Antipsychotic Drug Blocks Triple-Negative Breast Cancer Growth

The results of studies by a team of scientists in the U.K. and Spain suggest that the commonly used antipsychotic drug Pimozide could offer a new treatment approach to the most hard to treat form of breast cancer, and potentially for lung cancer. The research, headed by Mohamed El-Tanani, Ph.D., professor of molecular pathology and cancer therapeutics at the University of Bradford, found that Pimozide significantly reduced the size and number of human triple-negative breast cancer tumors in mice, and almost completely stopped the tumors from metastasizing to the lung.

Although previous studies have hinted that antipsychotic drugs may have some anticancer properties, the latest research, published in Oncotarget, is the first to suggest mechanisms by which the antipsychotic drug inhibits cancer. “Triple-negative breast cancer has lower survival rates and increased risk of recurrence,” comments Dr. El-Tanani. It is the only type of breast cancer for which only limited targeted treatments are available. Our research has shown that Pimozide could potentially fill this gap. And because this drug is already in clinical use, it could move quickly into clinical trials.”

The University of Bradford researchers, and colleagues at Queen’s University Belfast, and the University of Salamanca in Spain, report their findings in a paper titled, “The antipsychotic drug Pimozide is a novel chemotherapeutic for breast cancer.”

Antipsychotic drugs represent first-line treatment for disorders such as schizophrenia, and primarily target neurotransmitter receptors. Pimozide, for example, is an antipsychotic in the diphenylbutylpiperidine class, which selectively blocks the dopamine receptor D2 (DRD2) and is used to treat a range of mental/mood disorders, including chronic schizophrenia, as well as other psychotic disorders, the researchers write.

Interestingly, it has long been suggested that patients with schizophrenia have a lower incidence of cancer than is found in the general population, and a number of epidemiological studies have investigated this putative link. “Likewise, clinical data indicates that the use of medication for schizophrenia lowers the relative risk of cancer,” the authors write. And while “cancer risk in schizophrenic patients remains a controversial issue,” they continue, “antipsychotic drugs have been suggested as possible mediators of this effect.”

Prior work by Dr. El-Tanani’s team had shown that the protein Ran-GTPase (Ran) plays a role in enabling the growth and spread of cancers, including triple-negative breast cancer. They carried out a connectivity mapping analysis to search for small molecule compounds that could potentially suppress Ran, and identified Pimozide as the top candidate. Previous research had already shown that Pimozide can inhibit proliferation of a human breast cancer-derived cell line, and the drug had “gained attention as an anticancer agent,” the team notes.

Subsequent tests in an invasive human breast cancer cell line MDA-MB-231 and lung cancer cell line showed that Pimozide significantly inhibited cancer cell survival, resulting in significant DNA damage and promoting apoptosis. Pimozide administration also blocked Ran expression—at the mRNA and protein level—by up to 87%, inhibited AKT1 expression almost completely, and blocked AKT2 expression by up to 72%. The AKT signaling pathway plays a key role in tumor development and angiogenesis.

Pimozide also inhibited the migratory capacity of two different breast cancer cell lines, with analyses indicating that the drug reduced the expression of MMP1 and MMP14 RNA. Further studies confirmed that Pimozide led to reductions in multiple markers of cell motility, and also blocked expression of the epithelial to mesenchymal transition (EMT) markers Vimentin and Zo-1. “… Pimozide significantly inhibited MDA-MB-231 cell growth, migration, invasion, and tumorigenicity in vivo and these effects were associated with suppression of EMT, a process involving the breakdown of cell-cell junctions and loss of epithelial polarity,” the researchers write.

Encouragingly, Pimozide also inhibited the growth, proliferation, and metastasis of human breast cancer xenografts in mice. Tumor volume was reduced by up to 65%, and there were 94% fewer metastases. Immunohistochemical analyses confirmed a complete absence of AKT in tumors, while tumors from the Pimozide-treated mice also showed “a significant decrease in staining for Vimentin,” the authors state.

Further studies in the tumor-bearing mice and in breast cancer cell lines confirmed the anti-angiogenic effects of Pimozide treatment. The drug suppressed VEGFR2 production, and also prevented the differentiation of myofibroblasts that play a role in cancer metastasis, by blocking the production of αSMA in the mouse tumors. “This protein was completely depleted in breast tumors in mice treated with Pimozide compared to those in untreated mice, and the treated mice also had fewer lung metastases,” the researchers state. “Promoter analysis of the VEGFR-2 gene showed a clear dose- and time-dependent inhibitory response to Pimozide, indicating that this and other neuroleptic agents could exert antitumor effects through disrupting the vasculature in addition to promoting apoptosis in the tumor cells themselves.”

Interestingly the team found a strong correlation between mRNA levels of Ran and VEGFR2 in human breast cancer databases.

“Collectively this study provides strong evidence for multiple molecular mechanisms through which Pimozide exerts anti-tumor activity in breast cancer cells and therefore could be a useful agent for treatment in the future,” the authors conclude.

“This study is the first to report that an FDA-approved neuroleptic drug, Pimozide, which is already in clinical use, has multiple anticancer effects, since it inhibits cell proliferation, and has an anti-angiogenic and anti-metastatic activity … It was also demonstrated for the first time in this study that Pimozide acts as a potent anti-angiogenic modulator through the inhibition of the AKT and VEGF signaling pathways.”

“There are many molecular pathways that are hyperactive in cancer,” comments Dr. El-Tanani. “Our study shows that by acting as a RanGTP inhibitor, Pimozide was able to block a number of key pathways that contribute to triple negative breast cancer growing and spreading.”

The team is now looking for funding to move the Pimozide into clinical trials for treating cancer.

https://www.genengnews.com/gen-news-highlights/antipsychotic-drug-blocks-triple-negative-breast-cancer-growth/81256316

Eczema drug restores hair growth in patient with longstanding alopecia

Fine light hairs called vellus hairs appear on the scalp of a patient with alopecia totalis six weeks after she began dupilumab treatment for eczema. Credit: JAMANetwork.

Massachusetts General Hospital (MGH) physicians are reporting an unexpected side-effect from treatment with dupilumab, which is FDA approved for the treatment of moderate to severe eczema, also called atopic dermatitis. In their case report published in JAMA Dermatology, the physicians describe how their 13-year-old patient, who has alopecia totalis—a total lack of scalp hair—along with eczema, experienced significant hair regrowth while being treated with dupilumab, a drug marketed under the brand name Dupixent.

“We were quite surprised since this patient hadn’t grown scalp hair since the age of 2, and other treatments that can help with hair loss did not in her case,” says Maryanne Makredes Senna, MD, of the MGH Department of Dermatology, senior author of the JAMA Dermatology report. “As far as we know, this is the first report of hair regrowth with dupilumab in a patient with any degree of alopecia areata.”

In addition to longstanding alopecia, this patient had experienced extensive, treatment-resistant eczema since the age of 7 months. Treatment with prednisone and methotrexate, medications that can suppress the overactive immune system, led to limited improvement in the patient’s eczema but no hair regrowth and was therefore discontinued. In July 2017 she began to be treated with weekly injections of dupilumab, which had recently received FDA approval. After six weeks of treatment, which led to significant improvement in eczema symptoms, she also noticed that fine light hairs called vellus hairs were appearing on her scalp.

After 11 months of dupilumab treatment, significant pigmented hair has grown across the patient’s scalp. Credit: JAMA Network

After seven months of dupilumab treatment, the patient had grown a significant amount of the pigmented hair that typically grows on the scalp. Because of a change in her insurance coverage, she had to discontinue dupilumab for a two-month period, during which she noticed shedding of the recently regrown hair. But after she could resume treatment in April 2018, the hair growth resumed and has continued.

Senna explains that dupilumab’s mechanism of targeting a key immune system pathway known to be overactive in eczema could explain its action against alopecia, since recent studies have suggested other elements of the same pathway may induce autoimmune hair loss. “Right now, it’s hard to know whether dupilumab could induce hair growth in other alopecia patients, but I suspect it may be helpful in patients with extensive active eczema and active alopecia areata,” she says. “We’ve submitted a proposal for a clinical trial using dupilumab in this patient population and hope to be able to investigate it further in the near future.” Senna is the principal investigator of the Hair Academic Innovative Research (HAIR) clinical research unit at MGH and an instructor in Dermatology at Harvard Medical School.

 Explore further: Baldness caused by alopecia could soon be treatable

More information: JAMA Dermatology (2018). DOI: 10.1001/jamadermatol.2018.29

https://medicalxpress.com/news/2018-10-eczema-drug-hair-growth-patient.html

Bayer gets new trial on punitive damages in $289 million weed-killer case

Bayer AG’s Monsanto unit will get a new trial on the $250 million in punitive damages awarded by a jury to a groundskeeper who alleged the company’s glyphosate-based weed killers, including Roundup, gave him cancer.

According to Wednesday court filings in San Francisco’s Superior Court of California, Judge Suzanne Bolanos granted the company’s motion for a new trial on punitive damages.

A jury on Aug. 10 found Monsanto failed to warn school groundskeeper Dewayne Johnson and other consumers of the cancer risks posed by its weed killers. It awarded $39 million in compensatory and $250 million in punitive damages.

https://www.reuters.com/article/us-bayer-glyphosate-lawsuit/bayer-gets-new-trial-on-punitive-damages-in-289-million-weed-killer-case-idUSKCN1MK2QI

Celgene’s Ozanimod Versus Biogen’s Avonex: Celgene Has the Edge in MS

Celgene Corporation presented data at the 34^th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS) held in Berlin, Germany with results from two Phase III trials.

The company released post hoc analyses of data from the Phase III SUNBEAM and RADIANCE Part B trials. They evaluated the efficacy and safety of Celgene’s drug ozanimod compared to Biogen’s Avonex (interferon beta-1a) in patients with relapsing multiple sclerosis (RMS).

“Slowed cognitive processing, which is common in multiple sclerosis, often impairs quality of life for people living with this chronic condition,” said Bruce Cree, professor of Neurology at the University of California, San Francisco (UCSF) Weill Institute for Neurosciences and author of both analyses, in a statement. “The findings from these new analyses suggest that, when compared to interferon, ozanimod has a beneficial effect on processing speed.”

SUNBEAM studied two doses of ozanimod, 0.92 mg and 0.46 mg, in 1,346 patients with RMS treated for at least a year. Post hoc analysis of the data looked at cognitive processing speed based on performance on the Symbol Digit Modalities Test (SDMT). More patients showed clinically meaningful improvements in processing speed on ozanimod compared to Avonex.

A second analysis on annualized relapse rate (ARR) and MRI lesions was conducted, looking at the effect of ozanimod in patients with early RMS compared to patients with a more advanced disease. In patients with early RMS, ARR was lower at 12 months with ozanimod compared to Avonex. ARR was also lower on ozanimod than Avonex in patients with more advanced RMS.

“These analyses provide additional encouraging data for ozanimod in relapsing multiple sclerosis, from its potential to influence cognitive processing to showing results in patients with either early or more advanced forms of the disease,” said Jay Backstrom, Celgene’s chief medical officer, in a statement. “Ozanimod has the potential to offer the multiple sclerosis community a new oral option for the treatment of relapsing multiple sclerosis, and we continue to work with regulatory bodies in the U.S. and EU in our efforts to bring this treatment to patients.”

There is quite a bit of industry news coming out of ECTRIMS this week. Genentech, a Rochecompany, released data from a long-term clinical trial of Ocrevus (ocrelizumab) in multiple sclerosis. The research is five-year data from the Phase III open-label extension trials of OPERA I, OPERA II and ORATORIO. The data indicate that the efficacy of Ocrevus continues on key measures of disease activity as well as indicating that patients treated earlier with the drug had “superior disability progression outcomes” compared to patients who switched from interferon beta-1a or primary progressive MS (PPMS) patients who switched from placebo.

“From the moment of diagnosis, reducing disease progression is an important goal for people with MS,” said Stephen Hauser, chair of the Scientific Steering Committee of the OPERA studies, professor of neurology at the University of California, San Francisco, and director of the UCSF Weill Institute for Neurosciences. “The new data presented at ECTRIMS demonstrate that Ocrevus’ efficacy continued over five years in relapsing and primary progressive MS, and notably, include the largest body of evidence for any medicine to significantly slow disability progression in primary progressive MS.”

Earlier this week Novartis announced that both the U.S. Food and Drug Administration (FDA)and European Medicines Agency (EMA) had accepted its New Drug Application (NDA) and Marketing Authorization Application (MAA), respectively, for siponimod (BAF312) to treat secondary progressive multiple sclerosis (SPMS) in adults.

Novartis used a review voucher to expedite siponimod’s review in the U.S. Regulatory response in the U.S. is expected in March 2019, and in Europe in late 2019.

Of people with relapsing-remitting MS (RRMS), which is the most common form at the time of diagnosis, more than 80 percent go on to develop SPMS, with or without relapses. SPMS leads to progressive, irreversible disability, including the need for enhanced walking aids and wheelchairs, bladder dysfunction and cognitive decline. After the first RRMS course, the number of patients transitioning to SPMS gradually increase, with about 25 percent progressing by 10 years after onset, 50 percent by 20 years and more than 75 percent by 30 years.

And Germany’s Merck KGaA is presenting 23 studies, including safety and efficacy data on Rebif (interferon beta-1a), cladribine tablets (sold in Europe as Mavenclad), and evobrutinib.

“We are proud to be presenting new data across our Neurology and Immunology franchise at Merck KGaA, Darmstadt, Germany during ECTRIMS 2018,” said Luciano Rossetti, head of Merck KGaA’s global research and development for the biopharma business, in a statement. “As we continue to enhance our understanding of the benefit-risk profile of cladribine tablets and the use of Rebif, we are also excited by the presentation of the first clinical data for a BTK inhibitor (evobrutinib) in an MS patient population.”

https://www.biospace.com/article/celgene-s-ozanimod-versus-biogen-s-avonex-celgene-has-the-edge/

Novartis: Superior efficacy of Gilenya over Copaxone in MS

• Topline findings from ASSESS show adult relapsing remitting multiple sclerosis (RRMS) patients taking Gilenya (fingolimod) 0.5mg experienced significantly fewer relapses than patients on Copaxone (glatiramer acetate) 20mg
• Gilenya 0.5mg is the first and only disease modifying therapy to show superiority in reducing relapses vs Copaxone in a controlled, head-to-head trial
• Treatment discontinuations were overall more common in the Copaxone group due to adverse events and unsatisfactory therapeutic effects

Novartis announced today topline results from the Phase IIIb ASSESS study, which evaluated the efficacy and safety of oral, once daily Gilenya (fingolimod) 0.5mg and 0.25mg versus once daily subcutaneous injections of Copaxone (glatiramer acetate) 20mg in patients with relapsing remitting multiple sclerosis (RRMS). The data show that Gilenya 0.5mg met its primary endpoint of significantly reducing the annualized relapse rate (ARR) compared to Copaxone[1]. Treatment with Gilenya 0.5mg resulted in a 40.7% relative reduction in the rate of relapses over a period of one year, compared to Copaxone (ARR estimates of 0.153 vs. 0.258, respectively, p= 0.0138)[1]. Further initial findings showed adults taking Gilenya 0.25mg achieved a numerical risk reduction in relapses compared to the comparator, but did not reach statistical significance. The safety of Gilenya observed in ASSESS across both doses was consistent with the known safety profile of the drug, with overall more discontinuations due to adverse events and unsatisfactory treatment effects reported in the Copaxone group[1].

“ASSESS is the first controlled head-to-head study of a MS disease modifying therapy versus Copaxone to show superior efficacy in reducing relapses, a key measure of disease activity and a significant burden for patients,” said Bruce Cree, MD, PhD, MAS, George A. Zimmermann Endowed Professor in Multiple Sclerosis at the University of California San Francisco, and ASSESS Principal Study Investigator. “Head-to-head trials, such as ASSESS, are extremely important to help clinicians better understand the relative efficacy and safety of MS therapies, thereby making better-informed treatment decisions.”

“Gilenya reimagined MS care as the first oral treatment and is a testament to Novartis’ quest to stop MS,” said Danny Bar-Zohar, Global Head of Neuroscience Development, Novartis Pharmaceuticals. “The ASSESS data add to the robust body of evidence which show that Gilenya is a highly efficacious, cornerstone therapy in relapsing MS.”

Gilenya 0.5mg is a leading oral disease-modifying therapy, that has demonstrated high efficacy across multiple measures of disease activity in patients 10 years of age and through to adulthood. To date, Gilenya 0.5mg has been used to treat more than 255,000 patients worldwide[1]. Long-term experience has shown Gilenya treatment to be convenient for people to incorporate into everyday life, leading to high treatment satisfaction, long-term persistence, and ultimately, improved long-term outcomes[2],[3]. Gilenya 0.25mg is not approved for adults with RRMS.

Novartis will complete full analyses of the ASSESS data and intends to submit the full results to upcoming medical meetings and for peer-reviewed publication.

https://globenewswire.com/news-release/2018/10/10/1619621/0/en/Novartis-announces-new-data-from-the-first-direct-head-to-head-trial-to-demonstrate-superior-efficacy-of-Gilenya-over-Copaxone-in-patients-with-relapsing-remitting-multiple-scleros.html

Crispr Therapeutics, Vertex announce FDA lifts hold for CTX001, accepts IND

https://thefly.com/landingPageNews.php?id=2802492

Select Medical sees Q3 revenue $1.264B-$1.268B, consensus $1.28B

Select Medical expects its net operating revenue for the third quarter of 2018 to be in the range of $1.264B-$1.268B. Select Medical expects earnings excluding interest, income taxes, depreciation and amortization, stock compensation expense, non-operating gain (loss), and equity in earnings (losses) of unconsolidated subsidiaries, or Adjusted EBITDA for the third quarter of 2018 to be in the range of $150M-$154M. As of September 30, 2018, Select Medical’s revolving loan balance was $65M, compared to $150M as of June 30, 2018.
https://thefly.com/landingPageNews.php?id=2802495