing the risk of further air leaks. An alternative treatment pioneered by several independent groups of researchers and clinicians in Japan is pleural covering which reinforces the surface of the lung without attachment to the chest wall.... Read more »

Ebana H, Otsuji M, Mizobuchi T, Kurihara M, Takahashi K, & Seyama K. (2015) Pleural Covering Application for Recurrent Pneumothorax in a Patient with Birt-Hogg-Dubé Syndrome. Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia. PMID: 26370712  

  • October 16, 2015
  • 04:12 AM

A role for FLCN in modulating resistance to hyperosmotic stress

by Danielle Stevenson in BHD Research Blog

Water efflux in response to hyperosmotic stress causes cells to shrink, protein and DNA damage, cell cycle arrest and death. Cells must therefore adapt to changes in external osmolality; one conserved mechanism is to increase intracellular osmolytes to maintain osmotic homeostasis. New research from Possik et al., (2015) has identified a role for FLCN-1, mediated by AMPK activity, in the maintenance of glycogen stores required for rapid production of the osmolyte glycerol in C.elegans.... Read more »

Possik E, Ajisebutu A, Manteghi S, Gingras MC, Vijayaraghavan T, Flamand M, Coull B, Schmeisser K, Duchaine T, van Steensel M.... (2015) FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores. PLoS genetics, 11(10). PMID: 26439621  

  • October 9, 2015
  • 09:00 AM

Flcn-deficient renal cyst cells can be tumourigenic

by Danielle Stevenson in BHD Research Blog

Kidney-specific Flcn knockout in mice results in the development of large polycystic kidneys and uremia causing renal failure and death within three weeks (Chen et al., 2008). As this short time frame is insufficient for substantial solid tumour growth Wu et al., (2015) extracted renal cyst cells to assess their tumourigenic potential and response to mTOR inhibitors.... Read more »

  • September 18, 2015
  • 04:19 AM

Use of Cavitation Ultrasonic Surgical Aspirators for partial nephrectomies

by Danielle Stevenson in BHD Research Blog

Partial nephrectomies are technically challenging surgeries but preserve healthy renal tissue and therefore function. To minimise bleeding the major blood vessels are usually clamped and tumour extraction completed under ischemic conditions – the renal tissue is deprived of oxygen and nutrients due to restricted blood flow. Although ischemic conditions for less than 25 minutes have minimal reported impact on renal function (Volpe et al., 2015), more complex tumours result in prolonged ischemia making the preservation of healthy tissue more difficult. In recent years several zero-ischemic techniques, including minimally invasive and robotic approaches (Gill et al., 2011, Simone et al., 2013), have been developed that do not require renal artery clamping.... Read more »

  • September 11, 2015
  • 09:00 AM

Upcoming BHD and Upstate Kidney Cancer Symposium

by Danielle Stevenson in BHD Research Blog

On September 23-26th the Sixth BHD and First Upstate Kidney Cancer Symposium will be taking place in Syracuse, New York. Hosted by Dr Medhi Mollapour and Professor Gennady Bratslavsky of the Upstate Medical University (both also presenting), it will focus on scientific and clinical developments in BHD and renal cell cancer.... Read more »

  • September 4, 2015
  • 06:08 AM

Everolimus for the treatment of lymphangioleiomyomatosis

by Danielle Stevenson in BHD Research Blog

mTOR is dysregulated in a range of tumour types and can be targeted with mTOR inhibitor treatments such as everolimus and sirolimus. Tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyamatosis (LAM) result from mutations in TSC1 or TSC2 that disrupt mTOR signalling (Carsillo et al., 2000, Glasgow et al., 2010). The associated aberrant cell growth, survival and movement results in the formation of slow growing tumours in various tissues and pulmonary cyst formation with loss of pulmonary function. The pivotal role of mTOR signalling in the pathogenesis of TSC/LAM mean mTOR inhibitors have great potential as treatments.... Read more »

Goldberg HJ, Harari S, Cottin V, Rosas IO, Peters E, Biswal S, Cheng Y, Khindri S, Kovarik JM, Ma S.... (2015) Everolimus for the treatment of lymphangioleiomyomatosis: a phase II study. The European respiratory journal, 46(3), 783-94. PMID: 26113676  

  • August 28, 2015
  • 09:00 AM

Immunotherapy AGS-003 trial in localised renal cell carcinoma

by Danielle Stevenson in BHD Research Blog

Although targeted therapies have enhanced the efficiency of renal cell carcinoma (RCC) treatment, individual responses are usually limited with few complete remissions reported. An expanding therapy field in RCC is immunotherapy – small molecule and autologous treatments that can modulate the immune system to kill cancer cells. Although to date immunotherapies have only induced a response in a subpopulation of patients, a greater proportion of these responses are long lasting highlighting their potential.... Read more »

  • August 21, 2015
  • 09:00 AM

TDP-43 differentially splices FNIP1

by Danielle Stevenson in BHD Research Blog

Folliculin interaction protein 1 (FNIP1), through interactions with FLCN, plays a role in a range of cellular processes (Baba et al., 2006). Alternative splicing of FNIP1, under the control of MBNL1, was previously reported in late mesenchymal differentiation (Venables et al., 2013). New research from De Conti et al., (2015) has identified FNIP1 as also being differentially spliced by TDP-43 – a protein associated with neurodegeneration in ALS and fronto-temporal dementia (Neumann et al., 2006).... Read more »

  • August 14, 2015
  • 09:00 AM

Sharing genomic data to advance research

by Danielle Stevenson in BHD Research Blog

It is expected that genetic sequencing will advance both specialised and general healthcare leading to more personalised care based on an individual’s genome. It can be used to identify disease-specific mutations and those associated with more complex conditions. However, as discussed previously on this blog, understanding the effect of a single mutation can be difficult without comparison between healthy and disease patient samples. Sharing patient data accumulated by private and academic labs, voluntary databases, healthcare providers and large scale sequencing efforts such as the 100,000 genomes project, can provide researchers with the larger datasets required for accuracy.... Read more »

  • August 7, 2015
  • 09:00 AM

High-throughput screening to identify synthetic lethal compounds in RCC

by Danielle Stevenson in BHD Research Blog

Synthetic lethal compounds selectively kill cancer cells by targeting tumour cell-essential processes, but leave healthy cells unharmed. Research is ongoing to identify such compounds in a range of cancers (reviewed in McLornan et al., 2014) including renal cell carcinoma (RCC). New research from Wolff et al., (2015) has identified homoharringtonine (HHT) as synthetically lethal for a subset of clear cell RCC (ccRCC) tumours associated with VHL mutations.... Read more »

  • July 31, 2015
  • 04:13 AM

Everolimus: a new treatment for BHD renal cancer?

by Danielle Stevenson in BHD Research Blog

Last week the US National Cancer Institute announced a phase II clinical trial to test everolimus, a derivative of rapamycin, in BHD patients with renal cell carcinoma (RCC). The trial is also open to sporadic chromophobe RCC (chRCC) patients. Approximately 85% of BHD-RCC is either chRCC or a chromophobe-oncocytoma hybrid (Pavlovich et al., 2002), but there are no effective treatments available for this RCC subtype. Instead BHD patients undergo partial nephrectomies to excise tumours – while not often impacting greatly on renal function, repetitive surgeries can increase morbidity risks. It is hoped that cancer drugs, such as everolimus, can offer a valid alternative treatment.... Read more »

  • July 24, 2015
  • 05:07 AM

Analysing mutational heterogeneity to identify true cancer-associated genes

by Danielle Stevenson in BHD Research Blog

A recent blog post discussed the need to assess the pathogenicity of genetic variants to determine which mutations are truly causative and which are only background. This is highly important in the search for new cancer drugs as rapidly dividing tissues are more prone to accruing mutations. Large cancer genomic studies are identifying increasing numbers of apparently “significantly-mutated genes” across all major cancer types. However, these genes often include highly unlikely candidates. Analysis of 178 squamous lung cell carcinomas identified 450 significantly-mutated genes; almost a quarter of which were olfactory receptors (TCGA Research Network, 2012). It is necessary to be able to eliminate these false-positives and retain focus on true cancer-genes.
... Read more »

Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA.... (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature, 499(7457), 214-8. PMID: 23770567  

  • July 17, 2015
  • 09:00 AM

Distinct roles for VHL and hypoxia in RCC gene expression and metabolism

by Danielle Stevenson in BHD Research Blog

As discussed in last week’s blog renal cell carcinoma (RCC) cells show altered metabolism favouring lactate fermentation as the major energy source. Such metabolic changes can be a response to hypoxia or mutations in genes, such as VHL, that disrupt HIFα-proteasomal degradation. HIF signalling, directly and indirectly, regulates over 2% of human genes including those involved in angiogenesis, survival, proliferation and metabolism (Manalo et al., 2005). Hypoxia and VHL-loss are generally thought to result in the same changes in gene and protein expression, however, Leisz et al., (2015) have found differential effects in RCC cellular models.... Read more »

  • July 10, 2015
  • 04:31 AM

Grade-dependent metabolic reprogramming in RCC

by Danielle Stevenson in BHD Research Blog

It is well established that altered metabolism in cancer cells supports survival and growth. Understanding these biological changes could lead to treatments able to specifically target tumourigenic cells. However, despite the known variability in tumour biology, the majority of research is based on the same available cell lines. In renal cell carcinoma (RCC) research these lines frequently carry a VHL mutation: VHL gene alterations are associated with hereditary RCC in VHL syndrome and up to 91% of sporadic clear cell RCCs (Nickerson et al., 2008). The loss of pVHL results in aberrant HIF signalling and changes in metabolism (Keefe et al., 2013).... Read more »

Wettersten HI, Hakimi AA, Morin D, Bianchi C, Johnstone ME, Donohoe DR, Trott JF, Aboud OA, Stirdivant S, Neri B.... (2015) Grade-Dependent Metabolic Reprogramming in Kidney Cancer Revealed by Combined Proteomics and Metabolomics Analysis. Cancer research, 75(12), 2541-52. PMID: 25952651  

  • July 3, 2015
  • 06:06 AM

A new tissue-specific FLCN-deficient mouse model of renal tumourigenesis

by Danielle Stevenson in BHD Research Blog

Animal models can be useful for understanding disease pathology and as preclinical models for drug testing. As BHD patients develop renal cell carcinomas (RCCs) of varied histologies, associated with a loss of FLCN, BHD animal models could be used to study of a wide range of renal cancer subtypes. Current BHD mouse models include kidney-specific Flcn-knockouts (Chen et al., 2008, Baba et al., 2008) and ubiquitous knockouts (Hasumi et al., 2009, Hartman et al., 2009, Hudon et al., 2010). The former develop polycystic kidneys and die within three weeks, the latter can only be studied as heterozygotes with tumourigenesis dependent on a “second hit” resulting in variable penetrance and making them less suitable for drug studies.... Read more »

Chen J, Huang D, Rubera I, Futami K, Wang P, Zickert P, Khoo SK, Dykema K, Zhao P, Petillo D.... (2015) Disruption of tubular Flcn expression as a mouse model for renal tumor induction. Kidney international. PMID: 26083655  

  • June 12, 2015
  • 04:07 AM

A lactate-induced response to hypoxia

by Danielle Stevenson in BHD Research Blog

Hypoxia regulation ensures cell survival and growth in low oxygen environments. HIF signalling is a well-established element of this regulation but is also associated with tumourigenesis in BHD, VHL, HLRCC, TSC, and sporadic cancers. New research from Lee et al., (2015) has identified a second, HIF-independent, hypoxia response which can modify cell survival and growth signalling pathways – the lactate-induced activation of NDRG3-mediated signalling.... Read more »

Lee DC, Sohn HA, Park ZY, Oh S, Kang YK, Lee KM, Kang M, Jang YJ, Yang SJ, Hong YK.... (2015) A lactate-induced response to hypoxia. Cell, 161(3), 595-609. PMID: 25892225  

  • May 29, 2015
  • 09:00 AM

The potential use of BH3-mimetics to overcome apoptosis-resistance in renal cell carcinoma

by Danielle Stevenson in BHD Research Blog

Renal cell carcinoma (RCC), as well as other solid tumours, can prove resistant to standard cancer treatments such as chemotherapy. One mechanism likely to play a role in this resistance is activation of HIF signalling either as a result of hypoxia within the tumour or as the result of mutations as in BHD, VHL and TSC. Increased HIF activity, as well as altered PI3K/AKT/mTOR, MEK/ERK and TGFβ signalling, can shift the balance of anti- and pro-apoptotic factors enabling tumour cells to survive in unfavourable conditions.... Read more »

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