Vemurafenib: Result unchanged despite new data

In continuation of my update on Vemurafenib

Longer survival, but also major side effects

The drug approved since February 2012 can be an option for adults whose melanoma cannot be removed by surgery or has formed secondaries (metastases) and in whose cancer a change (mutation) has occurred in a certain gene (BRAF-V600). G-BA had specified the drug dacarbazine as the appropriate comparator therapy.

In its first AMNOG assessment in June 2012, the Institute concluded that vemurafenib had major advantages in overall survival, but also major disadvantages in the form of side effects. Overall, this resulted in an indication of a considerable added benefit.

Vemurafenib: Result unchanged despite new data

Supramolecular high-aspect ratio assemblies with strong antifungal activity : Nature Communications : Nature Publishing Group

Efficient and pathogen-specific antifungal agents are required to mitigate drug resistance problems. Here we present cationic small molecules that exhibit excellent microbial selectivity with minimal host toxicity. Unlike typical cationic polymers possessing molecular weight distributions, these compounds have an absolute molecular weight aiding in isolation and characterization. However, their specific molecular recognition motif (terephthalamide-bisurea) facilitates spontaneous supramolecular self-assembly manifesting in several polymer-like properties. Computational modelling of the terephthalamide-bisurea structures predicts zig-zag or bent arrangements where distal benzyl urea groups stabilize the high-aspect ratio aqueous supramolecular assemblies. These nanostructures are confirmed by transmission electron microscopy and atomic force microscopy. Antifungal activity against drug-sensitive and drug-resistant strains with in vitro and in vivo biocompatibility is observed. Additionally, despite repeated sub-lethal exposures, drug resistance is not induced. Comparison with clinically used amphotericin B shows similar antifungal behaviour without any significant toxicity in a C. albicansbiofilm-induced mouse keratitis model.

Supramolecular high-aspect ratio assemblies with strong antifungal activity : Nature Communications : Nature Publishing Group

Low-fat fish oil changes cancer tissue in prostate cancer, study shows

Men with prostate cancer who ate a low-fat diet and took fish oil supplements had lower levels of pro-inflammatory substances in their blood and a lower cell cycle progression score, a measure used to predict cancer recurrence, than men who ate a typical Western diet, UCLA researchers found.

"We found that CCP scores were significantly lower in the prostate cancer in men who consumed the low-fat fish oil diet as compare to men who followed a higher fat Western diet," Aronson said. "We also found that men on the low-fat fish oil diet had reduced blood levels of pro-inflammatory substances that have been associated with cancer."

This study appears in the early online edition of Cancer Prevention Research, a peer-reviewed journal of the American Association for Cancer Research.

This study is a follow-up to a 2011 study by Aronson and his team that found a low-fat diet with fish oil supplements eaten for four to six weeks prior to prostate removal slowed the growth of cancer cells in human prostate cancer tissue compared to a traditional, high-fat Western diet.

That short-term study also found that the men on the low-fat fish oil diet were able to change the composition of their cell membranes in both the healthy cells and the cancer cells in the prostate. They had increased levels of omega-3 fatty acids from fish oil and decreased levels of the more pro-inflammatory omega-6 fatty acids from corn oil in the cell membranes, which may directly affect the biology of the cells, Aronson said.

"These studies are showing that, in men with prostate cancer, you really are what you eat," Aronson said. "The studies suggest that by altering the diet, we may favorably affect the biology of prostate cancer."

Ref : http://cancerpreventionresearch.aacrjournals.org/content/early/2013/10/29/1940-6207.CAPR-13-0261

Low-fat fish oil changes cancer tissue in prostate cancer, study shows

Molecule critical to healing wounds identified

Skin provides a first line of defense against viruses, bacteria and parasites that might otherwise make people ill. When an injury breaks that barrier, a systematic chain of molecular signaling launches to close the wound and re-establish the skin's layer of protection. 

A study led by researchers from the University of Pennsylvania's School of Dental Medicine and published in the Journal of Cell Biology now offers a clearer explanation of the role of one of the players in the wound-healing process, a molecule called FOX01. Contrary to what had been expected, FOX01 is critical to wound healing, providing researchers with a possible new target for drugs that could help speed that process for people with impaired wound healing.

Senior author Dana Graves is a professor in Penn Dental Medicine's Department of Periodontics and is vice dean for scholarship and research. He collaborated on the study with Penn's Bhaskar Ponugoti, Fanxing Xu, Chenying Zhang, Chen Tian and Sandra Pacio.

A critical element of wound healing involves the movement of keratinocytes, the primary cells comprising the epidermis, or the outer layer of skin. Previous research had found that FOX01 was expressed at higher levels in wounds, but scientists did not understand what role the molecule was playing. In other scenarios, such as in cancer cells, FOX01 promotes cell death and interferes with the cell reproduction, two actions that would seem to be detrimental to healing.

To investigate the role of FOX01 in wound healing, Graves and colleagues bred mice that lacked the protein in their keratinocytes and then observed the wound healing process in these mice compared to mice with normal FOX01.

"We thought that deleting FOX01 would speed up the wound-healing process," Graves said, "but in fact it had the opposite effect."

The mice that lacked FOX01 showed significant delays in healing. Whereas all wounds on control mice were healed after one week, all of the experimental mice still had open wounds.

Digging deeper into this counterintuitive finding, the researchers examined the effect of reducing FOX01 levels on other genes known to play a role in cell migration. They found that many of these genes were significantly reduced, notably TGF-β1, a critical growth factor in wound repair. When the team added TGF-β1 to cells lacking FOX01, the cells behaved normally and produced the proper suite of molecules needed for healing, indicating that FOX01 acts upstream of TGF-β1 in the signaling pathway triggered during the healing process.

Further experimenting revealed that mice lacking FOX01 had evidence of increased oxidative stress, which is detrimental to wound healing.

"The wound healing environment is a stressful environment for the cell," Graves said. "It appears that upregulation of FOX01 helps protect the cell against oxidative stress."

Molecule critical to healing wounds identified

Combinatory therapy may be effective in suppressing drug resistance in treatment of melanoma

"About 50 percent of melanomas are driven by mutations in the BRAF gene, and about 60-80 percent of these melanomas initially respond to BRAF inhibitors such as vemurafenib and dabrafenib, but most develop resistance within seven to eight months," said Dr. Lo. "Our goal is to study comprehensively how this cancer escapes from BRAF inhibitors, so we can design new treatment approaches to overcome this resistance.

"It is very exciting to see work funded under a Stand Up To Cancer Innovative Research Grant (IRG) yield these important results," stated Sherry Lansing, co-founder & member of the SU2C Council of Founders and Advisors. "We created the IRG program to enable some of the best and brightest young researchers across disciplines to think out of the box and attempt to make major breakthroughs in their field with bold research projects." The SU2C IRG program is one of two initial funding models created by SU2C to focus on groundbreaking translational research aimed at getting new therapies to patients quickly. IRG grants support work that incorporates new ideas and new approaches to solve critical problems in cancer research. Dr. Lo's grant was one of the initial 13 IRG grants awarded in December 2009. Thirteen additional IRG grants were awarded in April 2011. To date, SU2C has funded $19.42 million for IRG research.

"There are several types of resistance, and one of these studies focused on early resistance, because most melanomas respond to BRAF inhibitors partially, leaving behind tumors subject to further evolutionary selection and development of late resistance," said Lo. "We found that suppressing the BRAF-regulated MAPK signaling quickly led to an increase in PI3K-AKT pathway signaling [causing early resistance] in many but not all melanomas. In those that do not display this early adaptive response, certain tumor subclones with the 'right' genetic variants in the PI3K-PTEN-AKT pathway would then have selective growth advantage during BRAF inhibitor therapy and eventually contribute to acquired [late] resistance," he explained.

Lo and colleagues studied melanoma tumors from patients collected before and early during treatment with BRAF inhibitors, and found that there was an increase in the amount of the activated form of a protein called AKT, early on after the start of treatment. They further confirmed these findings using melanoma cells cultured in the laboratory. This increase in activated AKT was associated with various inhibitors that block MAPK signaling at different points along the pathway, such as BRAF and MEK inhibitors.

Combinatory therapy may be effective in suppressing drug resistance in treatment of melanoma

Research: New drugs show ability to rapidly shrink melanoma tumors

Melanoma is the deadliest form of skin cancer, killing more than 8,000 in the U.S. each year. Approximately 40 percent of advanced melanoma tumors are driven to grow by the presence of mutations in a gene known as the BRAF gene. And although new drugs called BRAF inhibitors have shown an ability to rapidly shrink melanoma tumors, BRAF-mutated tumors often resist early treatment and only partially respond to BRAF inhibitors, which leaves behind cancer cells that can eventually grow into new tumors.

Today, two studies by researchers from UCLA's Jonsson Comprehensive Cancer Center were published online in the journal Cancer Discovery that provide critical insights into two important ways that tumors resist BRAF inhibitors. The researchers found the key cell-signaling pathways used by BRAF-mutant melanoma to learn how to become resistant to inhibitor drugs, and how the limited focus of BRAF inhibitors allows melanoma cells to evolve and become drug-resistant. The studies will appear later in the journal's print edition.

Led by Dr. Roger Lo, a member of the Jonsson Cancer Center and associate professor and director of the melanoma clinic in dermatology, the studies utilized patients' biopsy samples to give researchers powerful information that can be translated directly into the clinic. Specifically, the findings should help oncologists make better use of BRAF inhibitor drugs in combination with other drugs for melanoma patients.

In the first study, Lo and colleagues discovered how tumor cells escaped the effects of BRAF inhibitors by tracking the outgrowth of melanoma cells that had learned from different cell-signaling pathways how to become BRAF inhibitor-resistant. This work, based on an analysis of 100 biopsies from patients who had been treated with BRAF inhibitors, revealed that BRAF inhibitor-resistant tumors use a variety of different signaling routes to learn resistance and that people can have more than one resistance route. Clinical trials have rarely studied these phenomena at the molecular level, which Lo said provides a much more robust view of the scale and scope of the problem.

Ref : http://cancerdiscovery.aacrjournals.org/content/early/2013/11/19/2159-8290.CD-13-0642.abstract

Research: New drugs show ability to rapidly shrink melanoma tumors

Novel drug combats psychosis in Parkinson’s disease

The non-dopaminergic drug pimavanserin reduces psychotic symptoms in patients with Parkinson’s disease (PD) without worsening motor function, shows a randomized trial.

In a press statement, lead researcher Clive Ballard (King’s College London, UK) stressed that “the clinical benefits of pimavanserin were seen by patients, those caring for them, and independent blinded raters alike.”

Along with observed improvements in sleep, this suggests that tackling psychosis had “a broader effect on wellbeing of patients,” write Ballard and colleagues in The Lancet.

A total of 199 patients participated in the study, 185 of whom were included in the final analysis; all had a combined score of at least 6 on the neuropsychiatric inventory items delusions and hallucinations, or an individual score of at least 4. 

The researchers tried to provoke a placebo effect ahead of the start of drug treatment by first providing all patients with 2 weeks of psychosocial therapy. Nevertheless, patients assigned to the placebo group still had a 14% reduction in psychotic symptoms on the PD-adapted Scale for Assessment of Positive Symptoms (SAPS) over the 6-week study period.

However, patients taking pimavanserin – a selective serotonin 5-HT2A inverse agonist – had a significantly larger 37% improvement.

In an accompanying commentary, Susan Fox (Toronto Western Hospital, Ontario, Canada) writes: “Overall, the study opens up a new therapeutic avenue in treatment of Parkinson's disease psychosis.”

Ref : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)62106-6/fulltext

Novel drug combats psychosis in Parkinson’s disease

New compound could reverse loss of muscle mass in cancer, other diseases

New compound could reverse loss of muscle mass in cancer, other diseases

Toxin produced by bacteria could serve as model for next-generation antibiotics

The recent rise in antibiotic-resistant bacteria is a serious public health threat, and there is a need for new therapeutic strategies to combat these infections. A study published by Cell Press on November 14th in the journal Molecular Cell has revealed a new toxin that inhibits bacterial growth by blocking the DNA replication machinery, which is not targeted by currently available antibiotics. The findings open new therapeutic avenues for developing the next generation of antibiotics.

"One source of inspiration for new antibiotic targets is bacteria themselves," says senior study author Michael Laub of the Massachusetts Institute of Technology. "By studying the ways in which toxins produced by bacteria inhibit their growth, we may potentially find clues into targets that hadn't been considered previously."

Bacterial growth is regulated in part by sets of genes known as toxin-antitoxin (TA) systems, each of which typically encodes two proteins   the toxin and the antitoxin. These proteins normally form a non-toxic complex, but under stressful conditions, the antitoxin degrades and frees up the toxin, which then inhibits bacterial proliferation. Despite the key role TA systems play in regulating bacterial growth, relatively little is known about how they work, and they currently are not targeted by any antibiotics in clinical use.

In the new study, Laub and his team identified a novel TA system called SocAB. Unlike all other known TA systems, SocAB targets bacterial DNA replication machinery. The toxin, SocB, blocks DNA replication and inhibits bacterial growth by interacting with a protein called DnaN, a central hub in protein networks involved in multiple cellular processes. The researchers also pinpointed the region on DnaN that is critical for this interaction. The findings suggest that novel antibiotics that mimic the effects of SocB by targeting this region on DnaN could form the basis of a promising therapeutic strategy in the future.

"Our results reveal unexpected diversity in the molecular mechanisms underlying toxin-antitoxin systems, which are found throughout the bacterial kingdom," Laub says. "Because DnaN is highly conserved between bacteria, targeting this part of the DNA replication machinery may be a generalizable strategy to inhibit bacterial growth."

Ref : http://www.sciencedirect.com/science/article/pii/S0092867413007733

Toxin produced by bacteria could serve as model for next-generation antibiotics

Bitter melon extract may have potential to fight head, neck cancer

Extract taken from an Asian vegetable may have therapeutic qualities to treat head and neck cancer, a Saint Louis University researcher has found. Preliminary findings of the research were published in the Public Library of Science One Journal by Ratna Ray, Ph.D. associate professor of pathology at Saint Louis University. Ray found that bitter melon extract, a vegetable commonly used in Indian and Chinese diets, reduces the head and neck cancer cell growth in the animal model.

"We wanted to see the effect of the bitter melon extract treatment on different types of cancer using different model systems," said Ray, who first tested the extract in breast and prostate cancer cells. "In this study, the bitter melon extract treatment suppressed the head and neck cancer cell growth in the mouse model, reducing the growth of the tumor."

In a controlled lab setting, Ray found that bitter melon extract regulated several pathways that helped reduce the head and neck cancer cell growth in the animal model. After a period of four weeks, Ray found that the growth and volume of the tumor had reduced.

Bitter melon is a tropical vegetable that is commonly used in Indian and Chinese cooking. Ray, who is originally from India, often uses bitter melon in her meals. People in Asia use this vegetable in stir fries, salads, and also drink its juice as part of a healthy diet.

Although more research is needed, Ray believes the bitter melon extract may enhance the current treatment option.

"It's difficult to measure the exact impact of bitter melon extract treatment on the cell growth, but a combination of things -- existing drug therapy along with bitter melon   may help the efficacy of the overall cancer treatment," Ray said.

Head and neck cancers, which account for 6 percent of all cancer cases, start in the mouth, nose, sinuses, voicebox and throat. They frequently are aggressive, and often spread from one part of the head or neck to another.

Before moving to phase I clinical trial with head and neck cancer patients, Ray said she and her team would need to validate their results with other preclinical models.

Ray's initial research found that treatment with this natural substance halted the breast and prostate cancer cell growth, eventually stopping them from spreading.

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0078006

Bitter melon extract may have potential to fight head, neck cancer

University of Sydney researchers identify new type of medication for osteoporosis

University of Sydney researchers have discovered a new and promising treatment for osteoporosis which is easily delivered in water soluble form. 

After more than four years of investigation, researchers from the Ageing Bone Research Program (Sydney Medical School’s Nepean campus), have found the treatment has shown very promising results in animal experiments. 

The compound is called picolinic acid, a product derived of the essential amino acid tryptophan. 

Lead researcher Professor Gustavo Duque said the odorless compound can be easily dissolved in water. 

“This is a major step in the development of a completely new type of medication for osteoporosis,” he said. 

“Instead of stopping bone destruction, our compound instead stimulates bone formation."

“The product is easily dissolved in water, has a higher level of absorption and did not induce any side effects in the treated mice."

“When this medication was administered in the water of normal and menopausal mice, picolinic acid strongly and safely increased bone mass in normal mice and rescued bone from menopause-associated osteoporosis.”

Professor Duque said the team had patented the compound and will expand their trials to humans in the near future in a bid to address the increasing numbers of people developing the condition. 

“Osteoporosis affects an estimated 300 million people worldwide. One in three women over 50 will experience osteoporotic fractures, as will one in five men."

Ref : http://sydney.edu.au/news/84.html?newscategoryid=1&newsstoryid=12713

University of Sydney researchers identify new type of medication for osteoporosis

Repurposed drug may be first targeted treatment for serious kidney disease

A drug approved for the treatment of rheumatoid arthritis may also turn out to be the first targeted therapy for one of the most common forms of kidney disease, a condition that almost inevitably leads to kidney failure. A team led by Massachusetts General Hospital (MGH) researchers is reporting that treatment with abatacept (Orencia) appeared to halt the course of focal segmental glomerulosclerosis (FSGS) in five patients, preventing four from losing transplanted kidneys and achieving disease remission in the fifth. The report is being issued online in the New England Journal of Medicine to coincide with a presentation at the American Society for Nephrology annual meeting.

Repurposed drug may be first targeted treatment for serious kidney disease

Drug may guard against periodontitis, related chronic diseases

A drug currently used to treat intestinal worms could protect people from periodontitis, an advanced gum disease, which untreated can erode the structures   including bone   that hold the teeth in the jaw. The research was published ahead of print in Antimicrobial Agents and Chemotherapy. Current treatment for periodontitis involves scraping dental plaque, which is a polymicrobial biofilm, off of the root of the tooth. Despite this unpleasant and costly ordeal, the biofilm frequently grows back. But the investigators showed in an animal model of periodontitis that the drug Oxantel inhibits this growth by interfering with an enzyme that bacteria require for biofilm formation, says corresponding author Eric Reynolds, of the University of Melbourne, Australia. It does so in a dose-dependent manner, indicating efficacy.

The researchers began their search for a therapy for periodontitis by studying the symbioses of the periodontal pathogens, using genomics, proteomics, and metabolomics, in animal models of periodontitis. They soon found that the periodontal biofilm depended for growth on the availability of iron and heme (an iron-containing molecule related to hemoglobin), and that restricting these reduced levels of the enzyme, fumarate reductase. Since Oxantel (see structure)  was known to inhibit fumarate reductase in some bacteria, they then successfully tested its ability to inhibit fumarate reductase activity in Porphyromonas gingivalis, one of the major bacterial components of periodontitis biofilms. Fumarate reductase is absent from humans, making it an ideal drug target.

They also showed that Oxantel disrupted the growth of polymicrobial biofilms containing P. gingivalis, Tannerella forsythia, and Treponema denticola, a typical composition of periodontal biofilms, despite the fact that the latter alone is unaffected by Oxantel.

The researchers found that treatment with Oxantel downregulated six P. gingivalis gene products, and upregulated 22 gene products, all of which are part of a regulon (a genetic unit) that controls availability of heme.

Periodontitis affects an estimated 30-47 percent of the adult population with severe forms affecting 5-10 percent. It also increases the risks of diabetes, heart disease, stroke, arthritis, and dementia, says Reynolds. These risks arise due to the pathogenic bacteria that enter the blood stream from periodontitis, as well as from the chronic inflammation caused by this disease, he says. Additionally, periodontitis correlates with increased risk of cancers of the head and neck, the esophagus, the tongue, and the pancreas, the investigators report.

http://aac.asm.org/content/early/2013/10/22/AAC.01375-13

Drug may guard against periodontitis, related chronic diseases

Peptide derived from cow's milk kills human stomach cancer cells in culture

New research from a team of researchers in Taiwan indicates that a peptide fragment derived from cow's milk, known as lactoferricin B25 (LFcinB25), exhibited potent anticancer capability against human stomach cancer cell cultures. The findings, published in the Journal of Dairy Science^®, provide support for future use of LFcinB25 as a potential therapeutic agent for gastric cancer.

"Gastric cancer is one of the most common causes of cancer-related mortality worldwide, especially in Asian countries," says Wei-Jung Chen, PhD, of the Department of Biotechnology and Animal Science of National Ilan University, Taiwan Republic of China. "In general, the main curative therapies for gastric cancer are surgery and chemotherapy, which are generally only successful if the cancer is diagnosed at an early stage. Novel treatment strategies to improve prognosis are urgently needed."

Investigators evaluated the effects of three peptide fragments derived from lactoferricin B, a peptide in milk that has antimicrobial properties. Only one of the fragments, LFcinB25 reduced the survival of human AGS (Gastric Adenocarcinoma) cells in a dose-dependent and time-dependent manner.

Under a microscope the investigators could see that after an hour of exposure to the gastric cancer cells, LFcinB25 migrated to the cell membrane of the AGS cells, and within 24 hours the cancer cells had shrunken in size and lost their ability to adhere to surfaces. In the early stages of exposure, LFcinB25 reduced cell viability through both apoptosis (programmed cell death) and autophagy (degradation and recycling of obsolete or damaged cell parts). At later stages, apoptosis appeared to dominate, possibly through caspase-dependent mechanisms, and autophagy waned.

"This is the first report describing interplay between apoptosis and autophagy in LFcinB-induced cell death of cancer cells," says Dr. Chen.

Ref : http://www.journalofdairyscience.org/article/S0022-0302(13)00722-4/abstract

Peptide derived from cow's milk kills human stomach cancer cells in culture

New antifungal composition effectively inhibits wide variety of fungi

In order to overcome resistance to antifungal variety of pathogenic fungi and yeast, researchers from the University of Alicante have developed a novel and efficient antifungal composition with pharmacological applications in agriculture and food industry, among others. 

The composition, developed and patented by the UA Research Group in Plant Pathology, is based on the combined use of chitosan, or chitosan oligosaccharides (right structure, COS), antifungal agents and additives that synergistically affect the growth of a variety of pathogenic fungi.

"Chitosan is a non-toxic biopolymer, biocompatible and naturally degradable, with antibacterial, antiviral and antifungal properties obtained from chitin, the main constituent of hard body parts of invertebrates, such as the shells of shrimp, lobsters, crabs, and other marine crustaceans, and is part of the fungal cell wall," as explained by lecturer Luis Vicente López Llorca, Director of the UA Research Group in Plant Pathology and head of the research work.

"Because many fungal pathogens develop resistance to prolonged treatment with antifungal drugs, it is desirable to find alternatives for their control in medical, agricultural and those applications in which the fungi cause damage. In clinics, pathogenic fungi resistant to antifungal drugs are a major cause of mortality in patients. Chitosan and the antifungal additives, some based on the identification of molecular targets of chitosan, contribute to produce a novel alternative to control fungal diseases and in particular antifungal resistant strains" López Llorca said.

The various experiments carried out by the research group are proof of the significant synergistic effect of the combination of chitosan (or COS) and other antifungals and ARL1 gene inhibitor, in inhibiting the growth of mold and yeast . "Chitosan is nontoxic to mammals, making it suitable for use as an antifungal in various applications," Luís Vicente López adds.

New antifungal composition effectively inhibits wide variety of fungi