DCA (dichloroacetic acid) - a possible future cancer treatment?

Dichloroacetic acid - Wikipedia, the free encyclopedia

There are wild rumors that DCA (dichloroacetic acid) "cures" cancer. Ignoring what seem to be premature and extreme claims, the facts about DCA are interesting to consider. Perhaps DCA may have a future in cancer treatment.

Genetic and Clinical Features of Multiple Endocrine Neoplasia Types 1 and 2

Genetic and Clinical Features of Multiple Endocrine Neoplasia Types 1 and 2

-C. Romei, et al.
Journal of Oncology, Volume 2012, Article ID 705036

MEN1 intragenic deletions appear common in sporadic primary hyperparathyroidism

MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

-M Alvelos, et al.
European Journal of Endocrinology, October 23, 2012 EJE-12-0327

MEN Syndrome and M.E.N. 1: Parathyroid, Pituitary, Pancreas, Thyroid Tumors and MEN type 1 Syndrome - Disorders of the Parathyroid, Pituitary, and Pancreas

MEN Syndrome and M.E.N. 1: Parathyroid, Pituitary, Pancreas, Thyroid Tumors and MEN type 1 Syndrome - Disorders of the Parathyroid, Pituitary, and Pancreas

An overview of MEN1, its treatment, and what patients can expect.

By James Norman MD, FACS, FACE
Norman Parathyroid Center
http://www.parathyroid.com/Parathyroid-Surgeon.htm

Prolactin produced in the breast may play a role in breast cancer

http://www.medicalnewstoday.com/releases/250906.php

• "...prolactin has long been thought to play a role in human breast cancer, however this has typically been assumed to be due to circulating prolactin produced by the pituitary. Since the PI3K-Akt signaling pathway is commonly activated in human cancers, this new finding suggests the important possibility that prolactin produced by the breast itself may play a role in breast cancer."
  
• "Since the PI3K-Akt pathway is one of the most commonly activated oncogenic pathways in human cancer, its identification as an upstream regulator of prolactin production in the mammary gland has intriguing potential implications for understanding the pathology of human breast cancer and as well as improving its treatment..."
  

-Medical News Today, October 2, 2012

MD Anderson Cancer Center announces "Moon Shots Program"

"The University of Texas M.D. Anderson Cancer Center is launching a multibillion-dollar initiative on Friday aimed at reducing cancer deaths over the next decade, saying a flurry of recent advances in genomics and other technologies has laid a foundation for making major new strides against the disease.

The effort, which the institution calls the Moon Shots program, is expected to spend as much as $3 billion over 10 years in a bid to reduce the toll of eight different cancers, and to develop an infrastructure and strategies for collecting and analyzing data that leaders of the effort say will be applied to other cancers as well."

Wall Street Journal, 21 September 2012

See the full Moon Shots News Release

The MEN 1 Pancreas: Tumor Development and Haploinsufficiency

The MEN 1 Pancreas: Tumor Development and Haploinsufficiency

-H Lejonklou, et al.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206; 792. ISBN 978-91-554-8415-6.

• A collection of four papers on MEN1 and PNET (pancreatic neuroendocrine tumors).
  

MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas

MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas
-G Walls, M Lemos, et al.
Journal of Cancer Research, OnlineFirst August 21, 2012; doi: 10.1158/0008-5472.CAN-12-1821

• "In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1+/- mice, using a recombinant non-replicating adenoviral serotype 5 vector..."
  
• "Menin expression was higher in the Men1.rAd5-treated mice when compared to other groups. Daily proliferation rates assessed by BrdU incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control treated tumors."
  
• "Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation."
  

Testing Of New Drug For Patients With Neuroendocrine Tumors

Testing Of New Drug For Patients With Neuroendocrine Tumors

• "Pasireotide is a novel multireceptor-targeted somatostatin analogue that binds to four of the five known somatostatin receptor subtypes... Because of its binding ability, it may offer symptom reduction for patients who have eventually failed to respond to traditional therapy."
  
• The multicenter clinical trial, conducted at sites in the United States and Europe, enrolled 89 patients and evaluated 44 for efficacy and 45 for tolerability. Pasireotide "effectively controlled symptoms." Evaluation of tumor response in 23 patients showed 13 with stable disease and 10 with progressive disease. The drug was "effective and well-tolerated" and adverse events, most commonly gastrointestinal, were "mild or moderately severe."
  
• A Phase III study evaluating pasireotide versus octreotide is ongoing for patients with advanced NET whose disease-related symptoms have been inadequately controlled.
  
  

What Extent of Pancreatic Resection Do Patients with MEN-1 Require?

What Extent of Pancreatic Resection Do Patients with MEN-1 Require?
-C. D. Adkisson, et al.
JOP. J Pancreas (Online) 2012 Jul 10; 13(4):402-408.

• "In patients with MEN-1 and pancreatic endocrine tumors, preoperative workup underestimates extent of disease and total pancreatectomy should be considered for complete tumor removal."
  

Dopamine And Sleep Regulation

Dopamine And Sleep Regulation

• "These results are interesting as they demonstrate a mechanism in which dopamine, normally increased at times of stimulation, can directly inhibit production and release of a molecule, melatonin, that induces drowsiness and prepares the body for sleep..."

Chronic Inflammation and Gastroenteropancreatic Neuroendocrine Tumors

The Association of Chronic Inflammation and Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)
-Maja Cigrovski Berković, Davorka Herman Mahečić, Vedran Tomašić, Davor Hrabar and Vanja Zjačić-Rotkvić (2012).
The Association of Chronic Inflammation and Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs), Neuroendocrine Tumor, Dr. Anthony Lowell (Ed.), ISBN: 978-953-51-0653-1, InTech,
Available from: http://www.intechopen.com/books/neuroendocrine-tumor/the-association-of-chronic-inflammation-and-gastroenteropancreatic-neuroendocrine-tumors-gep-nets-

Vitamin D and cancer

Vitamin D and cancer
-Vuolo L, Di Somma C, Faggiano A and Colao A (2012) Vitamin D and cancer.
Front. Endocrin. 3:58. doi: 10.3389/fendo.2012.00058

Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin

Genome-Wide Characterization of Menin-Dependent H3K4me3 Reveals a Specific Role for Menin in the Regulation of Genes Implicated in MEN1-Like Tumors
-S Agarwal, R Jothi
PLoS ONE 7(5): e37952. doi:10.1371/journal.pone.0037952

The Genetics of Pituitary Adenomas

The Genetics of Pituitary Adenomas
-Monica Fedele, Giovanna Maria Pierantoni and Alfredo Fusco (2011). The Genetics of Pituitary Adenomas, Contemporary Aspects of Endocrinology, Dr. Evanthia Diamanti-Kandarakis (Ed.), ISBN: 978-953-307-357-6, InTech, Available from: http://www.intechopen.com/books/contemporary-aspects-of-endocrinology/the-genetics-of-pituitary-adenomas

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations

Prolactin Receptor in Primary Hyperparathyroidism – Expression, Functionality and Clinical Correlations
-Haglund F, et al. PLoS ONE May 2012, Volume 7, Issue 5, e36448.

• "...the prolactin receptor is highly abundant in human parathyroid tissues"
• "...PRLr isoforms expression and PRLr subcellular localisation are altered in parathyroid tumours."
• "Responsiveness of PRLr to physiological levels of prolactin was observed in the form of increased PTH secretion and altered gene transcription with significant increase of RIG-I like receptor, JAK-STAT and Type II interferon signalling pathways."
• "These data suggest a role of the prolactin receptor in parathyroid adenomas."

The Cabergoline-Resistant Prolactinoma Patient: New Challenges

The Cabergoline-Resistant Prolactinoma Patient: New Challenges
-Molitch M. The Journal of Clinical Endocrinology & Metabolism December 1, 2008 vol. 93 no. 12 4643-4645, doi: 10.1210/jc.2008-2244

• "11 of 60 previously untreated patients (18.3%) required more than 2 mg/wk cabergoline to normalize PRL levels. Of these, four required 3 mg/wk, two required 6 mg/wk, four required 9 mg/wk, and one required 11 mg/wk to normalize PRL levels."
  
• "Of 150 patients, normalization of PRL was eventually achieved in all but one, but doses had to be raised to high levels in many."

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas
-Casanueva F, et al. Clinical Endocrinology (2006) 65, 265–273

• "Doses [of cabergoline] over 3 mg per week are rarely necessary."

Cabergoline Resistance in Pediatric Prolactinomas

Cabergoline Resistance in Pediatric Prolactinomas
-Spinks J, et al. Journal of Pediatric Hematology/Oncology May 2009 - Volume 31 - Issue 5 - pp 377-379 doi: 10.1097/MPH.0b013e31819b71eb

• "We report 3 cases of cabergoline resistance in adolescents with prolactinomas. All patients failed to respond to conventional doses of cabergoline."

Dopamine agonist-resistant prolactinomas

Dopamine agonist-resistant prolactinomas
-Oh MC, Aghi MK Journal of Neurosurgery 2011 May;114(5):1369-79. published online January 7, 2011; DOI: 10.3171/2010.11.JNS101369.

• "Dopamine agonist-resistant prolactinomas exhibit aggressive behavior and tend to be large, invasive, hyperangiogenic tumors with high mitotic indices, which makes their management via surgery, radiosurgery, or alternative medical therapies challenging, thus underscoring the need for novel medical therapies or treatment regimens that target these lesions."
  
• "...slightly less than 10% of patients with prolactinomas do not experience normalization of their prolactin levels in response to dopamine agonists, and harbor tumors that are resistant to dopamine agonist therapy."
  
• "...a minimum pharmacological definition of dopamine agonist resistance would seem to require a failure to respond to 3 months of treatment with up to 3.5 mg of cabergoline per week."
  
• "Although very rare, secondary or acquired resistance to dopamine agonist therapy has also been described, in which patients who were initially responsive to... either bromocriptine or cabergoline, later develop dopamine agonist resistance, with elevated prolactin levels and sometimes an enlarging tumor volume several years after beginning treatment... According to a recent report... there have been only 5 reported instances of patients who demonstrated secondary resistance to dopamine agonist therapy (2 to bromocriptine and 3 to cabergoline).
  
• DARPs (dopamine agonist resistant prolactinomas) are more likely to exhibit cavernous sinus invasion... [71% vs 10% for dopamine agonist-responsive prolactinomas]."
  
• "DARPs typically do not metastatize."
  
• "Transsphenoidal surgery is recommended for prolactinomas instead of medical treatment if
  • ...2) inadequate prolactin reduction despite high cabergoline doses...
    
  • 3) a female patient desires fertility, which may not occur while on dopamine agonists...
    
  • 5) the patient cannot tolerate dopamine agonist therapy due to side effects.
• transsphenoidal surgery:
  • prolactin was normalized in 36% of patients with DARPs in one study.
    
  • prolactin was normalized in 75% of patients with DARPs that were microprolactinomas.
    
  • "Temozolomide... has been used to treat 3 patients with cabergoline-resistant DARPs... with good results in all 3 cases."

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings

Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm: Morphological findings
-Kovacs K, et al. Human Pathology Volume 38, Issue 1 , Pages 185-189, January 2007

• "Based on the clinical, laboratory, and morphological findings, we recommend temozolomide therapy in patients with pituitary tumors not responding adequately to other treatment options."

The Endoscopic Endonasal Transsphenoidal Approach to the Suprasellar Cistern

The Endoscopic Endonasal Transsphenoidal Approach to the Suprasellar Cistern
-Schwartz T, et al. Clinical Neurosurgery, Volume 54, 2007.

• Description of endoscopic transsphenoidal surgery.

Transsphenoidal Surgery for Pituitary Tumors in the United States, 1996–2000: Mortality, Morbidity, and the Effects of Hospital and Surgeon Volume

Transsphenoidal Surgery for Pituitary Tumors in the United States, 1996–2000: Mortality, Morbidity, and the Effects of Hospital and Surgeon Volume
-Barker F, II, et al. Journal of Clinical Endocrinology & Metabolism 88(10):4709–4719, ©2003 by The Endocrine Society, doi: 10.1210/jc.2003-030461

• Results of transsphenoidal surgery for pituitary tumors, as a function of hospital volume, surgeon volume, and more.

Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas

Endoscopic endonasal transsphenoidal surgery for functional pituitary adenomas
-Hofstetter C, et al. Neurosurg Focus 30 (4):E10, 2011

• Description of endoscopic endonasal transsphenoidal surgery.
• Results from the resection of 86 functional pituitary adenomas at Weill Cornell Medical College, New York–Presbyterian Hospital, from 2004-2010.

Prolactinomas: Diagnosis and Treatment: Management

Prolactinomas: Diagnosis and Treatment: Management
-Nassiri F, et al. Medscape Education CME Released: 02/29/2012.

• "Despite the effectiveness of [dopamine agonists]... some [patients] do not respond at therapeutic levels or higher. Such patients are considered to be DA resistant. The mechanism of resistance seems to be mediated by a decreased number of D2 receptors without a decreased affinity for DA agonists, and an altered signal transduction mechanism."
• "In resistant patients, treatment options include switching DA agonists, increasing DA agonist dosage beyond convention and surgery and/or radiotherapy."
• "Although doses of 2 mg/week exceed recommended package levels for cabergoline, some patients may require up to 3 mg/day for normalization of PRL levels."
• "Temozolomide therapy has even reduced tumor volume and normalized PRL levels in a resistant macroprolactinoma suggesting a possible role for temozolomide in resistant prolactinomas."

Asymptomatic children with multiple endocrine neoplasia type 1 (MEN1) mutations harbour pancreatic and pituitary tumours

Asymptomatic children with multiple endocrine neoplasia type 1 (MEN1) mutations harbour pancreatic and pituitary tumours
-Newey P, et al. Endocrine Abstracts (2009) 19 P171

• "...These two cases highlight the importance of screening children with MEN1 mutations as early diagnosis and treatment is likely to reduce both morbidity and mortality."

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists

Pituitary surgery for small prolactinomas as an alternative to treatment with dopamine agonists
-Babey M, et al. Pituitary Volume 14, Number 3 (2011), 222-230, DOI: 10.1007/s11102-010-0283-y

• "Ninety percent of symptomatic patients experienced significant improvement of their signs and symptoms upon surgery... [Among 34 patients] postoperative PRL levels (median 3.45 μg/l) returned to normal in 94% of patients with small prolactinomas. There was no mortality and no major morbidities."
• "Patients with small prolactinomas can safely consider pituitary surgery in a specialized centre with good chance of long-term remission as an alternative to long-term DA therapy."

MEN1 and pituitary adenomas

MEN1 and pituitary adenomas
-Delemer B. Service d’endocrinologie-diabète-nutrition

"MEN1 [pituitary] tumors seem more aggressive, invasive and resistant to treatment requiring a very careful long-life follow-up. Occurrence of these tumors can be described in the pediatric population and it can be the first and only manifestation of MEN1 for some years asking the question of the systematic screening for MEN1 gene mutation in pediatric population with pituitary adenoma."

Care for patients with multiple endocrine neoplasia type 1: the current evidence base

Care for patients with multiple endocrine neoplasia type 1: the current evidence base.

-Pieterman CRC, et al. Familial Cancer, Volume 10, Number 1 (2011), 157-171, DOI: 10.1007/s10689-010-9398-6.

• "The endocrine manifestations of MEN1 cannot be viewed upon as coinciding sporadic tumors."
• "In conclusion we state that the care for MEN1 patients is complex and should be provided by a centre of expertise. With the endocrinologist as primary caregiver, all important decisions should be made in a regular meeting of a multidisciplinary team, comprising of an endocrinologist, endocrine surgeon, radiologist, specialist nuclear medicine and paediatrician; if necessary expanded with a neurosurgeon, (radiation) oncologist, pathologist and clinical geneticist."
• Recommended protocol for periodic screening (summarized for patients at least 15 years of age):

  facility	frequency	treatment
  outpatient clinic	Every 2 years	History and physical exam
  labs	Every 2 years	Ionized calcium, chloride, phosphate, parathyroid hormone, fasting glucose, fasting insulin, fasting c-peptide, glucagon, fasting gastrin, pancreatic polypeptide, prolactin, insulin-like growth factor 1, platelet serotonin, chromogranin A
  imaging	Every 2 years	MRI of upper abdomen
  	Every 2-3 years	MRI of pituitary (intravenous contrast with gadolinium
  	Every 3-5 years	CT of thorax

Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study

Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study
-Verges, et al. Journal of Clinical Endocrinology & Metabolism 87(2):457–465, ©2002 by The Endocrine Society.

• Among the 85 prolactinomas [treated surgically, medically, or with radiotherapy] PRL levels were normalized in only 37 patients (44%).
• "Compared with pituitary adenomas in the non-MEN1 population, pituitary lesions in MEN1 are characterized by a higher frequency of macroadenomas and a worse response to treatment. This suggests that pituitary adenomas in MEN1 may be more aggressive than those occurring in the non-MEN1 patients."

The treatment of sporadic versus MEN1-related pituitary adenomas

The treatment of sporadic versus MEN1-related pituitary adenomas
-Beckers A, et al. Journal of Internal Medicine, 2003; 253: 599-605.

• MEN1-related adenomas [appear to be] more aggressive and less responsive to therapy than their sporadic counterparts."
• "...prolactinomas are over-represented in MEN1."
• [In non-invasive, sporadic cases, about] 92% of cases of prolactinoma or hyperprolactinemia were normalized with Cabergoline.
• 10-15% of patients are resistant to Bromocriptine. Cabergoline normalized PRL in more than 70% of patients intolerant or resistant to Bromocriptine.
• "In the future, somatostatin analogues with greater affinity to receptors subtype 5 (SSTR5) -frequently present at the cell surface of prolactinomas- may be tried.
• "Malignancy does not appear a characteristic of pituitary tumours in MEN1."
• "it appears therefore probable that MEN1 pituitary adenomas are more aggressive than the sporadic counterpart."
• In MEN1 patients with pituitary adenomas, "aggressive therapy is more frequently needed!"

Pituitary tumors in patients with MEN1 syndrome

Pituitary tumors in patients with MEN1 syndrome
-Syro LV, et al. Copyright © 2012 Hospital das Clínicas da FMUSP

• "pituitary tumors in MEN1 ...are more often resistant to medical therapy."
• "...normalization of pituitary hypersecretion was much less frequent in MEN1 patients than in non-MEN1 subjects (42% vs. 90%)."

Direct Binding of DNA by Tumor Suppressor Menin

Direct Binding of DNA by Tumor Suppressor Menin
-Ping La, et al. Journal of Biological Chemistry, Vol. 279, No. 47. Nov. 2004.

• "Menin directly binds to double-stranded DNA."
• "The COOH terminus of menin mediates binding to DNA, but MEN1 disease-derived mutations in the COOH terminus abolish the ability of menin to bind DNA."
• "MEN1 disease-related menin mutants also fail to repress cell proliferation as well as cell cycle progression at the G2/M phase."
• "Collectively, these results demonstrate... a novel biochemical activity of menin, binding to DNA, and link its DNA binding to the regulation of cell proliferation."

Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation

Mechanisms of disease: multiple endocrine neoplasia type 1-relation to chromatin modifications and transcription regulation
-Dreijerink KM, et al. Nat Clin Pract Endocrinol Metab. 2006 Oct;2(10):562-70.

• "Menin maintains transforming growth factor beta mediated signal transduction involved in parathyroid hormone and prolactin gene expression;"
• "We propose that menin links transcription-factor function to histone-modification pathways and that this is crucial for MEN1 tumorigenesis."

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription
-Huang J, et al. 2012 Nature.

• "...menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but... can have opposite effects on transcription.
• "The menin–JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription."
• "In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket..."

Endocrine Neoplasia

Endocrine Neoplasia
-Sturgeon C, editor. 2010 Springer Science. e-ISBN 978-1-4419-0857-5

• This book includes sections on tumors of the thyroid, parathyroid, adrenal, and pancreas, and a section on multiple endocrine neoplasia. The book's list price is over $150, but I found a 'used' copy in unused condition on Amazon for $5. Can't beat that.

DNA - A Graphic Guide to the Molecule that Shook the World

DNA - A Graphic Guide to the Molecule that Shook the World
-Rosenfield I, et al. 2011 Columbia University Press. ISBN 978-0-231-14270-0

• Don't let the 'comic book' design of this book fool You. This book is a great introduction to DNA and genetics! It's well written -even fun- and it has been extremely helpful in learning the basics of DNA structure, gene transcription, and more. Recommended.

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas

Epigenetic and Posttranscriptional Alterations of Tumor Suppressor Genes in Sporadic Pituitary Adenomas
-Henriett Butz, et al. InTech, February 2012, ISBN 978-953-307-879-3.

Knockdown of Menin Affects pre-mRNA Processing

Knockdown of Menin Affects pre-mRNA Processing and Promoter Fidelity at the Interferon-gamma Inducible IRF1 Gene
-Auriemma L, et al. Epigenetics & Chromatin 2012, 5:2 doi:10.1186/1756-8935-5-2.

• MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing.
• IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells.

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1
-Wikipedia

• An overview of MEN1.

Multiple endocrine neoplasia type 1: a chromatin writer’s block

Multiple endocrine neoplasia type 1: a chromatin writer’s block -Dreijerink, K. M. A., Lips, C. J. M. and Timmers, H. T. M. (2009). Journal of Internal Medicine, 266: 53–59. doi: 10.1111/j.1365-2796.2009.02115.x

• Menin is important for the writing of histone H3K4 trimethylation.
• In MEN1 tumors, writing of H3K4me3 on specific target genes is blocked.
• Compounds that interfere with the removal of the histone methylation mark are being developed.
• Specific targeting of menin-HMT to treat tumors poses a great challenge for future research.

Genome-Wide Analysis of Menin Binding Provides Insights into MEN1 Tumorigenisis

Genome-Wide Analysis of Menin Binding Provides Insights into MEN1 Tumorigenisis -Scacheri, et al. PLoS Genet. 2006 April; 2(4): e51.

• menin functions as a general regulator of transcription.
• HLXB9 is overexpressed in islets in the absence of menin.

Expression analysis of endogenous menin

Expression analysis of endogenous menin, the product of the multiple endocrine neoplasia type 1 gene, in cell lines and human tissues
-Wauto V, et al.
Int J Cancer. 2000 Mar 15;85(6):877-81.

Menin represses tumorigenesis via repressing cell proliferation

Menin represses tumorigenesis via repressing cell proliferation
-Ting Wu, Xianxin Hua.
Am J Cancer Res. 2011; 1(6): 726–739.

• What does the protein menin do?

Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1
-Orphanet J Rare Dis. 2006; 1: 38.

F Marini et al.

• A good introduction to MEN1.

Multiple Endocrine Neoplasia Type 1

Multiple Endocrine Neoplasia Type 1
-National Endocrine and Metabolic Diseases Information Service, National Institutes of Health

• An overview of MEN1.

Endoscopic Removal of Pituitary Tumors

Endoscopic transphenoidal resection of pituitary tumors at UCLA.

Drug-resistant hyperprolactinemia

MEN1 frequently involves pituitary disease. One study found pituitary disease occurred in 42% of MEN1 patients.⁽¹⁾ Depending on the specific type of pituitary disorder, treatment may include the surgical removal of an adenoma, the use of hormones or drugs to normalize pituitary function, or radiotherapy.

A prolactinoma, for example, is a non-cancerous pituitary tumor that produces the hormone prolactin; it's the most common form of pituitary tumor.⁽²⁾ Prolactinomas tend to cause hyperprolactinemia, abnormally high blood levels of prolactin. This can cause a variety of symptoms, including interfering with normal ovulatory function in women.

Normally, prolactin-producing cells are down-regulated, or inhibited, by dopamine signals from the hypothalamus.⁽³⁾ Therefore, hyperprolactinemia often is treated by dopamine agonists, usually Cabergoline or Bromocriptine.

Cabergoline usually is more effective than Bromocriptine at normalizing prolactin levels and restoring gonadal function.⁽⁴⁾ Yet it is not always successful in lowering prolactin to normal levels.

One particular patient, "P", was found to have hyperprolactinemia which then prompted an MRI scan and diagnosis of a pituitary adenoma. Treatment with Cabergoline was started. Within four months, the adenoma shrank and was no longer detectable via MRI, and P's prolactin level dropped to normal levels. But not for long. The prolactin level began to rise, and P's doctor responded with increasing dosage of Cabergoline. This went on for eight years, with Caborgoline dosage of up to 2.5mg/wk and prolactin levels typically about 50-100 mg/dL. When Cabergoline was discontinued, the prolactin would shoot up to about 180, and when Cabergoline was resumed, prolactin would reduce but not normalize. Periodic MRIs suggested possible empty sella syndrome and no sign of adenoma.

P's treatment subsequently was switched to Bromocriptine for a year, but her prolactin did not respond as well as it did to Cabergoline, and so Cabergoline was resumed.

What is there to do for a patient whose hyperprolactinemia does not respond sufficiently to dopamine agonist therapy, and who does not exhibit an operable adenoma?
__________

⁽¹⁾ Bruno Vergès, et al. Pituitary Disease in MEN Type 1 (MEN1): Data from the France-Belgium MEN1 Multicenter Study. The Journal of Clinical Endocrinology & Metabolism February 1, 2002 vol. 87 no. 2, 457-465.
⁽²⁾ http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001377/
⁽³⁾ http://en.wikipedia.org/wiki/Dopamine#Regulating_prolactin_secretion
⁽⁴⁾ Webster, et al. A Comparison of Cabergoline and Bromocriptine in the Treatment of Hyperprolactinemic Amenorrhea. N Engl J Med 1994; 331:904-909

The amino acid sequence of menin

The human gene MEN1 (also the name of the disorder associated with a mutant MEN1 gene) encodes the protein menin. UniProt specifies three isoforms of menin, Isoform 1 being called the 'canonical' sequence.¹ It is 615 amino acids in length, the others being 610 and 575 amino acids in length, respectively.

Menin Isoform 1:

        10         20         30         40         50         60
MGLKAAQKTL FPLRSIDDVV RLFAAELGRE EPDLVLLSLV LGFVEHFLAV NRVIPTNVPE

        70         80         90        100        110        120 
LTFQPSPAPD PPGGLTYFPV ADLSIIAALY ARFTAQIRGA VDLSLYPREG GVSSRELVKK 

       130        140        150        160        170        180 
VSDVIWNSLS RSYFKDRAHI QSLFSFITGW SPVGTKLDSS GVAFAVVGAC QALGLRDVHL 

       190        200        210        220        230        240 
ALSEDHAWVV FGPNGEQTAE VTWHGKGNED RRGQTVNAGV AERSWLYLKG SYMRCDRKME

       250        260        270        280        290        300 
VAFMVCAINP SIDLHTDSLE LLQLQQKLLW LLYDLGHLER YPMALGNLAD LEELEPTPGR 

       310        320        330        340        350        360
PDPLTLYHKG IASAKTYYRD EHIYPYMYLA GYHCRNRNVR EALQAWADTA TVIQDYNYCR 

       370        380        390        400        410        420
EDEEIYKEFF EVANDVIPNL LKEAASLLEA GEERPGEQSQ GTQSQGSALQ DPECFAHLLR 

       430        440        450        460        470        480 
FYDGICKWEE GSPTPVLHVG WATFLVQSLG RFEGQVRQKV RIVSREAEAA EAEEPWGEEA

       490        500        510        520        530        540 
REGRRRGPRR ESKPEEPPPP KKPALDKGLG TGQGAVSGPP RKPPGTVAGT ARGPEGGSTA

       550        560        570        580        590        600
QVPAPTASPP PEGPVLTFQS EKMKGMKELL VATKINSSAI KLQLTAQSQV QMKKQKVSTP

       610 
SDYTLSFLKR QRKGL 

The table contains standardized single-letter codes for the various amino acids. Wikipedia offers a table describing these codes.²
For example, the "Q" at amino acid position 64 represents glutamine, which is encoded either by codons CAA or CAG.³
__________
¹ UniProt entry on "MEN1_HUMAN"
² http://en.wikipedia.org/wiki/Amino_acid#Table_of_standard_amino_acid_abbreviations_and_properties (Wikipedia: Amino Acid).
³ http://en.wikipedia.org/wiki/Genetic_code#RNA_codon_table (Wikipedia: Genetic Code).

Cells use DNA methylation to control gene expression

• "Methylation of DNA (not to be confused with histone methylation) is a common epigenetic signaling tool that cells use to lock genes in the 'off' position."
• DNA methylation occurs at the cytosine bases of eukaryotic DNA, which are converted to 5-methylcytosine by DNA methyltransferase (DNMT) enzymes.
• ...methylation near gene promoters varies considerably depending on cell type, with more methylation of promoters correlating with low or no transcription.
• Although patterns of DNA methylation appear to be relatively stable in somatic cells, patterns of histone methylation can change rapidly during the course of the cell cycle. Despite this difference, several studies have indicated that DNA methylation and histone methylation at certain positions are connected.
• Tumor suppressor genes are often silenced in cancer cells due to hypermethylation.

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The Role of Methylation in Gene Expression. Theresa Phillips, Ph.D. 2008, Nature Education.

DNA methylation

Allfrey in 1964 described methylation as a chemical mark upon histones.^[Ref.1] According to newer sources, methylation also takes place on some CpG sequences of the DNA itself.^[Ref.11] CpG denotes a cytosine base next to a guanine base, a combination that tends to occur frequently. A methyl group (CH₃) may attach to the cytosine in a CpG pair, forming Me-CpG. DNA methylation is associated with the regulation of gene expression.

In human DNA about 80%-90% of CpG sites are methylated, but there are certain areas known as CpG islands where none of the sites are methylated. These are associated with the promoters of 56% of mammalian genes, including all ubiquitously expressed genes. ⁽¹⁾

MEN1 is a ubiquitously expressed gene^[Ref.6], so it would seem that we should take a closer look at methylation.
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⁽¹⁾Methylation. Wikipedia.

The Molecule that Shook the World

I've been reading a short book on DNA and genetics, and it has really surpassed my expectations. "DNA - A Graphic Guide to the Molecule that Shook the World", by Israel Rosenfield, Edward Ziff, and Borin Van Loon (2011, Columbia University Press), is designed much like a comic book. At first glance I didn't know whether to take the book seriously, but halfway through this little book I think it's a winner!

250 pages of serious material presented clearly and in a very readable, even entertaining form. DNA, replication, the genetic code, gene expression, chromosomes, epigenetics, the Human Genome Project, and much more... and every page illustrated to illuminate the material and to keep the reading brisk and with a sense of (occasionally bawdy) humor. This is a layman's book, a self-described "popular work" and "graphic novel". But unless You're a seasoned expert in the field, You may find this book very informative and enjoyable. Highly recommended.

This book may be one of the best, first sources to read for a layman who wants to begin to understand genetics and MEN1 a little more deeply.

Chemical marks on histones

Chemical 'marks' that can be written upon histones include:

• acetylation
• methylation
• ubiquitination
• phosphorylation

The possible combinations of histone marks are nearly unlimited, and are referred to as the 'histone code'.
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Multiple endocrine neoplasia type 1: a chromatin writer’s block. Dreijerink, K. M. A., Lips, C. J. M. and Timmers, H. T. M. (2009). Journal of Internal Medicine, 266: 53–59. doi: 10.1111/j.1365-2796.2009.02115.x
Acetylation and Methylation of Histones and Their Possible Role in the Regulation of RNA Synthesis. Allfrey VG, et al. Proc Natl Acad Sci USA. 1964 May; 51(5): 786–794. PMCID: PMC300163.

A chromatin writer's block

Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. This material includes histones, the core proteins around which are tightly wound DNA. I used to think all the information that genetically defines organisms is contained in DNA. Apparently this is not the case. The core histones also are capable of storing epigenetic information. They can written upon, read, and erased by other molecules. These messages affect the expression and silencing of genes without altering the underlying nucleotide sequence.

• MLL (mixed-lineage leukemia) is a writer of H3K4me3, the histone H3K4 trimethylation mark.
• Menin is important for the writing of H3K4me3.
• Menin contains a LLWLL amino acid motif, which "is in fact a nuclear receptor interaction domain."
• Reduction of menin mRNA levels... results in reduced levels of H3K4 trimethylation on hormone responsive genes and decreased transcription of these genes.
• In MEN1 tumors, writing of H3K4me3 on specific target genes is blocked.
• Loss of H3K4 trimethylation appears to contribute to MEN1 tumor development.
• As loss of menin function leads to reduced H3K4me3 levels on target genes an inhibitor of H3K4 demethylase activity, causing persistence of remaining H3K4 trimethylation, could be an effective approach. Compounds that interfere with the removal of the histone methylation mark are being developed.
• Histone deacetylase inhibitors (HDACis) are a well-known class of histone modification regulating drugs, with very promising effects in preclinical and clinical studies.
• Specific targeting of menin-HMT to treat tumors poses a great challenge for future research.

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Multiple endocrine neoplasia type 1: a chromatin writer’s block. Dreijerink, K. M. A., Lips, C. J. M. and Timmers, H. T. M. (2009). Journal of Internal Medicine, 266: 53–59. doi: 10.1111/j.1365-2796.2009.02115.x
Mixed-lineage lukemia. Wikipedia

How does DNA replicate?

An animated presentation on DNA replication, by John Kyrk: http://www.johnkyrk.com/DNAreplic.swf

Packing six feet of DNA into every cell

Human DNA strands are approximately 6 feet in length (7). To store them compactly within cells they are tightly wound around proteins called histones.Read more: /wiki/Histone
(photo from http://en.wikipedia.org/wiki/Histone)


A single DNA strand is wrapped around multiple histones, in a beads-on-a-string structure. These are then compacted, forming the 30nm fiber, then further compressed onto scaffold proteins to form chromosomes.
Read more: /wiki/Nucleosome
(photo from http://en.wikipedia.org/wiki/File:Chromatin_Structures.png)

Is a cure possible?

If Your life is touched by MEN1 it's important not to give in to fear. It's a serious condition, but effective treatments are available for many of its manifestations. Medical science is advancing rapidly in this area, driven especially by research in the areas of cancer and genetics. There is good reason to hope for continued advances in MEN1 research and treatment ...and someday a cure.

But first things first. If You or a loved one has MEN1, You'll want to seek out the best treatment available. MEN1 is complex, and in order to find the best available treatments it will help to learn more about MEN1 and better understand what You're up against.

I am not a physician, nor any kind of medical professional. But I've got a loved one with MEN1, and we want to make sure she gets the best care possible. So I want to learn more.

On this website we plan to offer resources for those who want to learn more about MEN1. It is our firm belief that MEN1 patients, their loved ones, and friends, can help overcome the challenges of MEN1 by better understanding the condition, its treatments, and something of the research surrounding it. If knowledge is power, then learning about MEN1 improves our ability to secure the best treatment for the MEN1 patients we care for. And in some way, to learn is to join our efforts -even if only in a fraternal sense- with those involved directly in medical research and treatment, and with families around the world who face the challenge of MEN1. This is no small thing.

With our study, prayers, and if possible, financial support of ongoing research, let's help pave the path to a cure.

Will You join in me in learning about MEN1? In promoting MEN1 education, treatment, and research? In supporting those who are fighting this disorder? And in working -and, yes, praying- for a cure?

Brainstorming for a cure

Suppose we could design a virus or bacteria that attacks and kills any cell that is unable to produce menin, but has no effect on other cells. This would seem to prevent MEN1 tumors from developing. But how would this really work? Do we design the virus so that it is unable to harm cells containing menin? Perhaps the virus is able to infect all types of cells, but is inactivated in the presence of menin.

But this would seem to depend on there always being at least some minimum level of menin production in all normal cells. I don't know whether this is the case. It has been reported that menin "is ubiquitously expressed in tissues examined, although its expression levels are variable among different tissues"(3). If we're lucky, we develop a virus that is able to destroy individual menin-deficient cells surrounded by cells that are not menin-deficient, and the result is that any cells unable to produce menin are destroyed, and all other cells are unaffected.

If we're not quite so lucky, maybe we find that normal cells sometimes produce very little or no menin during part of their life cycle, and we wouldn't want them destroyed by our hypothetical virus. But in this case perhaps there is a different method our virus could use to detect cells whose MEN1 genes are both nonfunctional.

What is MEN1?

Multiple Endocrine Neoplasia Type 1 is a genetic disorder that greatly increases the risk of developing multiple cancerous and noncancerous tumors in glands such as the parathyroid, pituitary, and pancreas. These endocrine tumors may produce excessive levels of hormones that lead to secondary disease.

Individuals with MEN1 are born with one mutated copy of the MEN1 tumor suppressor gene in each cell. Cells that later develop a mutation in the remaining copy of the MEN1 gene then are left unable to produce menin, an important tumor suppressor protein. With no functional MEN1 gene, such cells may divide uncontrollably, resulting in the development of tumors.

MEN1 is also known as: MEN Type 1, MEN-1, Multiple Endocrine Adenomatosis Type 1, MEA Type 1, MEA 1, Wermer's syndrome.

references:
http://www.mayoclinic.org/men1/
http://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia_type_1

Why promote MEN1 awareness?

MEN1 isn't very common: only about 1 in 30,000 people have this genetic disorder. But that's 10,000 in the United States, and more than 250,000 worldwide.

When a disease is "rare" and unknown to our family and friends we tend not to think much about it... But when it strikes a loved one, "rare" no longer has much meaning.

We want to promote greater awareness, research, and improved treatment of MEN1.