New combination therapy holds promise for treating HER2-positive breast cancer

Resistance to therapy is a major problem in the cancer field. Even when a treatment initially works, the tumors often find ways around the therapy. Using human cell lines of the HER2-positive breast cancer subtype, researchers from the UNC School of Medicine and UNC Lineberger Comprehensive Cancer Center have detailed the surprising ways in which resistance manifests and how to defeat it before it happens.

The discovery, published today in the journal CELL Reports, provides the experimental evidence for the potential development of a novel combination therapy for HER2-positive breast cancer. The combination includes the FDA approved drug lapatinib (right structure) and a new experimental drug called a BET bromodomain inhibitor -JQ1 (see structure left), which works by disrupting the expression of specific genes.

 

This study, a collaboration of 20 University of North Carolina researchers, is the first time a BET bromodomain inhibitor has been shown to prevent the onset of resistance to drugs such as lapatinib in breast cancer cells.

"This research was done in cell lines of human HER2-positive breast cancer, not in patients; but the results are very striking," said Gary Johnson, PhD, Kenan Distinguished Professor and chair of the department of pharmacology, member of the UNC Lineberger Comprehensive Cancer Center, and senior author of the paper. "The combination treatments are currently being tested in different mouse models of breast cancer. Our goal is to create a new kind of therapy that could help oncologists make the response to treatment more durable and lasting for breast cancer patients."

Ref : http://www.nature.com/nature/journal/v468/n7327/abs/nature09504.html

New combination therapy holds promise for treating HER2-positive breast cancer

New high-throughput screening method may uncover novel treatments for kidney disease .

CKD affects more than 13% of adults in the United States, with diabetes, hypertension and atherosclerosis being common risk factors. Most patients rely on antihypertensive medications for treatment, and there are no therapies available that directly and specifically target the kidney.

A team led by Vineet Gupta, PhD and Jochen Reiser, MD, PhD (Rush University Medical Center) has now developed a system that can be used to identify novel drug candidates that protect the function of kidney podocytes, cells that are critical for filtering the blood. Damage to these cells is a hallmark of CKD.

"A key barrier to the rational development of podocyte-directed therapeutics has been a lack of cell-based assays for use in high-throughput drug discovery environment," said Dr. Gupta. "Our report describes what we believe to be the  first  podocyte  cell-based highcontent screening assay for the identification of novel podocyte-directed therapeutics in a high-throughput fashion."

Using the assay, which analyzes thousands of podocytes under different conditions in multi-well plates, the investigators identified 24 small molecules that protected podocytes against injury. When they treated mice and rats with one   of  the  molecules, called   pyrintegrin, the
animals' podocytes remained healthy despite being exposed to damaging agents.Pyrintegrin activates β1 integrin, a protein that acts as a molecular bridge to help podocytes hold onto the outside of blood vessels and maintain the filtration apparatus in the kidney.

"We believe that this assay could provide the much needed boost in fueling the discovery and development of kidney directed therapeutics, development of which has significantly lacked in recent times," said Dr. Reiser.

Ref : http://jasn.asnjournals.org/content/early/2015/04/09/ASN.2014090859

New high-throughput screening method may uncover novel treatments for kidney disease -- 

Allergy drug inhibits hepatitis C in mice

Chlorcyclizine (Di-Paralene,  Mantadil, Pruresidine, Trihistan) is a first-generation antihistamine of the phenylpiperazine class marketed in the United States and certain other countries. It is used primarily to treat allergy symptoms such as rhinitis,urticaria, and pruritus, and may also be used as an antiemetic. In addition to its antihistamine effects, chlorcyclizine also has some anticholinergic, antiserotonergic, and local anesthetic properties. It also has been studied as a potential treatment forhepatitis C.

The hepatitis C virus (HCV) causes liver inflammation and often leads to serious complications such as cirrhosis. Early diagnosis and treatment of HCV can prevent liver damage. Drugs are available to treat HCV, but costs can reach tens of thousands of dollars.

"Although hepatitis C is curable, there is an unmet need for effective and affordable medication," said lead author T. Jake Liang, M.D., senior investigator at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "CCZ is a promising candidate for part of a treatment regimen for this potentially life-threatening disease."

Conducted at the NIH campus in Bethesda, Maryland, the study found that CCZ blocked the early stage of HCV infection likely by impairing the ability of the virus to enter human liver cells grafted in the mice. The outcome was similar to that of commonly used antiviral drugs but without those drugs' toxic side effects.

"Using an innovative high-throughput screening process, we identified CCZ as a potent inhibitor of hepatitis C," said Anton Simeonov, Ph.D., acting scientific director of NIH's National Center for Advancing Translational Sciences (NCATS), which collaborated in the study. "Identifying already approved drugs from the NCATS Pharmaceutical Collection may offer a faster route to potential discovery of treatments for all diseases."

The researchers will next study how the drug affects people. CCZ is currently used for the treatment of allergies, not for HCV. "People should not take CCZ to treat their hepatitis C until it has been demonstrated that CCZ can be used safely and effectively for that purpose," cautions Liang.

Ref : http://stm.sciencemag.org/content/7/282/282ra49

Allergy drug inhibits hepatitis C in mice  

Enzalutamide: Indication of major added benefit for over 75-year-olds

In continuation of my update on enzalutamide

According to the findings, in comparison with watchful waiting the drug can prolong overall survival and delay the occurrence of disease complications. In men aged 75 years or older, IQWiG sees an indication of a major added benefit. There is also an indication of an added benefit in younger men; however, the extent is rated as "considerable."

Approval study terminated prematurely

The assessment was based on a randomized controlled trial (PREVAIL), which was the approval study for the indication described above. In this study, patients received either enzalutamide or a placebo, while the hormone-blocking medication was continued in all patients. In each study arm, treatment was continued until either the disease worsened (progression) or safety concerns arose, for example, because toxicity was too high.

As the interim analysis planned for the outcome "overall survival" had already shown good efficacy of enzalutamide, this was considered as the final Analysis.

Survival advantage depends on age

The difference in overall survival is statistically significant between the two study arms. However, as the further analysis of the data shows, this advantage is age dependent. It is greater in older men (75 years or more) than in younger ones. In each case, the IQWiG researchers derive an indication of an added benefit from these results, albeit with a different extent (major or minor).

Bone-related complications occur later

The study data also showed relevant group differences in favour of enzalutamide for other outcomes. For instance, bone-related complications occurred later in patients receiving enzalutamide than in those receiving placebo. IQWiG sees an indication of an added benefit here.

In addition, it took longer until opiates were used, that is, severe pain occurred later in patients receiving enzalutamide. This also applies to the occurrence of side effects (severe and serious adverse events) and the discontinuation of treatment due to side effects. Health-related quality of life also deteriorated later.

Enzalutamide: Indication of major added benefit for over 75-year-olds  

Nintedanib in lung cancer: Added benefit depends on disease severity

In continuation of my update on Nintedanib

According to the findings, there is an indication of a minor added benefit of nintedanib in combination with docetaxel in patients without brain metastases. However, in patients with brain metastases, the new drug has more disadvantages than chemotherapy with docetaxel alone. This results in a hint of a lesser benefit of nintedanib with the extent "considerable."

Findings from the only study are biased: at most indications can be derived

In its dossier the drug manufacturer compares treatment comprising nintedanib plus docetaxel with treatment comprising placebo plus docetaxel. As the treatment period in the nintedanib arm was longer than in the placebo arm (median: 4.3 versus 3 months), the observation periods for the study arms differed. Except for overall survival, the results are therefore uncertain for all outcomes.

In principle, at most an indication of an added benefit can be derived from the results of the only study included in the manufacturer dossier. As the analysis of the data shows, the advantages or disadvantages of nintedanib in combination with docetaxel primarily depend on whether patients already had brain metastases at the start of the study or not.

Patients without brain metastases live longer

Patients without brain metastases who received nintedanib in combination with docetaxel lived longer than study participants who were only treated with docetaxel (median: 13.5 versus 10.3 months). This results in an indication of a minor added benefit of nintedanib.

Although diarrhoea was more frequent in patients receiving nintedanib, this disadvantage does not challenge the survival advantage. Therefore, overall an indication remains of a minor added benefit for patients without brain metastases.

More symptoms in patients with brain metastases

Nintedanib in lung cancer: Added benefit depends on disease severity  

Pomegranate-date cocktail a day keeps the doctor away

Pomegranate-date cocktail a day keeps the doctor away 

A team of researchers at the Technion-Israel Institute of Technology, led by Professor Michael Aviram of the Rappaport Faculty of Medicine and Rambam Medical Center, has discovered that the combination of pomegranate juice and dates along with their pits provide maximum protection against atherosclerosis (plaque buildup or hardening of the arteries), which can cause a heart attack or stroke. The findings were published in the most recent issue (March 26, 2015) ofFood & Function, a journal of The Royal Society of Chemistry.

A number of risk factors are involved in the development of atherosclerosis, including cholesterol oxidation, which leads to accumulation of lipids in the arterial wall. Natural antioxidants can slow down the oxidation process in the body, and serve to reduce the risk of heart attack. For the past 25 years, Prof. Aviram and his research team have been working on isolating and researching those antioxidants, in order to keep plaque buildup at bay.

Going into the most recent study, the team was aware of the individual benefits provided by pomegranates and dates. Pomegranate juice, rich in polyphenolic antioxidants (derived from plants), has been shown to most significantly reduce oxidative stress. Dates, which are rich sources of phenolic radical scavenger antioxidants, also inhibit the oxidation of LDL (the so-called "bad cholesterol") and stimulate the removal of cholesterol from lipid-laden arterial cells. Prof. Aviram had a hunch that since dates and pomegranate juice are composed of different phenolic antioxidants, the combination could thus prove more beneficial than the sum of its parts.

In a trial performed on arterial cells in culture, as well as in atherosclerotic mice, the Technion team found that the triple combination of pomegranate juice, date fruits and date pits did indeed provide maximum protection against the development of atherosclerosis because the combination reduced oxidative stress in the arterial wall by 33% and decreased arterial cholesterol content by 28%.

The researchers conclude that people at high risk for cardiovascular diseases, as well as healthy individuals, could benefit from consuming the combination of half a glass of pomegranate juice (4 ounces), together with 3 dates. Ideally, the pits should be ground up into a paste and eaten as well, but even without the pits, the combination is better than either fruit alone.

Ref : http://pubs.rsc.org/en/Content/ArticleLanding/2015/FO/C4FO00998C#!divAbstract

Study on new treatment for prostate cancer

A new study represents the first time LTPs have been applied on cells grown directly from patient tissue samples. Taking both healthy prostate cells and prostate cancer tissue cells from a single patient, the study allowed for direct comparison of the effectiveness of the treatment. Scientists discovered that LTPs may be a potential option for treatment of patients with organ confined prostate cancer, and a viable, more cost-effective alternative to current radiotherapy and photodynamic therapy (PDT) treatments.

Study on new treatment for prostate cancer  

Ref : http://www.nature.com/bjc/journal/vaop/ncurrent/full/bjc2015113a.html

Enriched broccoli reduces cholesterol

In continuation of my update on broccoli

Including a new broccoli variety in the diet reduces blood LDL-cholesterol levels by around 6 percent, according to the results of human trials. The broccoli variety was bred to contain two to three times more of a naturally occurring compound glucoraphanin. It is now available in supermarkets in England, under the name Beneforte.

The broccoli variety was bred to contain two to three times more of a naturally occurring compound glucoraphanin. It is now available in supermarkets, under the name Beneforte.

Working with colleagues at the University of Reading, in two independent studies, the researchers gave a total of 130 volunteers 400g of the high glucoraphanin broccoli per week to include in their normal diet.

After 12 weeks, they saw the levels of LDL-cholesterol in their blood drop by an average of about 6%. Elevated LDL cholesterol is a recognised risk factor for heart disease. Although the reduction seen in these trials is small, at a population level, a 1% reduction in LDL-cholesterol has been associated with a 1-2% reduction in risk of coronary artery disease.

Glucoraphanin is thought to work by helping our bodies retune cellular metabolism. Mitochondria, the energy centres of the cell, convert sugars and fats into energy. But if they aren't working efficiently, or if we overload them with too much fat or sugar, one response is to channel excess into cholesterol.

Glucoraphanin is converted in the body to sulphoraphane, which turns on specific genes that activate our bodies' defences against this happening, rebalancing metabolism away from the production of LDL cholesterol. This new study, published in the journal Molecular Nutrition and Food Research, provides the evidence for this reduction.

High glucoraphanin Beneforté broccoli was developed using traditional breeding techniques at IFR's partners on the Norwich Research Park, the John Innes Centre and the University of East Anglia, and Seminis Vegetable Seeds Inc.

This study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC), Innovate UK and Seminis Vegetable Seeds Inc.

Other foods or ingredients that have been proven to lower LDL-cholesterol are beta-glucans in oats and plant stanols. These work by reducing cholesterol absorption into the body. As glucoraphanin works by reducing how much our bodies make, eating these foods together is likely to have an additive effect.

Enriched broccoli reduces cholesterol 

Journal of Drugs in Dermatology publishes findings on new injectable drug ATX-101

In continuation of my update on ATX-101    .......

Double chins are clinically defined by accumulation of subcutaneous fat in the submental area. The result? A double chin that impacts perceptions of facial attractiveness. In "A Phase I Safety and Pharmacokinetic Study of ATX-101: Injectable, Synthetic Deoxycholic Acid for Submental Contouring," Patricia Walker MD PhD, Jere Fellmann PhD, and Paul F. Lizzul MD PhD MBA MPH explain how ATX-101 (deoxycholic acid [DCA] injection) has the potential to provide a less invasive alternative for submental fat reduction and contouring. Both in vivo and in vitro studies show that, when injected into submental subcutaneous fat tissue, ATX-101 results in the targeted destruction of fat cells. The data support favorable safety and efficacy observations. Adverse events were bruising and swelling associated with the treatment area that are mild or moderate in severity. FDA approval for use of ATX-101 above the chest is expected in May 2015.

Journal of Drugs in Dermatology publishes findings on new injectable drug ATX-101

Low doses of imatinib drug can push immune system to combat bacterial infections

In contiuation of my update on Imatinib

Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory researchers have found.

The results were published March 30, 2015 in the journal PLOS Pathogens.

The findings suggest imatinib, known commercially as Gleevec , or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.

"We think that low doses of imatinib are mimicking 'emergency hematopoiesis,' a normal early response to infection," says senior author Daniel Kalman, PhD, professor of pathology and laboratory medicine at Emory University School of Medicine.

Ref : http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004770

Low doses of imatinib drug can push immune system to combat bacterial infections

Old leukemia drug may help in fight against cancer

A drug used for decades to treat leukemia may have other uses in the fight against cancer, researchers at the University of Missouri have found. Previously, doctors used 6-Thioguanine, or 6-TG, as a chemotherapy treatment to kill cancer cells in patients with leukemia.

Old leukemia drug may help in fight against cancer

Pharmalink AB acquires anti-inflammatory drug candidate from Synartro AB

Pharmalink AB, a specialty pharma company, announces that it has acquired a novel product candidate in development for treating inflammation from Synartro AB. No financial details are disclosed.

The product candidate, which consists of an anti-inflammatory drug conjugated to a biopolymer, has been developed using Synartro's drug delivery technology to create locally acting pharmaceuticals with limited systemic exposure. Pharmalink intends to develop the product for osteoarthritis, an indication where it has demonstrated promising results in pre-clinical studies. Pharmalink will apply its formulation and clinical development expertise to advance the candidate product through clinical trials towards market.

 

Pharmalink has extensive experience in developing locally delivered anti-inflammatory drugs with limited systemic uptake. Its most advanced product is Nefecon®, (a new oral formulation of the glucocorticosteroid, budesonide above structures respectively), modified-release capsule of the corticosteroid, budesonide, in Phase 2b clinical development for treating patients with IgA nephropathy at risk of developing end-stage renal disease, despite optimized standard-of-care therapy.

Pharmalink AB acquires anti-inflammatory drug candidate from Synartro AB

Novel molecule inhibits cancer-causing transcription factors

A novel molecule designed by scientists at the University of Massachusetts Medical School and the University of Virginia inhibits progression of a hard-to-treat form of recurring acute myeloid leukemia (AML) in patient tissue. The small molecule is one of the first designed to specifically target a cancer-causing transcription factor. Previously thought to be an undruggable target, this strategy may be used to design other novel molecules that can specifically inhibit cancer-causing transcription factors. Details of the work were published in Science.

Transcription factors are single- or multi-protein complexes that regulate transcription of DNA into messenger RNA and gene expression by binding to regions on the genome next to a gene. Mutations in transcription factors can result in altered gene expression programs that give way to new, cancer-causing functions. Although these aberrant transcription factors are promising targets for new therapeutics, the complexity of interrupting very specific protein-to-protein interactions has made it difficult to find small molecules or design drugs that treat these cancers.

"When we look at inhibitors, they usually target an enzyme or receptor. There aren't a lot of good examples of transcription factor inhibitors in clinical trials," said Lucio H. Castilla, PhD, associate professor of molecular, cell and cancer biology and co-leader of the study. "Here, we've used our extensive knowledge of a mutant transcription factor found in a subset for acute myeloid leukemia patients to design a molecule that can specifically sequester only the oncogenic mutant. This leaves the normal transcription factor to bind to the DNA and restore gene expression.".......

Ref : http://www.sciencemag.org/content/347/6223/779.abstract?sid=73b04258-783e-43e4-8e1d-09fe5eb7d331

Novel molecule inhibits cancer-causing transcription factors

Pharmalink AB acquires anti-inflammatory drug candidate from Synartro AB

Pharmalink AB, a specialty pharma company, announces that it has acquired a novel product candidate in development for treating inflammation from Synartro AB. No financial details are disclosed.

The product candidate, which consists of an anti-inflammatory drug conjugated to a biopolymer, has been developed using Synartro's drug delivery technology to create locally acting pharmaceuticals with limited systemic exposure. Pharmalink intends to develop the product for osteoarthritis, an indication where it has demonstrated promising results in pre-clinical studies. Pharmalink will apply its formulation and clinical development expertise to advance the candidate product through clinical trials towards market.

 

Pharmalink has extensive experience in developing locally delivered anti-inflammatory drugs with limited systemic uptake. Its most advanced product is Nefecon®, (a new oral formulation of the glucocorticosteroid, budesonide above structures respectively), modified-release capsule of the corticosteroid, budesonide, in Phase 2b clinical development for treating patients with IgA nephropathy at risk of developing end-stage renal disease, despite optimized standard-of-care therapy.

Pharmalink AB acquires anti-inflammatory drug candidate from Synartro AB

GFT505 demonstrates dose-dependent efficacy on primary endpoint in phase 2 NASH trial

GENFIT (Euronext: GNFT; ISIN: FR0004163111), today announces topline results of the phase 2 GOLDEN-505 trial in NASH.

Due to the unexpected rate of resolution of NASH in patients randomized to placebo who had early NASH (NAS of 3, placebo response rate>57%), along with the high number of sites for a limited sample size, the study as initially designed did not enable the trial to meet directly the primary endpoint. With correction for this baseline severity and site heterogeneity by a standardized statistical analysis, GFT505 120mg meets the primary endpoint: Reversal on NASH without worsening of fibrosis, as detailed below.

Treatment with GFT505 provides a significant beneficial effect on the primary endpoint (GFT505 120mg vs placebo, p=0.016, RR=2.03) in the global randomized population (n=274, full analysis set), where patients without an end of treatment biopsy were considered as non-responders. The primary endpoint was also achieved in the evaluable population of patients who underwent both baseline and end of study liver biopsies (n=237, ITT; p=0.027 vs placebo; RR=1.94). In the evaluable patient population, GFT505 120mg also has a beneficial effect of a decrease of NAS-score ≥2 (p=0.04 vs placebo).

Early NASH patients with NAS=3 were not included in other recent NASH trials. If the same is done in the GOLDEN-505 study, keeping patients with more severe disease defined by NAS≥4 (n=202), GFT505 120mg demonstrates a doubling of responders on the primary endpoint (22.4% vs 12.7%, p=0.046, RR=1.9), thus providing evidence of a clinically meaningful benefit in patients with more advanced disease.

GFT505 demonstrates dose-dependent efficacy on primary endpoint in phase 2 NASH trial