Mutations in Two Genes, USP48 and BRAF, Linked to Cushing’s Disease

Mutations in USP48 and BRAF genes contribute to the overproduction of adrenocorticotropin (ACTH) hormone by the pituitary gland and consequent development of Cushing’s disease, a study shows, linking these genes to the disease for a first time.

The study, “Identification of recurrent USP48 and BRAF mutations in Cushing’s disease,” published in the journal Nature Communications, also identified a possible treatment for patients with BRAF-related mutations.

Cushing’s disease is a condition characterized by excessive cortisol levels that, if left untreated, can lead to serious cardiovascular problems, infections, and mood disorders. It usually arises from benign pituitary tumors that produce too much of ACTH hormone, which in turn stimulates the adrenal glands to secrete cortisol.

It is still not clear why some people develop these tumors, but studies have pointed to mutations in the USP8 gene as a possible cause. They are present in 35%–62% of all tumor cases, and influence treatment response and long-term outcomes.

But major disease drivers in people whose tumors have no evidence of  USP8 mutations are unknown. Recognizing this gap, researchers in China examined tumor tissue samples from 22 patients with pituitary ademonas but a normal USP8 gene.

Their analysis revealed four genes that were recurrently mutated, including two — BRAF and USP48 — never before reported in this disease setting. Then, looking at 91 samples from patients, researchers found BRAF mutations in 17% of cases and USP48 mutations in 23% of patients.

These mutations were also found in patients with USP8-mutant pituitary tumors, but at a much lower rate — 5.1% for BRAF and 1.2% for USP48 mutations.

However, mutations in these two genes were not seen in patients with pituitary tumors producing other hormones, suggesting they are “unique genetic signatures of [ACTH-producing] adenomas,” the researchers wrote.

The team also found that BRAF and USP48 mutations activate signaling pathways that lead to the production of proopiomelanocortin (POMC), which is the precursor of ACTH.

“ACTH overproduction is a hallmark of Cushing’s disease and appears to be frequently induced by mutations in genes that tightly regulate POMC gene transcription in the pathogenesis of this disease,” investigators wrote.

Patients with BRAF and USP48 mutations had significantly higher levels of midnight plasma ACTH and midnight serum cortisol, compared to patients without these mutations. Tumor size, however, was similar among the two groups.

Interestingly, the team found that the BRAF inhibitor Zelboraf (vemurafenib) effectively reduced ACTH production in cells from ACTH-producing pituitary tumors. Zelboraf, marketed by Genentech, is approved in the U.S. and Europe to treat cancers with BRAF mutations, and findings suggest it may be a good therapeutic candidate for some people with Cushing’s disease.

“The mutational status of BRAFUSP8, and USP48 in corticotroph adenomas may be used in the future to characterize the molecular subtypes and guide targeted molecular therapy,” the researchers suggested.

From https://cushingsdiseasenews.com/2018/11/20/mutations-in-usp48-braf-genes-contribute-for-cushings-disease-study-finds/

New Phase 3 Data Further Support Recorlev’s Ability to Safely Lower Cortisol Levels in Cushing’s Patients

Strongbridge Biopharma released additional positive results from a Phase 3 trial evaluating whether the company’s investigational therapy Recorlev (levoketoconazole) is safe and effective for people with endogenous Cushing’s syndrome.

The latest results were presented in the scientific poster “Safety and Efficacy of Levoketoconazole in Cushing Syndrome:  Initial Results From the Phase 3 SONICS Study,\” at the 18th Annual Congress of the European NeuroEndocrine Association (ENEA), which took place in Wrocław, Poland, last month.

The SONICS study (NCT01838551) was a multi-center, open-label Phase 3 trial evaluating Recorlev’s safety and effectiveness in 94 patients with endogenous Cushing’s syndrome.

The trial consisted of three parts: a dose-escalation phase to determine the appropriate Recorlev dose that achieved normalization of cortisol levels; a maintenance phase in which patients received the established dose for six months; and a final extended phase, in which patients were treated with Recorlev for an additional six months, with the possibility of dose adjustments.

Its primary goal was a reduction in the levels of cortisol in the patients’ urine after six months of maintenance treatment, without any dose increase during that period. Among secondary goals was a reduction in the characteristically high risk of cardiovascular disease in these people, through the assessment of multiple cardiovascular risk markers.

Strongbridge announced top-line results of the SONICS study in August, which showed that the trial had reached its primary and secondary goals. It concluded last month.

After six months of maintenance therapy, Recorlev successfully lowered to normal the levels of cortisol in 30% of patients without a dose increase. It also led to statistically and clinically significant reductions in cardiovascular risk biomarkers, including blood sugar, cholesterol levels, body weight, and body mass index.

Maria Fleseriu, MD, director of the Oregon Health Sciences University Northwest Pituitary Center, presented additional and detailed results of SONICS at the congress.

Additional analyses showed that among the 77 patients who completed the dose-escalation phase and entered the study’s maintenance phase, 81% had their cortisol levels normalized.

At the end of the six months of maintenance treatment, 29 (53%) of the 55 patients who had their cortisol levels assessed at the beginning of the study and at the end of the maintenance phase had achieved normalization of cortisol levels, regardless of dose increase.

Among all patients who completed maintenance treatment (including patients with some missing data) and regardless of dose increase, 38% had achieved normalization of cortisol levels and 48% recorded a 50% or more decrease or normalization.

The results also highlighted that Recorlev substantially reduced patients’ cortisol levels regardless of their levels at the study’s beginning (which were on average about five-fold higher than the upper limit of normal). In those patients with the highest levels of cortisol in their urine, Recorlev led to a median reduction of more than 80%.

As previously reported, Recorlev was found to be generally well-tolerated, with no new safety concerns, and only 12 participants (12.8%) stopped treatment due to adverse events.

Ten patients had three- or five-fold increased levels of alanine aminotransferase — a liver enzyme used to assess liver damage — which were fully resolved without further complications. These liver-related adverse events “were all noted in the first 60 days, thus suggesting a timeline interval for monitoring,” Fleseriu said in a press release.

“We continue to be encouraged by the positive efficacy results of SONICS and the overall benefit-to-risk profile of Recorlev and look forward to sharing additional planned analyses from the study in the near future,” said Fredric Cohen, Strongbridge’s chief medical officer.

From https://cushingsdiseasenews.com/2018/11/01/new-data-from-phase-3-trial-supports-recorlev-ability-to-safely-treat-cushings-syndrome/

Measuring TSH Levels Could Improve Diagnosis for Cushing’s Syndrome

Measuring the variation in thyroid stimulating hormone blood levels between midnight and morning may be better for diagnosing Cushing’s syndrome than current approaches, a study suggests. 

The study, “TSH ratio as a novel diagnostic method for Cushing’s syndrome,” was published in the Endocrine Journal

Cushing’s syndrome (CS) is a condition characterized by excess cortisol in the blood, which can lead to a variety of issues, including obesity, high blood pressure, abnormal lipid levels, osteoporosis, depression, and cognitive impairments.

In some cases, patients have high cortisol levels, but lack the typical physical features of Cushing’s syndrome. These patients are considered to have subclinical Cushing’s syndrome (SCS), and are at higher risk for cardiovascular disease.

Being able to properly diagnose CS and SCS is of utmost importance for proper intervention and treatment of these patients.

Current methods of diagnosis rely on dexamethasone suppressing tests or late-night salivary and blood cortisol tests, as well as measurements of cortisol in urine. However, because cortisol is a stress-hormone, it can be elevated in cases of mental or physical stress, leading to false positive results on these tests. 

Researchers in this study examined if another hormone, called the thyroid stimulating hormone (TSH), could be used to diagnose Cushing’s syndrome with better accuracy.

TSH is a hormone that stimulates the thyroid gland and whose secretion is affected by the body’s circadian rhythm. Its highest levels in the blood are usually seen in the late evening or early morning. However, patients with CS or SCS lack this nocturnal increase in TSH levels, which could be useful as a new diagnostic approach.

The study recruited 142 patients with suspected CS and SCS, and 21 patients with depression, being treated at the Osaka University Hospital in Japan.

Patients received the ordinal screening tests for Cushing’s syndrome, along with measurements of their midnight-to-morning TSH levels.

After taking the tests, only 20 patients were diagnosed as having Cushing’s, including 12 with over (normal) Cushing’s syndrome and 10 with subclinical Cushing’s syndrome.

Patients with Cushing’s had significantly lower midnight TSH levels than non-Cushing’s patients. No differences were seen in morning levels between the groups. Of note, TSH ratio was maintained in patients with depression, suggesting TSH levels could be used to diagnose Cushing’s in patients with depression.

Researchers observed that serum TSH ratio had powerful diagnostic accuracy. Among patients identified as having Cushing’s, 90% actually had the disease. And among patients excluded for Cushing’s, 95% did not have the condition. These sensitivity and specificity rates were better than with current diagnostic approaches.

However, when considering this test, patients with a severe TSH deficiency must be taken into account.

Overall, these results suggest that the midnight-to-morning serum TSH ratio is a potential new way to diagnose both CS and SCS with a higher specificity than the current diagnostic methods

“The strength of our current survey is its prospective design and the evaluation of not only overt CS but also SCS. The limitation is the relatively small number of CS group patients, especially overt CD,” the researchers wrote.

“New prospective studies will be needed with a larger number of patients in order to further clarify the optimal TSH ratio in the diagnosis of CS,” the study concluded. 

From https://cushingsdiseasenews.com/2018/06/28/measuring-tsh-levels-may-improve-cushings-syndrome-diagnosis-study/

Study Describes 6 Common Surgical Failures in Cushing’s Disease Treatment

To help improve the effectiveness of surgical treatment of Cushing’s disease, researchers conducted a study to determine common failures. They classified these failures into six different categories.

Results were reported in the study, “Root cause analysis of diagnostic and surgical failures in the treatment of suspected Cushing’s disease,” published in the Journal of Clinical Neuroscience.

The surgical removal of lesions that secrete excess adrenocorticotropic hormone (ACTH) is the first line of treatment for patients with Cushing’s disease. But while this approach is effective in reducing cortisol levels, up to 31 percent of patients fail to achieve remission.

When initial surgery is ineffective, additional surgical procedures may help to improve patient outcomes. Medications also are used for those who do not see results from surgery.

Recognizing the factors that contribute to the failure of surgical treatment is crucial to avoiding a deterioration of patient health and to improving long-term outcomes.

Researchers at Harvard Medical School examined the clinical records of 51 patients suspected of having Cushing’s disease. These patients were followed and surgically treated at the Brigham and Women’s Hospital in Boston, from April 2008 to July 2017.

In more than 82 percent of the cases, tissue removed during surgery confirmed that the patients had excess ACTH caused by benign tumors in the adrenal gland. Among the remaining patients, two had additional ACTH-secreting tumors, four had no obvious tumor or abnormal tissue, one had a pituitary mass without ACTH secretion, and one had no evidence of tissue changes despite the detection of a tumor during exploratory surgery.

They were followed for an average of 18.3 months, during which 42 patients achieved remission as confirmed by blood tests. Of these, 34 patients did not require additional treatment; four patients needed additional surgeries to achieve control over cortisol levels; and four patients required additional radiosurgery.

Based on long-term patient outcomes, researchers were able to identify six categories of common diagnostic and surgical failures. They include:

  • persistently high cortisol levels despite the successful removal of lesions
  • the failure of tumor resection
  • recurrence of disease
  • a failure to identify the source of ACTH secretion
  • the absence of identifiable lesions during exploratory surgery
  • concurrent tumors.

While the first three are common among patients with a visible lesion on imaging scans, the latter three are characteristic of patients in whom physicians fail to detect a lesion.

Investigators believe that anticipating and recognizing these common failures may help to improve the effectiveness of surgery, symptom management, and overall treatment outcomes.

“The success of surgical intervention can be enhanced greatly by improving patient selection and surgical management by anticipating and subsequently deterring the six common failures described above,” the team concluded. They added that better imaging methods also might improve outcomes for Cushing’s disease patients.

From https://cushingsdiseasenews.com/2018/05/15/cushings-disease-surgery-6-common-failures-found-retrospective-study/

Blood Lipid Levels Linked to High Blood Pressure in Cushing’s Disease Patients

High lipid levels in the blood may lead to elevated blood pressure in patients with Cushing’s disease, a Chinese study shows.

The study, “Evaluation of Lipid Profile and Its Relationship with Blood Pressure in Patients with Cushing’s Disease,” appeared in the journal Endocrine Connections.

Patients with Cushing’s disease often have chronic hypertension, or high blood pressure, a condition that puts them at risk for cardiovascular disease. While the mechanisms of Cushing’s-related high blood pressure are not fully understood, researchers believe that high levels of cortisol lead to chronic hypertension through increased cardiac output, vascular resistance, and reactivity to blood vessel constrictors.

In children and adults with Cushing’s syndrome, the relationship between increased cortisol levels and higher blood pressure has also been reported. Patients with Cushing’s syndrome may remain hypertensive even after surgery to lower their cortisol levels, suggesting their hypertension is caused by changes in blood vessels.

Studies have shown that Cushing’s patients have certain changes, such as increased wall thickness, in small arteries. The renin-angiotensin system, which can be activated by glucocorticoids like cortisol, is a possible factor contributing to vascular changes by increasing the uptake of LDL-cholesterol (LDL-C) — the “bad” cholesterol — in vascular cells.

Prior research showed that lowering cholesterol levels could benefit patients with hypertension and normal lipid levels by decreasing the stiffness of large arteries. However, the link between blood lipids and hypertension in Cushing’s disease patients is largely unexplored.

The study included 84 patients (70 women) referred to a hospital in China for evaluation and diagnosis of Cushing’s disease. For each patient, researchers measured body mass index, blood pressure, lipid profile, and several other biomarkers of disease.

Patients with high LDL-cholesterol had higher body mass index, blood pressure, cholesterol, triglycerides, and apolipoproteinB (apoB), a potential indicator of atherosclerosis and cardiovascular disease.

Data further revealed an association between blood pressure and lipid profile, including cholesterol, triglycerides, apoB and LDL-c. “The results strongly suggested that CHO (cholesterol), LDL-c and apoB might predict hypertension more precisely in [Cushing’s disease],” the scientists wrote.

They further add that high cholesterol, LDL-cholesterol, and apoB might be contributing to high blood pressure by increasing vessel stiffness.

Additional analysis showed that patients with higher levels of “bad” cholesterol — 3.37 mmol/L or higher — had higher blood pressure. This finding remained true, even when patients were receiving statins to lower their cholesterol levels.

No association was found between blood pressure and plasma cortisol, UFC, adrenocorticotropic hormone, or glucose levels in Cushing’s disease patients.

These findings raise some questions on whether lipid-lowering treatment for high blood pressure and cardiovascular disease would be beneficial for Cushing’s disease patients. Further studies addressing this question are warranted.

Adapted from https://cushingsdiseasenews.com/2018/04/24/blood-pressure-linked-lipid-levels-cushings-disease-study/

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