Link discovered between MEN1 and much-studied Hedgehog signal pathway

Menin Epigenetically Represses Hedgehog Signaling in MEN1 Tumor Syndrome
-Xianxin Hua, MD, PhD, Buddha Gurung, PhD, Perelman School of Medicine, University of Pennsylvania
Cancer Research April 15, 2013 73:2650-2658; Published OnlineFirst April 15, 2013;

Link discovered between MEN1 and much-studied cell pathway
A research team led by Xianxin Hua, MD, PhD, associate professor of Cancer Biology at the Abramson Family Cancer Research Institute, report in Cancer Research that menin suppresses signaling in the much-studied Hedgehog pathway in endocrine organs.

• "This study uncovered a new layer of regulation of pro-proliferative genes by menin via the Hedgehog signaling pathway," Hua says.
  
• "These pro-replication genes are regulated through GAS1 and PRMT5."
  
• The GAS1 protein promotes Hedgehog signaling.
  
• Menin interacts with the methylating enzyme PRMT5, and binds to the promoter of the Gas1 gene, inhibiting Gas1 gene transcription.
  
• By inhibiting Gas1 expression, menin and PRMT5 inhibit the pathway's tendency towards cell proliferation.
  
• Mutant menin proteins are impaired in their ability to interact with PRMT5, and lead to increased Hedgehog signaling and cell proliferation.
  
• Hua's team found that treating a mouse model of human MEN1 with a Hedgehog pathway inhibitor called Erivedge reduced proliferation of tumor cells and blood insulin levels. Hua says that this suggests a potential new treatment for MEN1 patients.
  

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.

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.
  
  

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."

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

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.

__________
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