The National Institute of Health in Bethesda, Maryland holds a Pediatric & Wildtype GIST Clinic. Experts from all over the world attend to share information amongst themselves as well as educate patients, caregivers and parents on how this subset of GIST is unique. The patients who attend and who have attended this Clinic donate tissue samples and DNA (saliva) that stays on file for future research. The Clinic is held annually, usually in June. All patients with a GIST diagnosis who are 18 years or younger, or those with a "wildtype" GIST diagnosis, are encouraged to apply. International patients as well as US patients are accepted. Contact and application information can be found at: https://ccr.cancer.gov/gist
Inspired by the Pediatric and Wildtype GIST clinic at the National Institute of Health in America, the Pediatric, Adolescent, Wildtype, Syndromic GIST (PAWS-GIST) has been formed. PAWS-GIST is a UK based alliance of medical specialists who serve patients in the UK and Europe. They hold an annual Clinic, usually in April, at Addenbrooke's Hospital, Cambridge, UK. Contact and application information can be found at: https://www.pawsgistclinic.org.uk/clinic-location.htm
Patients with known or suspected or pheochromocytomas may be seen at the NIH in Bethesda, Maryland. The NIH holds an Annual Pheo/PGL Clinic, by invitation. Contact and application information can be found at: https://science.nichd.nih.gov/confluence/display/pheo/Frequently+Asked+Questions
Donation of tumor tissue is of upmost importance. If you know you are having surgery for any SDH-related cancer or Wildtype GIST we would encourage you to reach out to the SDH-RA to pre-arrange to have your tumor tissue sent to researchers. We can be reached at: email@example.com
A Phase II Trial of the DNA Methyl Transferase Inhibitor, Guadecitabine (SGI-110), in Children and Adults With Wild Type GIST,
Pheochromocytoma and Paraganglioma Associated With Succinate Dehydrogenase Deficiency and HLRCC-associated Kidney Cancer
Follow this link to view the trial on the clinicaltrials.gov website: https://clinicaltrials.gov/ct2/show/NCT03165721
A Phase I Trial of the Glutaminase Inhibitor CB-839 on Solid Tumors
Follow this link to view the trial on clinicaltrials.gov website: https://clinicaltrials.gov/ct2/show/NCT02071862?term=glutaminase&cond=gist&rank=1
Trial contact: Trial Administrator firstname.lastname@example.org
A Phase I Trial of HIF-2a Transcription Factor Inhibitor PT2977 with Advanced Solid Tumors
Follow this link to view the trial on the clinicaltrialsgov
Trial contact: Richard Kelley, (972) 629-4088 email@example.com
Articles describing the rationale behind use of HIF-2a inhibitors:
New HIF2A inhibitors: implications for pheochromocytomas and paragangliomas
Rodrigo Almeida Toledo, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
recently developed inhibitors of hypoxia-inducible factor 2-alpha (HIF2α). This Commentary is based on the recognition of similar molecular drivers in ccRCC and the endocrine neoplasias pheochromocytomas and paragangliomas (PPGLs), ultimately leading to stabilization of HIFs. HIF-stabilizing mutations have been detected in the von Hippel-Lindau (VHL) gene, as well as in other genes, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), and transcription elongation factor B subunit 1 (TCEB1), as well as the gene that encodes HIF2α itself: EPAS1HIF2α.
The now available therapeutic opportunity to successfully inhibit HIF2α pharmacologically with PT2385 and PT2399 will certainly spearhead a series of investigations in several types of cancers, including patients with SDHB-related metastatic PPGL for whom limited therapeutic options are currently available.
HIF-2alpha: Achilles' heel of pseudohypoxic subtype paraganglioma and other related conditions
Sri Harsha Tella, David Taïeb, Karel Pacak'
The main aim of this perspective is to address the possibility of HIF-2α antagonists in the management of tumours, beyond clear cell renal cell carcinoma, where the dysfunctional hypoxia-signalling pathway, especially HIF-2α, referred here as the Achilles' heel, plays a unique role in tumorigenesis and other disorders. These tumours or disorders include PGLs, somatostatinomas, hemangioblastomas, gastrointestinal stromal tumours, pituitary tumours, leiomyomas/leiomyosarcomas, polycythaemia and retinal abnormalities. We hope that HIF-2α antagonists are likely to emerge as a potential effective treatment of choice for HIF-2α–related tumours and disorders.
Hypoxia and hypoxia-inducible factors in neuroblastoma.
Påhlman S*, Mohlin, Lund University, Sweden.
Hypoxia (i.e., low oxygen levels) is a known feature of aggressive tumors. Cells, including tumor cells, respond to conditions of insufficient oxygen by activating a transcriptional program mainly driven by hypoxia-inducible factors (HIF)-1 and HIF-2.
In this review, we discuss these non-conventional actions of HIF-2α, its putative role as a therapeutic target and the constraints it carries, as well as the importance of HIF-2 activity in a vascularized setting, the so-called pseudo-hypoxic state.
A drug that inactivates HIF-2 activity by binding to the HIF-2 alpha subunit and thereby preventing its binding to the beta-subunit. The
effect, seen in some renal cell carcinoma models, is the inhibition of HIF-2-driven gene transcription, which is thought to manifest an aggressive tumor phenotype.
Germline SDHB mutations will lead to an activated HIF-2 and in theory, an HIF-2 inhibitor can have positive effects on your tumor.*
The mutated HIF-2a in paraganglioma and pheochromocytoma results in stabilization of the protein so it is not degraded in oxygenated tissues and thus can complex with the beta subunit and form a functional transcription complex. This means that the factor can work under these "normal" conditions and promote a tumor phenotype and behaviour. In theory, a HIF2a inhibitor might have a positive effect on tumor cells that carry SDHB mutations, and that the HIF-2 inhibitor in conjunction with established chemotherapy might destroy HIF-2a positive stem cell pools.*
GIST Support International - Wildtype/SDH GIST - www.gistsupport.org
SDH-deficient/Pediatric/Wildtype GIST Listserv Group - http://www.gistsupport.org/gsi-community/join-our-gist-community/wildtype-amp-pediatric-gist-listserv/
The Liferaft Group - www.liferaftgroup.org
GIST Cancer Awareness Foundation - www.gistawareness.org
GIST Cancer Research Fund - www.gistinfo.org/gist-information/pediatric-gist
Pediatric and Wildtype GIST Clinic at NIH - www.ccr.cancer.gov/gist
PAWS-GIST (Paediatric Adolescent Wild-type & Syndromic GIST) UK - http://www.pawsgistclinic.org.uk
ForIan.org - https://www.forian.org
Pheo-Para Coalition - http://www.sdhbcoalition.org
Pheo-Para Alliance - http://www.pheo-para-alliance.org
PheoParaTroopers - http://www.pheoparatroopers.org
ParaDifference Foundation - http://www.paradifference.org
Dr. Jason Sicklick, GIST surgeon, Moores Cancer Center, UCSD La Jolla, California
Dr. Michael Heinrich, GIST oncologist, Knight Cancer Institute, OHSU, Portland, Oregon
Dr. Kevin Billingsley, GIST surgeon, Knight Cancer Institute, OHSU, Portland, Oregon
Dr. Rodney Pommier, NET surgeon, Knight Cancer Institute, OHSU, Portland, Oregon
Dr. Karel Pacak, Senior Investigator Paraganglioma and Pheochromocytoma, NIH, Bethesda, Maryland
Dr. Constantine Stratakis, Senior Investigator, geneticist, NIH/NICDH, Bethesda, Maryland
Dr. Sosipatros Boikos, Wildtype GIST oncologist, Massey Center, Virginia Commonwealth University, Richmond, Virginia
Dr. Brian Van Tine, Oncologist, Siteman Cancer Center, Washington University, St. Louis, Missouri
Dr. JP Bayley, Paraganglioma Research Group, Department of Human Genetics,
Leiden University Medical Center, The Netherlands. Link is to SDHB Database of Known Germline Variances
Dr. Katherine Janeway, Pediatric Oncologist, Dana-Farber/Harvard, Boston, Massachusetts
Dr. Margaret Von Mehren, Wildtype GIST oncologist, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Dr. Jonathan Trent, Wildtype GIST oncologist, Sylvester Comprehensive Cancer Center, Miami, Florida
NIH Pediatric Clinic Analysis of SDH deficient GIST patients - 2012, Dr. Su Young Kim
VIDEO - Analysis of the Pediatric Gist Clinic at NIH in 2012. Nice clear explanation of SDH deficient GIST
Administrator's take: Dr. Su Young Kim, a friend to us who had the pleasure to meet him, giving a talk/analysis of Pediatric/SDH deficient GIST
Succinate dehydrogenase (SDH)-deﬁcient neoplasia
A.J. Gill, 2018, NSW
A detailed description of SDH mutations with their prevelence in Pheo/Paras, Gists, and other tumors
Surgical Management of Adolescents and Young Adults With Gastrointestinal Stromal Tumors:
A US Population-Based Analysis.
This study found that adolescent and young adult GIST patients are more likely to undergo surgical management than older adult patients. Operative management is associated with improved overall survival, including those with metastatic disease
Administrator's take: Surgery is still the best often for wildtype and SDH-Deficient GIST patients
Translating Genetic Data into Actionable Clinical Guidelines: Succinate Dehydrogenase Subunit A Variants of Unknown Significance in Gastrointestinal
Stromal Tumors (2017). Scholar Archive. 3972 by Amber Bannon
A dissertation by Amber Bannon, OHSU. I had the pleasure to meet Amber and this paper talks about how some gene mutations (SDHA) are more likely to produce tumors than other variances. The key seems to be that the mutations proximity to the center of the gene which contains "Flavin" are more likely to be pathogenic.
Note, the paper is long and might take some time to load, it is worth reading.
Prognosis and management of adult wild type gastrointestinal stromal tumours (GISTs): A pooled analysis and review of literature
•Adults with WT GISTs have a similar molecular pathway to pediatric GISTs.
•Survival in both these subtypes is similar and more favourable compared to other GISTs.
Mean survival in adults was 15.7 years ± 0.78 and in children was 18.8 years ± 1.3 (p = 0.241). Median disease free survival in adults was 10 years while 5-year overall survival was 88%. Overall survival in adults with WT GISTs is favourable compared to other adult GIST subtypes likely reflects a common molecular pathway similar to pediatric GIST.
Administrator's take: Pediatric GIST and wildtype GIST patients have a longer survival rate than regular GIST
Diagnosis, Localization, Pathophysiology, and Molecular Biology of Pheochromocytoma and Paraganglioma
Karel Pacak, MD, PhD, DSc
What I found interesting:
The paper has a comparison of the Ga-Dotatate scan verse F-FDopa scan with superior clariety in the Ga-Dotatatate.
Then some things we know:
PPGLs with mutations in SDHB are the most aggressive forms of the disease, partly owing to their pseudo-hypoxic character, metabolic abnormalities, and elevated levels of reactive oxygen species (ROS).
Some tumor suppressor solutions they thought possible include two herbal:
Piperlongumine (PL), a natural product with cytotoxic properties
Topoisomerase I inhibitor, LMP-400
ATP5B antibody led to statistically significant inhibition of proliferation.
They were able to get a working mouse model using this technique:
NOD-scid gamma (NSG) mice xenografts of primary human PGLs took
Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations
Analysis of the Leiden Open Variation Database http://www.lovd.nl/3.0/home
Gists: 26 SDHA, 14 SDHB, 9 SDHC, 6 SDHD - Total SDH deficient Gist 55
Paras/Pheos: 7 SDHA, 211 SDHB, 42 SDHC, 141 SDHD - Total SDH deficient Para/Pheo 401
Familial PCC/PGL syndromes were initially
thought to predispose only to PCCs and PGLs, but several tumors, including GISTs, RCCs, and PAs, have expanded the SDH-associated tumor spectrum. Extensive clinical variability can be expected, even among carriers of an
identicalSDH germ-line mutation, with tumor phenotypes being only partially expressed, as in the
These GISTs are characterized by unique clinicopathological features and biological properties: (i) female preponderance; (ii) gastric location (predilection for the distal stomach/antrum); (iii) common multifocality; (iv) a multinodular/plexiform growth pattern; (v) epithelioid cytomorphology, either pure or combined with a spindle-cell component; (vi) SDHA and/or SDHB immunonegativity; (vii) KIT (and DOG1) immunopositivity despite the lack of KIT/PDGFRA mutations; (viii) metastatic potential (often to lymph nodes); (ix) a relatively indolent clinical course, even in the presence of metastatic disease; and (x) insensitivity to imatinib
The SDHD gene was discovered by Dr. Baysal who was studying people in the Andes who got paragangliomas. An email from him two weeks ago and he again advised me not live at in high altitudes NOR fly in airplanes. Airplanes are known to have 80% of the oxygen that is on the ground. SDHx patients have a compromised oxygen sensor. Resource links to follow.
There are three breeds of dogs that by nature of the breed develop chronic hypoxia and they develop chemodectomas (the old word for paragangliomas and what is on my father's death certificate). I just found a paper confirming this theory by two researchers in The Netherlands. I contacted Dr. Bayley there who has been doing SDHB research for years and he said it was a colleague of his that wrote the paper. I was hoping the research over the years on these breeds of dog would produce a chemo but the recommended procedure is surgery.
I then found a paper from 1974, the year my father died, that also said chronic hypoxias as in these dog breeds and people in the Andes causes paragangliomas! Thus this information has been written about since 1974.
I think there are other means of hypoxia that could also eventually lead to disease such as sleep apnea, extreme sport activities, smog . . . And the wildfire smoke I have to live with for 5 weeks every summer that has air quality at "harzardous".
I also think a compromised system could be a trigger. My own case I think comes from mold (house mold in my case) and research shows 3-NPs are "suicide" to the SDHB gene. I had long exposure to environmental mold in a house I rented for my daughter for college as well as finding black mold inside the graphics studio I've worked in for 35 years.
Vet Comp Oncol. 2017 Jan 25. doi: 10.1111/vco.12291. [Epub ahead of print]
Pheochromocytomas and paragangliomas in humans and dogs.
Galac S1, Korpershoek E2.
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are described in several species. In humans and dogs they have many similarities: the excessive catecholamine release in hormonally active PCC causes similar clinical signs, the frequency of metastasis is similar, and they are histopathologically almost identical. Surgery is curative when PCC and PGL have not metastasized, while only palliative treatment is possible for patients with metastatic disease. Mutations in succinate dehydrogenase subunit B (SDHB) are associated with metastatic behaviour in human PCC/PGL and the same mutation has been described in dogs. The dog might therefore be a suitable model for study of the pathogenesis of metastatic PCC and PGL in humans. Further molecular studies of common tumourigenic pathways and comparative studies of histopathology of human and canine PCC and PGL are warranted.
What Baysal found was a mutation in the gene, named SDHD, that makes a protein eventually transported to the mitochondria— “the powerhouse and brains of the carotid bodies,”according to Baysal. The mutation causes the mitochondria to react as if they were in an oxygen-deprived environment, even though that is not the case. Consequently—as experienced by Andean Mountain dwellers—this tissue never stops working. The number of cells increases, and the increased mass eventually results in tumors.
Chemodectomas in Dogs: Epidemiologic Comparisons With Man2
Howard M. Hayes, Jr., D. V.M. Joseph F. Fraumeni, M.D.
JNCI: Journal of the National Cancer Institute, Volume 52, Issue 5, 1 May 1974, Pages 1455–1458,
Fifty dogs with a confirmed diagnosis of chemodectoma were identified at 11 veterinary school clinic-hospitals. As in man, some evidence was found of genetic determinants: 2 brachycephalic breeds (Boston terriers and boxers) had a significantly greater risk compared to all other purebred dogs combined. An excessive risk was detected in males, though it was not statistically significant, and in older dogs. There was a significantly high frequency of 4 concurrent tumors (seminoma and interstitial-cell tumors of the testis, adenomatous thyroid neoplasms, and hemangiomas); but in man, with chemodectoma, the reported tendency to multiple primary tumors has been confined to the chemoreceptor system. The etiologic role of chronic hypoxia, suggested by the high incidence of carotid body tumors among Peruvians in the Andes, may be clarified by further studies of chemodectoma in brachycephalic breeds.
Altitude chart with amount of oxygen
Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis
Succinate is an important metabolite at the cross-road of several metabolic pathways, also involved in the formation and elimination of reactive oxygen species. However, it is becoming increasingly apparent that its realm extends to epigenetics, tumorigenesis, signal transduction, endo- and paracrine modulation and inflammation.
3-Nitropropionic Acid Is a Suicide Inhibitor of Mitochondrial Respiration That, upon Oxidation by Complex II, Forms a Covalent Adduct with a Catalytic Base Arginine in the Active Site of the Enzyme*
The plant and fungal toxin 3-nitropropionic acid, an irreversible inactivator of succinate dehydrogenase, forms a covalent adduct with the side chain of Arg297.
The toxin 3-nitropropionic acid (3-NP) is produced by certain plants and fungi. It is a specific inhibitor of mitochondrial respiratory complex II. Fatalities after eating moldy sugarcane have been linked to 3-NP toxicity (,1, 2). Ruminants grazing in regions with 3-NP-producing plants acquire resistance because of reduction of the nitro group to an amine by ruminal bacteria.
Nitropropionic acid (3-NPA), an irreversible inhibitor of SDH activity (Huang et al., 2006).
beta-Nitropropionic acid (3-nitropropanoic acid, BPA, 3-NPA, C3H5NO4) is a mycotoxin, a potent mitochondrial inhibitor, toxic to humans. It is produced by a number of fungi, and found widely in food, in sugar cane, as well as Japanese fungally fermented staples miso, soy sauce, katsuobushi, and some traditional Chinese medicines. Spices are susceptible substrate for growth of mycotoxigenic fungi and mycotoxin production. Red chilli, black pepper, and dry ginger were found to be the most contaminated spices.
Contents acculumlated by Cathy Freeman, SDHB Deficient Gist Patient