New discoveries offer possible Cushing’s disease cure

LOS ANGELES — More than a century has passed since the neurosurgeon and pathologist Harvey Cushing first discovered the disease that would eventually bear his name, but only recently have several key discoveries offered patients with the condition real hope for a cure, according to a speaker here.

There are several challenges clinicians confront in the diagnosis and treatment of Cushing’s disease, Shlomo Melmed, MB, ChB, FRCP, MACP, dean, executive vice president and professor of medicine at Cedars-Sinai Medical Center in Los Angeles, said during a plenary presentation. Patients who present with Cushing’s disease typically have depression, impaired mental function and hypertension and are at high risk for stroke, myocardial infarction, thrombosis, dyslipidemia and other metabolic disorders, Melmed said. Available therapies, which range from surgery and radiation to the somatostatin analogue pasireotide (Signifor LAR, Novartis), are often followed by disease recurrence. Cushing’s disease is fatal without treatment; the median survival if uncontrolled is about 4.5 years, Melmed said.

“This truly is a metabolic, malignant disorder,” Melmed said. “The life expectancy today in patients who are not controlled is apparently no different from 1930.”

The outlook for Cushing’s disease is now beginning to change, Melmed said. New targets are emerging for treatment, and newly discovered molecules show promise in reducing the secretion of adrenocorticotropic hormone (ACTH) and pituitary tumor size.

“Now, we are seeing the glimmers of opportunity and optimism, that we can identify specific tumor drivers — SST5, [epidermal growth factor] receptor, cyclin inhibitors — and we can start thinking about personalized, precision treatment for these patients with a higher degree of efficacy and optimism than we could have even a year or 2 ago,” Melmed said. “This will be an opportunity for us to broaden the horizons of our investigations into this debilitating disorder.”

Challenges in diagnosis, treatment

Overall, about 10% of the U.S. population harbors a pituitary adenoma, the most common type of pituitary disorder, although the average size is only about 6 mm and 40% of them are not visible, Melmed said. In patients with Cushing’s disease, surgery is effective in only about 60% to 70% of patients for initial remission, and overall, there is about a 60% chance of recurrence depending on the surgery center, Melmed said. Radiation typically leads to hypopituitarism, whereas surgical or biochemical adrenalectomy is associated with adverse effects and morbidity. Additionally, the clinical features of hypercortisolemia overlap with many common illnesses, such as obesity, hypertension and type 2 diabetes.

“There are thousands of those patients for every patient with Cushing’s disease who we will encounter,” Melmed said.

The challenge for the treating clinician, Melmed said, is to normalize cortisol and ACTH with minimal morbidity, to resect the tumor mass or control tumor growth, preserve pituitary function, improve quality of life and achieve long-term control without recurrence.

“This is a difficult challenge to meet for all of us,” Melmed said.

Available options

Pituitary surgery is typically the first-line option offered to patients with Cushing’s disease, Melmed said, and there are several advantages, including rapid initial remission, a one-time cost and potentially curing the disease. However, there are several disadvantages with surgery; patients undergoing surgery are at risk for postoperative venous thromboembolism, persistent hypersecretion of ACTH, adenoma persistence or recurrence, and surgical complications.

Second-line options are repeat surgery, radiation, adrenalectomy or medical therapy, each with its own sets of pros and cons, Melmed said.

“The reality of Cushing’s disease — these patients undergo first surgery and then recur, second surgery and then recur, then maybe radiation and then recur, and then they develop a chronic illness, and this chronic illness is what leads to their demise,” Melmed said. “Medical therapy is appropriate at every step of the spectrum.”

Zebrafish clues

Searching for new options, Melmed and colleagues introduced a pituitary tumor transforming gene discovered in his lab into zebrafish, which caused the fish to develop the hallmark features of Cushing’s disease: high cortisol levels, diabetes and cardiovascular disease. In the fish models, researchers observed that cyclin E activity, which drives the production of ACTH, was high.

Melmed and colleagues then screened zebrafish larvae in a search for cyclin E inhibitors to derive a therapeutic molecule and discovered R-roscovitine, shown to repress the expression of proopiomelanocortin (POMC), the pituitary precursor of ACTH.

In fish, mouse and in vitro human cell models, treatment with R-roscovitine was associated with suppressed corticotroph tumor signaling and blocked ACTH production, Melmed said.

“Furthermore, we asked whether or not roscovitine would actually block transcription of the POMC gene,” Melmed said. “It does. We had this molecule (that) suppressed cyclin E and also blocks transcription of POMC leading to blocked production of ACTH.”

In a small, open-label, proof-of-principal study, four patients with Cushing’s disease who received roscovitine for 4 weeks developed normalized urinary free cortisol, Melmed said.

Currently, the FDA Office of Orphan Products Development is funding a multicenter, phase 2, open-label clinical trial that will evaluate the safety and efficacy of two of three potential doses of oral roscovitine (seliciclib) in patients with newly diagnosed, persistent or recurrent Cushing disease. Up to 29 participants will be treated with up to 800 mg per day of oral seliciclib for 4 days each week for 4 weeks and enrolled in sequential cohorts based on efficacy outcomes.

“Given the rarity of the disorder, it will probably take us 2 to 3 years to recruit patients to give us a robust answer,” Melmed said. “This zebrafish model was published in 2011, and we are now in 2019. It has taken us 8 years from publication of the data to, today, going into humans with Cushing’s. Hopefully, this will light the pathway for a phase 2 trial.”

 Offering optimism’

Practitioners face a unique paradigm when treating patients with Cushing’s disease, Melmed said. Available first- and second-line therapy options often are not a cure for many patients, who develop multimorbidity and report a low quality of life.

“Then, we are kept in this difficult cycle of what to do next and, eventually, running out of options,” Melmed said. “Now, we can look at novel, targeted molecules and add those to our armamentarium and at least offer our patients the opportunity to participate in trials, or at least offer the optimism that, over the coming years, there will be a light at the end of the tunnel for their disorder.”

Melmed compared the work to Lucas Cranach’s Fons Juventutis (The Fountain of Youth). The painting, completed in 1446, shows sick people brought by horse-drawn ambulance to a pool of water, only to emerge happy and healthy.

“He was imagining this ‘elixir of youth’ (that) we could offer patients who are very ill and, in fact, that is what we as endocrinologists do,” Melmed said. “We offer our patients these elixirs. These Cushing’s patients are extremely ill. We are trying with all of our molecular work and our understanding of pathogenesis and signaling to create this pool of water for them, where they can emerge with at least an improved quality of life and, hopefully, a normalized mortality. That is our challenge.” – by Regina Schaffer

Reference:

Melmed S. From zebrafish to humans: translating discoveries for the treatment of Cushing’s disease. Presented at: AACE Annual Scientific and Clinical Congress; April 24-28, 2019; Los Angeles.

Disclosure: Melmed reports no relevant financial disclosures.

 

From https://www.healio.com/endocrinology/neuroendocrinology/news/online/%7B585002ad-640f-49e5-8d62-d1853154d7e2%7D/new-discoveries-offer-possible-cushings-disease-cure

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

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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