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Terça-feira, 02.02.16

Afatinib Demonstrates Activity in EGFR Mutation-positive NSCLC

Afatinib Demonstrates Activity in EGFR Mutation-positive NSCLC

Afatinib may demonstrate clinical activity in patients with EGFR mutation-positive non-small cell lung cancer and brain metastasis.
Afatinib may demonstrate clinical activity in patients with EGFR mutation-positive non-small cell lung cancer and brain metastasis.

Afatinib may demonstrate clinical activity in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) and asymptomatic brain metastasis, according to a study published in the Journal of Thoracic Oncology.

Researchers led by Martin Schuler, MD, of the University Duisburg-Essen in Germany looked at results of a phase 3 study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) as well as a randomized, open-label phase 3 study of BIBW 2992 vs chemotherapy as first-line treatment for patients with stage 3B or 4 adenocarcinoma of the lung with EGFR-activating mutation (LUX-Lung 6).

In both studies, prespecific subgroup analyses were conducted for progression-free survival, overall survival, and objective response rate in patients with asymptomatic brain metastases at baseline.

 

RELATED: Adding Selumetinib to Erlotinib Does Not Improve Advanced NSCLC Outcomes

The researchers noted a trend toward improved progression-free survival with afatinib compared to chemotherapy in both studies among patients with brain metastases, with a similar magnitude in progression-free survival improvement with afatinib among patients without brain metastases.

Upon combined analysis, progression-free survival was significantly improved with afatinib compared with chemotherapy in patients with brain metastases. Afatinib was also found to improve objective response rate compared to chemotherapy in these patients.

Reference

  1. Schuler M, Wu Y, Hirsh V, et al. First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases [published online ahead of print January 24, 2016]. J Thorac Oncol. doi: http://dx.doi.org/10.1016/j.jtho.2015.11.014.

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por cyto às 20:51

Terça-feira, 02.02.16

Nivolumab Plus Ipilimumab Approved for Melanoma Regardless of BRAF Status

Nivolumab Plus Ipilimumab Approved for Melanoma Regardless of BRAF Status

 
The FDA approved nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of patients with melanoma.
The FDA approved nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of patients with melanoma.

The U.S. Food and Drug Administration (FDA) approved nivolumab (Opdivo) plus ipilimumab (Yervoy) for the treatment of patients with BRAF V600 wild-type andBRAF V600 mutation-positive unresectable or metastatic melanoma.

This approval expanded the original indication for the immunotherapy combination for the treatment of BRAFwild-type unresectable or metastatic melanoma to include patients with BRAFmutation-positive disease.1

The FDA also expanded the use of single-agent nivolumab to include treatment-naïve patients with BRAF­ mutation-positive advanced melanoma. It was previously approved for only those with BRAF V600 wild-type disease.

“For nearly a decade, our researchers have worked tirelessly to find treatment options that could improve outcomes for patients with late-stage melanoma, a particularly aggressive cancer, and we are incredibly proud of today's approval to expand the use of the Opdivo + Yervoy Regimen to include patients with BRAF mutation-positive unresectable or metastatic melanoma,” said Chris Boerner, Head of US Commercial, Bristol-Myers Squibb.

Approval is based on findings from the phase 3 CheckMate-067 trial. The study demonstrated a statistically significant improvement in progression-free survival in both patients with BRAF V600 mutant and wild-type advanced melanoma treated with nivolumab and ipilimumab and with single-agent nivolumab compared with ipilimumab alone. Both treatments also resulted in higher confirmed objective response rates than ipilimumab monotherapy.

In the study, serious adverse reactions, adverse reactions resulting in treatment discontinuation or dosing delays, and grade 3 or 4 adverse events were all more common in the combination arm compared with nivolumab alone. The most common adverse events with the immunotherapy combination were fatigue, rash, diarrhea, nausea, pyrexia, vomiting, and dyspnea.

 

RELATED: Narrow Excision Margins Not Superior to Larger Margins for Cutaneous Melanoma

“CheckMate-067 is the first phase 3 study to observe the efficacy and safety of both Opdivo as a single-agent as well as in combination with Yervoy versus Yervoy alone,” Boerner said.

“The melanoma community is excited to see the ongoing developments in research from the pharmaceutical industry, including Bristol-Myers Squibb, who made the first approved combination of 2 immuno-oncology treatments available to more patients fighting this disease,” said Tim Turnham, executive director, Melanoma Research Foundation.

“Today's expanded approvals continue to bring new treatment options to patients, and demonstrate the ongoing impact of immuno-oncology research.”

Reference

  1. Bristol-Myers Squibb's Opdivo (nivolumab) + Yervoy (ipilimumab) regimen receives expanded FDA approval in unresectable or metastatic melanoma across BRAF status [news release]. Princeton, NJ: Bristol-Myers Squibb; January 23, 2016. http://news.bms.com/press-release/bmy/bristol-myers-squibbs-opdivo-nivolumab-yervoy-ipilimumab-regimen-receives-expanded. Accessed January 25, 2016.

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por cyto às 20:42

Terça-feira, 02.02.16

MD Anderson Researchers Discover that Glucose Starvation May Be Vital to Tumor Suppression

MD Anderson Researchers Discover that Glucose Starvation May Be Vital to Tumor Suppression

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Dr. Junjie Chen, Ph.D., chair of Experimental Radiation Oncology at The University of Texas MD Anderson Cancer Center (MD Anderson) and his team of collaborating investigators recently published an important study that could create new opportunities for the successful treatment of cancerous tumors.  The study entitled “AMPK modulates Hippo pathway activity to regulate energy homeostasis” was published in the latest online edition ofNature Cell Biology.

Background Terminology:

  • Cell-signaling pathway: a system of cellular communication that governs cellular actions such as the ability of cells to perceive and correctly respond to their microenvironment by coordinating cellular activities like tissue repair, immune response, as well as normal tissue functioning.
  • Glucose: the human body’s key source of energy utilized through the breakdown of carbohydrates.
  • Adenosine triphosphate (ATP): known as the cells “unit of currency” for the chemical energy in various nutrients, such as glucose, is transferred to ATP. In this form it can be transported to provide the energy needed to carry out metabolic functions.

Cell-signaling pathways are very important in cancer research because everything at the beginning of the pathway has an impact on all processes leading to the final signal.  This impact can undermine the body’s normal molecular reactions such as breaking down blood sugar for energy, or in the case of cancer, feeding a tumor.

About the Study

In this study, investigators uncovered new evidence as to the relationship between the Hippo pathway, a key cell-signaling pathway for tissue overgrowth, and the regulation of cellular metabolism of glucose to ATP.  The evidence suggests that the Hippo pathway can be manipulated to regulate glucose, which feeds all tumor cells, thereby presenting new opportunities for cancer therapy.

 

Dr. Chen and his team uncovered this evidence by:

 

  • Experimentally starving cells of glucose, which activated the AMPK enzyme that deactivated YAP, a protein that has been previously shown to promote cancer growth.
  • This deactivation was a product of YAP’s regulation of a gene called GLUT3, which is involved in glucose metabolism.
  • This experimental result revealed a new role for YAP as a link between the Hippo pathway and the nutrient metabolism that allows cancer to metastasize.

In a press release about the study’s findings, Dr. Chen stated, “We have identified cross-talk between glucose metabolism and the Hippo pathway. This is a previously unknown function of the Hippo pathway in glucose metabolism. It is highly significant because it established a connection between a pathway involved in organ size control and nutrient availability. The discovery of AMPK’s effect on YAP extends our understanding of YAP regulation outside of the Hippo pathway. Our study proposes yet another cancer-related function of YAP. This provides an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention.”

Dr. Chen’s laboratory works to understand the molecular mechanisms underlying tumorigenesis. He and his team plan to use the evidence from this study to continue their investigations of the molecular mechanisms that promote metastasis.

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por cyto às 20:35

Terça-feira, 02.02.16

Potential Therapeutic Targets for Multiple Sclerosis Identified at MD Anderson

Potential Therapeutic Targets for Multiple Sclerosis Identified at MD Anderson

A study conducted by researchers at The University of Texas MD Anderson Cancer Centeridentified a protein regulator called Trabid as a key player on the complex chain of events that lead to autoimmune inflammation of the central nervous system (CNS) in patients with multiple sclerosis (MS).

The study, “Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid,” was published in the online issue of Nature Immunology.

Dr. Shao-Cong Sun, professor of immunology and the study’s senior author, and his team found that the removal of a protein-coding gene named Zranb1 – which encodes Trabid – in dendritic cells inhibited the expression of interleukin (IL)-12 and IL-23, inhibiting differentiation of inflammatory immune T-cells.

Both IL-12 and IL-23 are mediators of inflammation and associated with inflammatory diseases.

“Cells of the innate immune system, including dendritic cells and macrophages, have an important role in regulating the nature and magnitude of adaptive immune responses,” Sun said in a press release. “They recognize microbial components including various receptors that trigger intracellular signaling events that impact the function of those cells. Deregulated production of pro-inflammatory cytokines by cells of the innate immune system also contributes to autoimmune and inflammatory diseases.”

IL-12 and IL-23 are pro-inflammatory cytokines that connect innate responses and immune responses, according to the study’s authors. The innate immune system — the nonspecific immune system — is a critical subcategory of the overall immune system, and includes mechanisms and cells that shield the host against infection by foreign bodies.

“Our findings highlight an epigenetic mechanism for the regulation of the cytokine genes, IL-12 and IL-23, and established Trabid as an immunological regulator of inflammatory T-cell responses,” Sun said. “Trabid appeared to regulate histone modifications by controlling the fate of a histone demethylase called Jmjd2d.”

Sun believes that Trabid and Jmjd2d may be potential therapeutic targets for the treatment of inflammatory diseases, such as MS and cancer. “Since chronic inflammation is a major risk of cancer, future studies will examine whether Trabid and Jmjd2d also have a role in cancer development,” he said.

MS is a devastating inflammatory disease estimated to affect 2.3 million people worldwide. Inflammation is an important part of the body’s response against infections and tissue damage, but unresolved inflammation contributes to the pathogenesis of a variety of diseases and promotes cancer development.

MS and other inflammatory diseases may benefit from new findings identifying potential therapeutic targets such as Trabid.

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por cyto às 20:26

Terça-feira, 02.02.16

Combination HIV Antiretroviral Treatment Could Reduce Medication Frequency

Combination HIV Antiretroviral Treatment Could Reduce Medication Frequency

 

A combination treatment designed to protect the nervous system from HIV may be able to rid the body of HIV for months, allowing patients to replace daily medication with treatment taken several times a year.

Researchers supported by the National Institutes of Health (NIH), led by Harris Gelbard, MD, PhD, at the University of Rochester School of Medicine and Dentistry, developed the URMC-099 compound to protect against neurologic damagecaused by HIV. The compound is anti-inflammatory and has been shown to protect neuronal tissue. 

“Our ultimate hope is that we're able to create a therapy that could be given less frequently than the daily therapy that is required today,” said Dr Gelbard. “If a drug could be given once every six months or longer, that would greatly increase compliance, reduce side effects, and help people manage the disease, because they won't have to think about taking medication every day.”

Dr Gelbard and his team used a class of protease inhibitors developed by researchers at the University of Nebraska Medical Center, led by Howard Gendelman, MD. Researchers used nanotechnology to reconstitute the compound to increase its ability to target tissue. They transformed the drug into crystal form and added a protective coat.

This nano-antiretroviral therapy (nanoART) helps to penetrate immune cells and form areas of antiretroviral activity.

Researchers reasoned that the URMC-099 compound could act as a supplement taken with antiretroviral medication because of the compound's anti-inflammatory effects. They tested the combination therapy on HIV-infected mice who were introduced to human immune stem cells.

The combination therapy significantly decreased levels of HIV compared to using nanoART therapy alone.  In some cases, the therapy decreased HIV levels below detectability. It also increased the ability of nanoART to create antiretroviral depots of immune cells, which could inhibit HIV replication.

“The NIH Office of AIDS Research has identified the development of long acting HIV therapies and research towards a cure as high priority topics for research support,” noted Dianne Rausch, PhD, director of NIMH's Division of AIDS Research.  

“The nanoformulation strategies reported here could facilitate targeting HIV anatomic reservoirs such as lymph nodes and brain which are currently difficult to reach because of limited penetration of anti-retroviral drugs into tissue compartments.”

Reference

National Institute of Mental Health. Experimental Combination Surprises with Anti-HIV Effectiveness. January 20, 2016. http://www.nimh.nih.gov/news/science-news/2016/experimental-combination-surprises-with-anti-hiv-effectiveness.shtml. Accessed January 25, 2016.

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por cyto às 20:22


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