Friday, November 17, 2017

Onalespib could be an effective treatment for glioblastoma, preclinical studies show





AT13387.png

The targeted therapy onalespib has shown effectiveness in preclinical studies of glioblastoma by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Onalespib is designed to inhibit a molecule called HSP90. The molecule helps newly made protein molecules fold into their final functional form. A large number of receptor and DNA-damage-response proteins require HSP90 to achieve their functional conformation. In cancer cells, HSP90 can be expressed up to 10 times higher than in normal cells.

This study showed that onalespib blocked HSP90 activity and thereby reduced the expression of cell-survival proteins such as AKT and endothelial growth factor receptor in several glioma cell lines and in glioma stem cells obtained from patient tumors. This, in turn, reduced the survival, proliferation, invasion and migration of the cells.

In animal models of glioblastoma (GBM), the agent crossed the blood-brain barrier, and showed effectiveness as a single agent, and then greater effectiveness in combination with temozolomide, improving survival in both cases.
The findings are published in the journal Clinical Cancer Research.

"Our studies show that onalespib can efficiently breach the blood-brain barrier and reach tumor cells better than other HSP90 inhibitors," says principal investigator Vinay Puduvalli, MD, professor and director of the Division of Neuro-Oncology at Ohio State and a clinician-researcher at the OSUCCC – James.

"By inhibiting HSP90, onalespib disrupts several key signaling pathways that drive the proliferation, metastasis and survival of glioblastoma cells. These findings suggest that this agent, in combination with chemotherapeutic temozolomide, could be an exciting new therapy for GBM. Based on the results of this study, we have generated a clinical trial that will determine whether onalespib in combination with standard therapy is safe and effective in patients with newly diagnosed glioblastoma," he says.

Glioblastoma is the most common and deadly form of brain cancer. More than 12,000 new cases are expected to be diagnosed in 2017, with overall survival averaging 16-18 months. The disease remains incurable, largely because GBM is difficult to remove surgically, because the blood-brain barrier prevents most chemotherapy from reaching these tumors and because these tumors tend to be radiation resistant.

The study's key findings include:
  • Onalespib levels were higher in brain tissue compared with plasma after intravenous administration in a mouse model, showing that the agent can cross the blood-brain barrier.
  • Tumor cells derived from patients and implanted into a mouse model showed that onalespib plus temozolomide significantly survival compared with mice treated with a neutral agent or either agent alone.
 Ref : https://medicalxpress.com/journals/clinical-cancer-research/


Thursday, November 16, 2017

Drug 'melts away' fat inside arteries


Trodusquemine.svg 


 A new drug being trialled for treating breast cancer and diabetes has been shown to 'melt away' the fat inside arteries that can cause heart attacks and  strokes. Researchers fromthe University of Aberdeen, using pre-clinical mouse models, showedthat just a single dose of the drug (Trodusquemine) completely reversedthe effects of a disease that causes a host of heart problems.

Atherosclerosis is the build-up of fatty material inside the arteries. Over time this fatty material can grow bigger until your arteries become so narrow that not enough blood can pass through.

Atherosclerosis is the condition that causes most heart attacks and strokes. In pre-clinical tests, mice with set-in atherosclerosis, mimicking what happens in humans, had less fatty plaques in their arteries whether they had regular doses over time or just a single dose of Trodusquemine.

The drug works by stopping an enzyme called PTP1B, which is normally increased in people with obesity or diabetes and conditions involving prolonged inflammation such as sepsis, inflamed diabetic foot ulcers and allergic lung inflammation. The researchers found that it also stimulated the action of another protein (AMPK), which effectively mimics exercise and reduces chronic inflammation.

It has already been shown to be effective with diabetes and breast cancer patients but this is the first time the drug has been shown to have benefits for long-term cardiovascular disease.

The £236,000 study was funded by the British Heart Foundation. Professor Mirela Delibegovic and Dr Dawn Thompson from the University of Aberdeen's Institute of Medical Sciences who led the study said:

"All humans have some level of atherosclerosis. As you age you start to
develop these fatty streaks inside your arteries. It is a big problem
for people who are overweight or have underlying cardiovascular
conditions."

"Trodusquemine has already been trialled for treatment of diabetes and breast cancer but this is the first time it has been used in models of atherosclerosis. 

"These have only been tested at pre-clinical level, in mice, so far but the results were quite impressive and showed that just a single dose of this drug seemed to completely reverse the effects of arthrosclerosis.

"The next step is to test the ability of this drug to improve outcomes in human patients with developed atherosclerosis and cardiovascular disease".

Professor Jeremy Pearson, Associate Medical Director at the British Heart Foundation, said: "Trodusquemine is in early clinical trials for the treatment of diabetes. This study shows it can also limit the build-up of fatty atherosclerotic plaques in mice. If we see the same effect in patients, the drug may prove even more useful than currently hoped for.





 Ref : https://pubchem.ncbi.nlm.nih.gov/compound/Trodusquemine#section=2D-Structure

https://www.abdn.ac.uk/news/11280/







Drug 'melts away' fat inside arteries

Wednesday, November 15, 2017

AZD6738 found to slow some types of children's tumor growth in mouse models

Prior research has shown that cancer in children is very seldom the same as  cancer in adults—in many cases, tumors that grow in children differ markedly from tumors that grow in adults which means they require completely different types of treatment. Unfortunately, treatments for childhood tumors has progressed at a much slower pace than for adults. Just four of them, for example, have been approved for use in the U.S. over the last 25 years. One of the main ways to treat adult tumors is to apply chemicals that serve to actively reduce tumor size, an approach that has not worked well with children. To get around that problem, the researchers with this new effort have been studying a chemical that has shown an ability to stop tumor growth by preventing tumor cells from repairing their DNA.

AZD6738 Chemical Structure

The researchers began by noting that prior research had shown that many types of childhood tumors rely on a DNA pathway called nonhomologous end joining (NHEJ) to survive. That led them to search for a chemical that would disrupt the pathway, preventing the cell from repairing its own DNA. Such tumors, the researchers noted, appear to depend on NHEJ to help them overcome problems with handling the excess amounts of an enzyme called PGBD5 they produce.

After finding that applying the chemical AZD6738 to tumor cells directly prevented them from growing, the team then began testing it in mouse models (mice with human tumor cells implanted in them). They report that doing so caused two types of tumors to stop growing but did not work against two others. While promising, the researchers acknowledge that the chemical is not likely to represent a means for destroying tumors in human patients even if it were to pass clinical trials. It stops growth but does not decrease tumor size. But that would of course still be a far better outcome for treating patients who have no other options. 


AZD6738 found to slow some types of children's tumor growth in mouse models

Tuesday, November 14, 2017

Caffeine consumption may help kidney disease patients live longer

In continuation of my update on caffeine..

2D structure of caffeine
Caffeine consumption may prolong the lives in patients with chronic kidney disease (CKD), according to a study that will be presented at ASN Kidney Week 2017 October 31-November 5 at the Ernest N. Morial Convention Center in New Orleans, LA.  

Coffee consumption has been linked to a longer life in the general population. To see if this holds true for individuals with CKD, Miguel Bigotte Vieira, MD (Centro Hospitalar Lisboa Norte, in Portugal), and his colleagues examined the association of caffeine consumption with mortality among 2328 patients with CKD in a prospective US cohort, using the continuous National Health and Nutrition Examination Survey(NHANES) 1999-2010.

The team found a dose-dependent inverse association between caffeine and all-cause mortality. Compared with those in the lowest quartile of caffeine consumption, those in the second, third, and highest quartiles had 12%, 22%, and 24% lower risks of dying.

"Our study showed a dose-dependent protective effect of caffeine consumption on mortality among patients with CKD. This association was independent of potential confounders including age, gender, race, annual family income, education level, estimated GFR, albumin/creatinine ratio, hypertension, smoking status, dyslipidemia, body mass index, previous cardiovascular events and diet: consumption of alcohol, carbohydrates, polyunsaturated fatty acids, and fibers," said Dr. Bigotte Vieira. 

"These results suggest that advising patients with CKD to drink more caffeine may reduce their mortality. This would represent a simple, clinically beneficial, and inexpensive option, though this benefit should ideally be confirmed in a randomized clinical trial." Dr. Bigotte Vieira stressed that this observational study cannot prove thatcaffeine reduces the risk of death in patients with CKD, but onlysuggests the possibility of such a protective effect.

Friday, November 10, 2017

'Intelligent' nanoparticles could help treat cancer patients




Scientists from the University of Surrey have developed 'intelligent'  nanoparticles which heat up to a temperature high enough to kill  cancerous cells - but which then self-regulate and lose heat before they get hot enough to harm healthy tissue.
The self-stopping nanoparticles could soon be used as part of  hyperthermic-thermotherapy to treat patients with cancer, according to  an exciting new study reported in Nanoscale. Thermotherapy has long been used as a treatment method for cancer, but it is difficult to treat patients without damaging healthy cells. However, tumor cells can be weakened or killed without affecting normal tissue if temperatures can be controlled accurately within a range of 42°C to 45 °C.
This could potentially be a game changer in the way we treat people who have cancer . If we can keep cancer treatment sat at a temperature level high enough to kill the cancer, while low enough to stop harming healthy tissue, it will prevent some of the serious side effects of vital treatment.
It's a very exciting development which, once again, shows that the University of Surrey research is at the forefront of nanotechnologies - whether in the field of energy materials or, in this case, healthcare. Dr. Wei Zhang, Associate Professor from Dalian University of Technology said Magnetic induced hyperthermia is a traditional route of treating  malignant tumors. However, the difficulties in temperature control has significantly restricted its usage If we can modulate the magnetic  properties of the nanoparticles, the therapeutic temperature can be  self-regulated, eliminating the use of clumsy temperature monitoring and controlling systems.
By making magnetic materials with the Curie temperature falling in the range of hyperthermia temperatures, the self-regulation of therapeutics can be achieved. For the most magnetic materials, however,  the Curie temperature is much higher than the human body can endure. By  adjusting the components as we have, we have synthesized the nanoparticles with the Curie temperature as low as 34 °C. This is a major nanomaterials breakthrough.

Ref: