Researchers reveal how melanoma becomes resistant to promising new drug combo therapy

In a new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Roger Lo, researchers have uncovered how melanoma becomes resistant to a promising new drug combo therapy utilizing BRAF+MEK inhibitors in patients after an initial period of tumor shrinkage.

During the new two-year study, Lo and his team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitor combo drugs and then after they relapsed due to the melanoma developing drug resistance. The participants had all benefited from the combo therapy initially, but after periods of time the tumors regressed.

All the tumors biopsied from the patients were subjected to in-depth analysis of the genetic material extracted from the tumors. This analysis of patient-derived tumors then provided leads for the investigators to study how melanoma cells grown in Lo's laboratory rewired their growth circuitry to get around the combo inhibitors.

Researchers reveal how melanoma becomes resistant to promising new drug combo therapy

Study suggests that antibiotics may help fight norovirus

Antibiotics aren't supposed to be effective against viruses. But new evidence in mice suggests antibiotics may help fight norovirus, a highly contagious gastrointestinal virus, report scientists at Washington University School of Medicine in St. Louis.

The researchers found antibiotics could help prevent norovirus infections. The same team also showed that a recently identified immune system molecule can cure persistent norovirus infections even in mice with partially disabled immune systems. The surprising findings, available online in Science, will appear Jan. 16 in the journal's print edition.

Outbreaks of norovirus are notoriously difficult to contain and can spread quickly on cruise ships and in schools, nursing homes and other closed spaces.

The researchers found that norovirus works its way into gut tissue in mice that have been pretreated with antibiotics but that the virus cannot establish a persistent infection. Follow-up studies showed that norovirus needs a bacterial collaborator to establish a persistent infection in the gut. Eradicating the bacterial partner with an antibiotic can prevent persistent norovirus infection in mice.

"The virus actually requires the bacteria to create a persistent infection," said senior author Herbert W. Virgin IV, MD, PhD, the Edward Mallinckrodt Professor of Pathology and head of the Department of Pathology and Immunology. "The virus appears to have a symbiotic relationship with the bacteria they share the job of establishing persistence."

Study suggests that antibiotics may help fight norovirus

TSRI scientists identify novel synthetic compound that reduces activity of a cancer-related protein

Scientists from the Florida campus of The Scripps Research Institute (TSRI) have identified a novel synthetic compound that sharply inhibits the activity of a protein that plays an important role in in the progression of breast and pancreatic cancers.

In the new study, to be published in the February 2015 print edition of the journal Molecular Pharmacology, the scientists showed that the compound, known as SR1848, reduces the activity and expression of the cancer-related protein called "liver receptor homolog-1" or LRH-1.

"Our study shows that SR1848 removes LRH1 from DNA, shutting down expression of LRH-1 target genes, and halts cell proliferation," said Patrick Griffin, chair of the TSRI Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida. "It's a compound that appears to be a promising chemical scaffold for fighting tumors that are non-responsive to standard therapies."

TSRI scientists identify novel synthetic compound that reduces activity of a cancer-related protein

FDA grants orphan drug status to NBI-77860 for treatment of congenital adrenal hyperplasia

Neurocrine Biosciences, Inc. (NASDAQ: NBIX) announced that NBI-77860, a proprietary corticotropin releasing factor 1 (CRF) receptor antagonist, has been granted orphan drug status by the United States Food and Drug Administration (FDA) for the treatment of congenital adrenal hyperplasia (CAH) a disease that affects approximately 20,000-30,000 people in the United States.

"We are very pleased that the FDA has granted NBI-77860 orphan status to treat congenital adrenal hyperplasia, a devastating disease that is a significant challenge for both clinicians and patients," said Malcolm Lloyd-Smith, Chief Regulatory Officer of Neurocrine Biosciences. "This status represents a significant regulatory milestone for the CAH program and underscores the importance of bringing a safe and effective CAH therapy to market. We look forward to the results from our recently initiated 1401 Study of adolescents with classic CAH, in 2015."

FDA grants orphan drug status to NBI-77860 for treatment of congenital adrenal hyperplasia

Long-acting drug effectively prevents HIV-like infection in monkeys

Cabotegravir (USAN  and INN ) (also known as S/GSK1265744 or previously referred to by the research code GSK744) is an investigational new drug under development for the treatment of HIV infection. It is an integrase inhibitor, with a carbamoyl pyridone structure similar to dolutegravir. In investigational studies, the agent has been packaged intonanoparticles (GSK744LAP) conferring an exceptionally long half-life of 21–50 days following a single dose. In theory, this would make possible suppression of HIV with dosing as infrequently as once every three months.

-------------------------------------------------------------------------------
HIV researchers hope a new compound, known as cabotegravir, could make dosing easier for some because the drug would be administered by injection once every three months. A clinical trial testing long-acting cabotegravir's safety and acceptability has already begun at multiple U.S. sites including The Rockefeller University Hospital. Meanwhile two new studies, including one conducted by researchers at the Aaron Diamond AIDS Research Center (ADARC) and Rockefeller University, published today (January 15) inScience Translational Medicine, show that long-acting cabotegravir injections are highly protective in a monkey model of vaginal transmission of a virus similar to HIV.

"Clinical trial results have demonstrated that the effectiveness of preventive oral medications can range with results as high as 75 percent effective to as low as ineffective, and a lot of that variability appears to hinge on the patient's ability to take the pills as prescribed," says study researcher Martin
Markowitz, a professor at Rockefeller University and ADARC. "Long acting cabotegravir has the potential to create an option that could improve adherence by making it possible to receive the drug by injection once every three months."

Developed by ViiV Healthcare and GlaxoSmithKline, and previously known as GSK744 LA, cabotegravir is an antiretroviral drug. Antiretrovirals interfere with HIV's ability to replicate itself using a host cell and they are used to treat an HIV infection or to prevent those at high risk from acquiring it in the first place.

Long-acting drug effectively prevents HIV-like infection in monkeys 

In continuation of my update on Century-old drug reverses autism-like symptoms in fragile X mouse model.

In continuation of my update on Suramin

Researchers previously reported that a drug used for almost a century to treat trypanosomiasis, or sleeping sickness, reversed environmental autism-like symptoms in mice. Now, a new study suggests that a genetic form of autism-like symptoms in mice are also corrected with the drug, even when treatment was started in young adult mice.

Century-old drug reverses autism-like symptoms in fragile X mouse model  

Venom of cone snails provides leads for possible treatment of cancer...

There are approximately 500 known species in the genus Conus, and each have their own distinct venom.  These toxins are aptly named conotoxins.  Conotoxins are small, structured peptide toxins.  This means they are bonded by peptide bonds, which are bonds between the carboxylic end of one amino acid to the amine end of another.  These peptides work by targeting and blocking ion channels of either the voltage-gated or ligand-gated class.  These ion channels are where action potentials in neurons are created.  Therefore, if no ions can get through to the neuron, no action potentials can be made and sent to other neurons, and the prey organism is paralyzed.  It is most likely that differentConus members target different specific ion channels, depending on the animals they feed on.

While considered a delicacy in some parts of the world, snails have found a more intriguing use to scientists and the medical profession offering a plethora of research possibilities. Cone snails are marine mollusks, just as conch, octopi and squid, but they capture their prey using venom. The venom of these marine critters provides leads for detection and possible treatment of some cancers and addictions. Frank Marí, Ph.D., professor in the Department of Chemistry and Biochemistry in FAU's Charles E. Schmidt College of Science at Florida Atlantic University, has focused his research on cone snail venom and has published a study in the current issue of the Journal of Biological Chemistry.

"The venom produced by these animals immobilizes prey, which can be worms, other snails and fish," said Marí. "The venom is an extraordinary complex mixture of compounds with medicinal properties."

Venom of cone snails provides leads for possible treatment of cancer, addiction

PF-114 shows promise in therapy-resistant CML, Ph-positive ALL

PF-114, a selective tyrosine kinase inhibitor (TKI), is active against native and mutated forms of the BCR–ABL oncogene in Philadelphia chromosome (Ph)-positive leukaemias, according to preclinical cellular and in vivo results published in Leukemia.

Martin Ruthardt, from Goethe University in Frankfurt, Germany, and colleagues found that PF-114 was more selective than the second-generation TKIs dasatinib and nilotinib as well as the third-generation TKI ponatinib, which they speculate could reduce the potential for adverse effects.

At a 100 nM concentration, equivalent to an active plasma concentration, PF-114 inhibited at least 90% activity of 11 kinases compared with 47 and 36 kinases suppressed by ponatinib and dasatinib, respectively. Nilotinib blocked only four kinases at this concentration, but extrapolating the data to its clinically relevant concentration of 4 µM resulted in the number of inhibited kinases increasing to 21.

In cell-free assays, PF-114 inhibited not only native ABL kinase but also versions of the enzyme harbouring various clinically relevant mutations, including T315I. The agent also suppressed the proliferation of Ph-positive cell lines derived from patients with chronic myeloid leukaemia (CML) or acute lymphatic leukaemia (ALL).

Additionally, PF-114 was effective against patient-derived long-term cultures, including those responsive and resistant to TKIs as well as one with nonmutational TKI-resistance.

Treatment with PF-114 significantly increased the median survival of mice transplanted with cells expressing the native or T315I mutant form of p185BCR–ABL, inducing a CML-like disease, compared with untreated mice, from 28 days to 39 days and 68 to 132 days, respectively.

Ref : http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2014326a.html

PF-114 shows promise in therapy-resistant CML, Ph-positive ALL

U-M researchers identify how amlexanox drug improves metabolism of sugar

Amlexanox (trade name Aphthasol) is an anti-inflammatory antiallergic immunomodulator used to treat recurrent aphthous ulcers (canker sores), and (in Japan) several inflammatory conditions. This drug has been discontinued in the U.S

---------------------------------------------------------------------------------------------------------------------------

Researchers at the University of Michigan have identified how a promising drug in clinical trials for the treatment of obesity and related metabolic disorders improves the metabolism of sugar by generating a new signal between fat cells and the liver.

In addition to illuminating how the drug, amlexanox, reverses obesity, diabetes and fatty liver disease, the findings suggest a new pathway for future treatments. The research was published Jan.12 in Nature Communications.

Investigators in the lab of Alan Saltiel, the Mary Sue Coleman Director of U-M's Life Sciences Institute, had previously discovered that this drug, which had been used in the treatment of asthma, also has the ability to cause weight loss and improve diabetes in obese mice.

The current study revealed that amlexanox exerts its effects through a specialized type of fat cell by increasing the level of a second messenger molecule called cAMP. In turn, cAMP increases the rate by which cells "burn" fat so that the animal loses weight. But amlexanox also triggers the release of the hormone interleukin-6 from these fat cells, which then travels in the circulation to the liver. In the livers of diabetic mice, interleukin-6 reduces production of glucose, so that overall blood sugar is lowered.

"We know that amlexanox works to reverse obesity and insulin resistance in part by resolving chronic inflammation and increasing energy expenditure, but that's not the whole story of the drug's effects," said Shannon Reilly, first author of the study. "Understanding how the drug also enables crosstalk between fat cells and the liver in obese mice allows us to see more of the amlexanox picture--and also sheds light on communication between different tissues in the body."

U-M researchers identify how amlexanox drug improves metabolism of sugar

Review shows that fish compound can help combat cardiovascular disease

Urotensin-II (U-II) is a peptide ligand, initially isolated from the neurosecretory system of the Goby fish (Gillichthys mirabilis). For many years it was thought that U-II does not exhibit significant effects in mammalian systems; a view quickly overturned when it was demonstrated that Goby U-II produces slow relaxation of mouse anococcygeus muscle, in addition to contraction of rat artery segments. In 1998, the cDNA encoding a U-II precursor was cloned in humans, unequivocally demonstrating its existence in mammalian species.The vasoconstriction it induces can cause or exacerbate hypertension, congestive heart failure, and coronary artery disease.

In fish, U-II is secreted at the back part of the spinal cord, in a neurosecretory center called uroneurapophysa, and is involved in the regulation of the renal and cardiovascular systems. In mammals, it is involved in the regulation of the cardiovascular system.

-----------------------------------------------------------------------------------------------------------

A major international review of a peptide originally found in fish that could be used in the battle against cardiovascular disease has been published.

Professor David Lambert from the University of Leicester's Department of Cardiovascular Sciences contributed to the review, which has been largely written by the International Union of Basic and Clinical Pharmacology (IUPHAR) subcommittee, to pull together the vast literature on Urotensin II (UII), a peptide first isolated from teleost fish.

UII activates a G protein-coupled receptor called UT to modulate a number of signalling pathways including intracellular Calcium. Interestingly, the peptide can constrict some blood vessels yet dilate others.

The review, which is published in the high impact journal Pharmacological Reviews, has shown that UII can modulate a vast array of biologic activities encompassing the cardiovascular system, kidneys and central nervous system.

Professor Lambert said: "We have been working on this exciting peptide for a number of years; it exhibits a very interesting pharmacological profile. Design and evaluation of small molecule drugs has potential for use in the treatment of several cardiovascular diseases."

Review shows that fish compound can help combat cardiovascular disease