What Genes are Related to Cushing’s Disease?

Posted on July 29, 2015 by MaryO

genetic

 

The genetic cause of Cushing disease is often unknown. In only a few instances, mutations in certain genes have been found to lead to Cushing disease. These genetic changes are called somatic mutations. They are acquired during a person’s lifetime and are present only in certain cells. The genes involved often play a role in regulating the activity of hormones.

Cushing disease is caused by an increase in the hormone cortisol, which helps maintain blood sugar levels, protects the body from stress, and stops (suppresses) inflammation. Cortisol is produced by the adrenal glands, which are small glands located at the top of each kidney. The production of cortisol is triggered by the release of a hormone called adrenocorticotropic hormone (ACTH) from the pituitary gland, located at the base of the brain. The adrenal and pituitary glands are part of the hormone-producing (endocrine) system in the body that regulates development, metabolism, mood, and many other processes.

Cushing disease occurs when a noncancerous (benign) tumor called an adenoma forms in the pituitary gland, causing excessive release of ACTH and, subsequently, elevated production of cortisol. Prolonged exposure to increased cortisol levels results in the signs and symptoms of Cushing disease: changes to the amount and distribution of body fat, decreased muscle mass leading to weakness and reduced stamina, thinning skin causing stretch marks and easy bruising, thinning of the bones resulting in osteoporosis, increased blood pressure, impaired regulation of blood sugar leading to diabetes, a weakened immune system, neurological problems, irregular menstruation in women, and slow growth in children. The overactive adrenal glands that produce cortisol may also produce increased amounts of male sex hormones (androgens), leading to hirsutism in females. The effect of the excess androgens on males is unclear.

Most often, Cushing disease occurs alone, but rarely, it appears as a symptom of genetic syndromes that have pituitary adenomas as a feature, such as multiple endocrine neoplasia type 1 (MEN1) or familial isolated pituitary adenoma (FIPA).

Cushing disease is a subset of a larger condition called Cushing syndrome, which results when cortisol levels are increased by one of a number of possible causes. Sometimes adenomas that occur in organs or tissues other than the pituitary gland, such as adrenal gland adenomas, can also increase cortisol production, causing Cushing syndrome. Certain prescription drugs can result in an increase in cortisol production and lead to Cushing syndrome. Sometimes prolonged periods of stress or depression can cause an increase in cortisol levels; when this occurs, the condition is known as pseudo-Cushing syndrome. Not accounting for increases in cortisol due to prescription drugs, pituitary adenomas cause the vast majority of Cushing syndrome in adults and children.

Read more about familial isolated pituitary adenoma.

 

How do people inherit Cushing disease?

Most cases of Cushing disease are sporadic, which means they occur in people with no history of the disorder in their family. Rarely, the condition has been reported to run in families; however, it does not have a clear pattern of inheritance.

The various syndromes that have Cushing disease as a feature can have different inheritance patterns. Most of these disorders are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

From http://ghr.nlm.nih.gov/condition/cushing-disease

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7 health conditions that are responsible for making you fat

Posted on July 18, 2015 by MaryO

Cushing’s syndrome: Cushing’s syndrome or hypercortisolism is a condition caused when the adrenal glands produce too much cortisol. This leads to a buildup of fat in the face, upper back and abdomen. Cushing’s syndrome can also be a side-effect of certain medications.

Read the other 6 at 7 health conditions that are responsible for making you fat | Read Health Articles & Blogs at TheHealthSite.com.

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The low-dose dexamethasone suppression test: a reevaluation in patients with Cushing’s syndrome

Posted on July 9, 2015 by MaryO

J Clin Endocrinol Metab. 2004 Mar;89(3):1222-6.

Findling JW1, Raff H, Aron DC.

Abstract

Low-dose dexamethasone suppression testing has been recommended for biochemical screening when Cushing’s syndrome is suspected. The criterion for normal suppression of cortisol after dexamethasone is controversial.

To assess diagnostic utility (sensitivity), we report the results of low-dose dexamethasone suppression testing in 103 patients with spontaneous Cushing’s syndrome. There were 80 patients with Cushing’s disease (78%), 13 with the ectopic ACTH syndrome (13%), and 10 with cortisol-producing adrenocortical adenomas (10%). Fourteen (18%) of 80 patients with Cushing’s disease suppressed serum cortisol to less than 5 micro g/dl (<135 nmol/liter) after the overnight 1-mg test, whereas six patients (8%) actually showed suppression of serum cortisol to less than 2 micro g/dl (<54 nmol/liter). In addition, the 2-d, low-dose dexamethasone suppression test yielded false-negative results in 38% of patients when urine cortisol was used and 28% when urinary 17-hydroxycorticosteroids were used. Serum cortisol after the 1-mg test correlated with baseline urinary free cortisol (r = 0.705, P < 0.001), plasma ACTH level (r = 0.322, P = 0.001), and urinary free cortisol after the 2-d test (r = 0.709, P = 0.001).

This study provides evidence that low-dose dexamethasone may suppress either plasma cortisol or urinary steroids to levels previously thought to exclude Cushing’s syndrome and that these tests should not be used as the sole criterion to exclude the diagnosis of endogenous hypercortisolism.

PMID:
15001614
[PubMed – indexed for MEDLINE]

From http://www.ncbi.nlm.nih.gov/pubmed/15001614

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First Patient Dosed in IST of CDK Inhibitor Seliciclib in Cushing’s Disease, a Serious Endocrine Disorder

Posted on July 2, 2015 by MaryO
Source:Cyclacel Pharmaceuticals, Inc.

BERKELEY HEIGHTS, N.J., July 2, 2015 (GLOBE NEWSWIRE) — Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) (Cyclacel or the Company), a biopharmaceutical company developing oral therapies that target the various phases of cell cycle control for the treatment of cancer and other serious disorders today announced that the first patient has been dosed in an investigator sponsored trial (IST) of the Company’s oral cyclin dependent kinase (CDK) inhibitor seliciclib in Cushing’s disease (CD)1. Clinicians at Cedars-Sinai, Los Angeles, were awarded a grant from The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to evaluate seliciclib, a CDK2/9 inhibitor currently in clinical development to treat certain cancers, as a potential therapy for CD.

“Cushing’s disease is a serious debilitating endocrine disorder with limited treatment options for patients,” said Shlomo Melmed, M.D., Director of the Burns and Allen Research Institute, Principal Investigator and Dean of the Medical Faculty at Cedars-Sinai, Los Angeles. “We believe that seliciclib is unique among clinical stage CDK inhibitors in its potential effectiveness to treat this disease. Its mechanism of action has a dual effect as it impacts tumor growth by decreasing the levels and activity of cyclin E, as well as inhibiting ACTH production. If our trial with seliciclib proves successful, it could lead to dramatically improved treatment outcomes for patients with Cushing’s disease.”

CD is an endocrine disorder caused by adrenocorticotropin (ACTH)-producing pituitary tumors, often leading to obesity, diabetes, hypertension, osteoporosis and increased risk of death if inadequately controlled. Cell cycle dysregulation is a common feature of pituitary tumors, including upregulation of cyclin E, specifically seen in tumors of the corticotroph lineage, such as in CD. Dr. Melmed and Dr. Ning-Ai Liu have previously published preclinical proof-of-concept data showing that seliciclib is uniquely effective amongst CDK inhibitors in resolving the disease, with dual effects on pituitary growth and ACTH production2.

The trial is a Phase 2 proof-of-concept, open-label, single arm study to assess the safety and efficacy of seliciclib in CD. Sixteen patients with de novo, persistent or recurrent CD will receive seliciclib for 4 weeks prior to standard-of-care treatment. The primary objective is to establish the efficacy of seliciclib on normalizing urinary free cortisol levels in patients with CD.

About Cushing’s disease

CD is a rare endocrine, orphan disorder with estimated US prevalence of approximately 20,000. It is the most common cause of endogenous hypercortisolism, which predisposes patients to central obesity, diabetes, hypertension, osteoporosis and substantially increases their risk of infection, thrombosis and psychiatric disorders. If inadequately controlled, CD is fatal with mortality rate four-fold-higher than that of age- and sex-matched controls and median survival of 4.6 years. The leading cause of death in CD is cardiovascular disease. CD remains an unmet medical need despite available therapies.

About seliciclib and its mechanism of action in Cushing’s disease

Seliciclib, an orally-available CDK2/9 inhibitor, has been evaluated to date in approximately 450 patients and is currently being explored in combination with Cyclacel’s orally-available sapacitabine in patients with solid tumors.

Seliciclib has been shown in preclinical models to be uniquely effective amongst other CDK inhibitors. Seliciclib was subsequently shown, in mouse corticotroph tumor cells in vitro, to cause cell cycle arrest, accompanied by decreases in cyclin E levels, increased p27Kip1, p57Kip2 and p21Cip1 expression, and reduced Thr821 phosphorylation of the retinoblastoma (Rb) protein. Rb is reportedly a site phosphorylated by CDK2. In addition, ACTH concentrations in cell supernatant were also decreased by seliciclib, suggesting a dual impact of the compound on corticotroph tumorigenesis. In vivo, oral administration of seliciclib led to a 50% reduction in tumor weight, and consistent with in vitro observations, reduced plasma ACTH levels, serum cortisol levels and tumor PCNA staining.

1. ClinicalTrials.gov (NCT02160730).

2. Liu, N-A., Jiang, H., Ben-Shlomo, A., Wawrowsky, K. Fan, X-M., Lin, S. and Melmed, S. (2011) Targeting zebrafish and murine pituitary corticotroph tumours with a cyclin-dependent kinase (CDK) inhibitor. PNAS doi: 10.1073/pnas.1018091108

About Cyclacel Pharmaceuticals, Inc.

Cyclacel is a biopharmaceutical company developing oral therapies that target the various phases of cell cycle control for the treatment of cancer and other serious diseases. Sapacitabine, Cyclacel’s most advanced product candidate, is the subject of SEAMLESS, a Phase 3 trial, which has completed enrollment and is being conducted under an SPA with the FDA as front-line treatment for acute myeloid leukemia (AML) in the elderly, and other indications including myelodysplastic syndromes (MDS). Cyclacel’s pipeline includes an oral regimen of seliciclib in combination with sapacitabine in a Phase 1 study of patients with Homologous Recombination (HR) repair-deficient breast, ovarian and pancreatic cancers, including gBRCA positive tumors, and CYC065, a novel CDK2/9 inhibitor, with potential utility in both hematological malignancies and solid tumors. Cyclacel’s strategy is to build a diversified biopharmaceutical business focused in hematology and oncology based on a development pipeline of novel drug candidates. Please visit www.cyclacel.com for more information.

Forward-looking Statements

This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and intended utilization of Cyclacel’s product candidates, the conduct and results of future clinical trials, plans regarding regulatory filings, future research and clinical trials and plans regarding partnering activities. Factors that may cause actual results to differ materially include the risk that product candidates that appeared promising in early research and clinical trials do not demonstrate safety and/or efficacy in larger-scale or later clinical trials, trials may have difficulty enrolling, Cyclacel may not obtain approval to market its product candidates, the risks associated with reliance on outside financing to meet capital requirements, and the risks associated with reliance on collaborative partners for further clinical trials, development and commercialization of product candidates. You are urged to consider statements that include the words “may,” “will,” “would,” “could,” “should,” “believes,” “estimates,” “projects,” “potential,” “expects,” “plans,” “anticipates,” “intends,” “continues,” “forecast,” “designed,” “goal,” or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to the Company’s most recent Annual Report on Form 10-K and other periodic and other filings Cyclacel files with the Securities and Exchange Commission and are available at www.sec.gov. Such forward-looking statements are current only as of the date they are made, and Cyclacel assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

© Copyright 2015 Cyclacel Pharmaceuticals, Inc. All Rights Reserved. The Cyclacel logo and Cyclacel® are trademarks of Cyclacel Pharmaceuticals, Inc.

Cyclacel Pharmaceuticals, Inc.

Company:
Paul McBarron, (908) 517-7330, 
Investor Relations:
Russo Partners LLC, Robert Flamm, (212) 845-4226

– See more at: http://globenewswire.com/news-release/2015/07/02/749361/10140470/en/First-Patient-Dosed-in-IST-of-CDK-Inhibitor-Seliciclib-in-Cushing-s-Disease-a-Serious-Endocrine-Disorder.html#sthash.KgdD65N9.dpuf

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ALD403 (migraine drug) and ALD1613 (for Cushing’s disease)

Posted on July 2, 2015 by MaryO

As it moves into crucial Phase 3 drug trials for its flagship migraine treatment, Bothell-based Alder Biopharmaceuticals (Nasdaq: ALDR) is looking to raise a lot of cash.

Alder is offering up to $200 million shares of its common stock, according to SEC filings.

The company plans to use the money to develop its drugs ALD403 (its migraine drug) and ALD1613 (for Cushing’s disease), conduct clinical trials and commercialize these drugs. Funds will also go toward “general corporate purposes,” which might include the acquisition or licensing of other products, businesses or technologies, according to those filings.

From http://www.bizjournals.com/seattle/blog/health-care-inc/2015/06/alder-biopharmaceuticals-sets-out-to-raise-200m-to.html

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