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Terça-feira, 21.07.15

Novel cancer drug candidate developed in Singapore advances into clinical trials

 

Novel cancer drug candidate developed in Singapore advances into clinical trials

Published on July 17, 2015 at 2:01 AM

A made-in-Singapore cancer drug has advanced into clinical trials, charting a milestone in Singapore's biomedical sciences initiative that will go towards improving the lives of cancer patients in Singapore, and worldwide. The Agency for Science, Technology and Research (A*STAR) and Duke-National University of Singapore Graduate Medical School (Duke-NUS) today announced the start of a Phase I clinical trial of novel cancer drug candidate, ETC-159. This is the first publicly-funded drug candidate discovered and developed in Singapore to advance into first-in-human trials, and will target a range of cancers. Overall, cancer is the leading cause of death in Singapore, accounting for 30 percent of deaths in 2013. Cancer has also resulted in 8.2 million deaths world-wide .

ETC-159 targets a number of cancers including colorectal, ovarian and pancreatic cancers which contribute to a significant proportion of Singapore's cancer burden. These cancers are linked to a group of cell signalling pathways known as Wnt signalling, that have been identified to promote cancer growth and spread when elevated or dysregulated. As ETC-159 is an inhibitor of these pathways, it could suppress cancer proliferation and prevent cancer progression.

This drug candidate therefore offers a promising novel and targeted cancer therapy that could shape future cancer therapeutic strategies.

ETC-159 was discovered and developed through a collaboration between A*STAR's Experimental Therapeutics Centre (ETC), Drug Discovery and Development (D3) unit and Duke-NUS since 2009. This was based on the discovery work of Prof David Virshup from Duke-NUS, who has continued to contribute to the development of the drug candidate.

The Phase I clinical trial will evaluate the safety and tolerability of ETC-159 in advanced solid tumours of up to 58 patients. The first patient was dosed on 18 June 2015.

Dr Benjamin Seet, Executive Director of A*STAR's Biomedical Research Council, said, "This breakthrough, which closely follows local company MerLion Pharmaceuticals' recent success in obtaining FDA approval for one of its drugs, marks an inflection point in Singapore's biomedical sciences initiative. Despite the protracted process of drug discovery and development, I am confident that we will see more locally developed drugs in the pipeline being tested and implemented."

Prof Ranga Rama Krishnan, Chairman of the National Medical Research Council (NMRC), Singapore, said, "The first dosing of a drug developed by A*STAR based on a scientific discovery by Duke-NUS researchers, is an example of the terrific and exciting progress that has been made when different entities come together to work on a common problem. This will lead to developing new treatments that can benefit patients in Singapore and beyond."

Prof Alex Matter, Chief Executive Officer of ETC and D3 said, "The discovery and subsequent development of this drug candidate marks a major breakthrough in cancer therapeutics. It also demonstrates the world-class drug discovery and development capabilities we have built up at ETC and D3, complemented by valued partners like Duke-NUS. We will continue to strengthen these capabilities and partnerships to continue developing a pipeline of promising drug candidates and advancing them into the clinic."

Prof David Virshup, inaugural Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS, said, "As the drug candidate provides a targeted cancer therapy, it could potentially minimise side effects and make cancer treatments more bearable for cancer patients. This is a major milestone that was made possible by Singapore's ongoing investment in basic and translational biomedical research to address unmet medical needs. It is fitting that Singaporeans might be the first to benefit from this Singapore-developed drug."

A*STAR's ETC and Duke-NUS are the primary drivers of the discovery and development of the drug candidate. D3 joined the collaboration in 2013 to bring the project forward to achieve proof of concept in humans.

D3 has obtained ethics and regulatory approval for this trial from the SingHealth Centralised Institutional Review Board (CIRB) and the Singapore Health Sciences Authority (HSA) respectively. The first two sites for the trial are the National Cancer Centre Singapore (NCCS) and the National University Hospital (NUH), Singapore. Trial sites in the United States will be opened as the trial progresses.

Source:

Biomedical Sciences Institutes (BMSI)

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por cyto às 18:15

Terça-feira, 21.07.15

Patients' own genetically engineered immune cells show significant success against multiple myeloma

 

Patients' own genetically engineered immune cells show significant success against multiple myeloma

Published on July 21, 2015 at 2:37 AM 

In recent years, immunotherapy has emerged as a promising treatment for certain cancers. Now this strategy, which uses patients' own immune cells, genetically engineered to target tumors, has shown significant success against multiple myeloma, a cancer of the plasma cells that is largely incurable. The results appeared in a study published online today in Nature Medicine.

Patients received an infusion of altered immune cells known as T-cells - roughly 2.4 billion of them - after undergoing a stem cell transplantation of their own stem cells. In 16 of 20 patients with advanced disease, there was a significant clinical response. The scientists found that the T-cell therapy was generally well-tolerated and that modified immune cells traveled to the bone marrow, where myeloma tumors typically are found, and showed a long-term ability to fight the tumors. Relapse was generally associated with a loss of the engineered T-cells.

"This study suggests that treatment with engineered T-cells is not only safe but of potential clinical benefit to patients with certain types of aggressive multiple myeloma," says first author Aaron P. Rapoport, MD, the Gary Jobson Professor in Medical Oncology at the University of Maryland School of Medicine. "Our findings provide a strong foundation for further research in the field of cellular immunotherapy for myeloma to help achieve even better results for our patients."

The trial is the first published use of genetically modified T-cells for treating patients with multiple myeloma. The approach has been used to treat leukemia as well as lymphoma, according to Dr. Rapoport, who is the Director of the Blood and Marrow Transplant Program at the University of Maryland Marlene and Stewart Greenebaum Cancer Center.

More than 77,000 people in the United States have multiple myeloma, with about 24,000 new cases diagnosed each year. Patients are treated with chemotherapy and in many cases an autologous stem cell transplant, but long-term response rates are low, and median survival is three to five years.

"The majority of patients who participated in this trial had a meaningful degree of clinical benefit," Dr. Rapoport notes. "Even patients who later relapsed after achieving a complete response to treatment or didn't have a complete response had periods of disease control that I believe they would not have otherwise experienced. Some patients are still in remission after nearly three years."

The research is a collaboration between the University of Maryland School of Medicine, the Perelman School of Medicine at the University of Pennsylvania and Adaptimmune, a clinical stage biopharmaceutical company which owns the core T-cell receptor technology and funded the study. Dr. Rapoport and co-authors Edward A. Stadtmauer, MD, of the University of Pennsylvania Abramson Cancer Center, and Gwendolyn K. Binder-Scholl, PhD, of Adaptimmune, contributed equally to the research. Dr. Rapoport is the study's principal investigator.

In the clinical study, patients' T-cells were engineered to express an affinity-enhanced T-cell receptor (TCR) specific for a type of tumor antigen, or protein, known as a cancer-testis antigen (CT antigen). The target CT antigens were NY-ESO-1 and LAGE-1. Up to 60 percent of advanced myelomas have been reported to express NY-ESO-1 and/or LAGE-1, which correlates to tumor proliferation and poorer outcomes. According to Adaptimmune, the trial is the first published study of lentiviral vector mediated TCR gene expression in humans.

Of the 20 patients treated, 14 (70 percent) had a near complete or complete response three months after treatment. Median progression-free survival was 19.1 months and overall survival was 32.1 months. Two patients had a very good partial response three months post treatment. Half the patients were treated at the University of Maryland Greenebaum Cancer Center and half at the University of Pennsylvania Abramson Cancer Center. Researchers note that the response rate was better than would be expected for a standard autologous stem cell transplant. In addition, patients did not experience side effects which have been associated with another type of genetically engineered T-cells (chimeric antigen receptors, or CARS) used to treat other cancers.

The study was originally developed by Carl H. June, MD, of the University of Pennsylvania Abramson Cancer Center, and Dr. Rapoport, who have been research collaborators for 18 years.

"Multiple myeloma is a treatable but largely incurable cancer. This study reveals the promise that immunotherapy with genetically engineered T-cells holds for boosting the body's ability to attack the cancer and provide patients with better treatments and control of their disease," says E. Albert Reece, MD., PhD, MBA, vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. "This trial is also an excellent example of significant scientific advances that result from collaborations between academic medical institutions and private industry."

Source:

University of Maryland Medical Center

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por cyto às 18:10

Sábado, 04.07.15

Harvard Medical School scientists reveal structure of vesicular stomatitis virus protein

Harvard Medical School scientists reveal structure of vesicular stomatitis virus protein

Published on July 3, 2015 at 5:17 AM 

Viruses need us. In order to multiply, viruses have to invade a host cell and copy their genetic information. To do so, viruses encode their own replication machinery or components that subvert the host replication machinery to their advantage.

Ebola virus and rabies virus, two of the most lethal pathogens known to humans, belong to an order of RNA viruses that share a common strategy for copying their genomes inside their hosts. Other relatives include Marburg virus, measles, mumps, respiratory syncytial virus and vesicular stomatitis virus (VSV). Scientists study VSV, which causes acute disease in livestock but typically does not lead to illness in people, as a model for viruses that are harmful to humans.

Now a team from Harvard Medical School, using electron cryomicroscopy (imaging frozen specimens to reduce damage from electron radiation), has for the first time revealed the structure of a VSV protein at the atomic level. Called polymerase protein L, it is required for viral replication in this group of RNA viruses. The findings are published in Cell.

"We now have a better understanding of how RNA synthesis works for these viruses," said Sean Whelan, HMS professor of microbiology and immunobiology and senior author of the paper. "I think if you were trying to develop a viral-specific target to block the replication of one of these viruses, having the structure of the polymerase protein would help."

Scientists already know how these RNA viruses infect cells. They start by delivering a large protein RNA complex, which is viral RNA enclosed in a protein coat. The protein that copies viral RNA is polymerase protein L, which conducts all the enzymatic activities needed to synthesize RNA and then add a cap structure to its end to ensure it doesn't get destroyed by the cell--and to ensure that it can be translated into protein.

While researchers have known the atomic structures of the protein that coats the viral RNA, there are no data on protein L's atomic structure.

Antiviral drugs that target polymerase molecules are based in part on knowing their structure. That approach has been successful against HIV and herpes and hepatitis C viruses. But for the class of viruses known as nonsegmented negative-strand RNA viruses, finding the structure of polymerase protein L has been challenging.

The "L" stands for large. Larger proteins are often difficult to produce and to purify, Whelan said. Protein L is also flexible, with many functional fragments that are hard to isolate. The viruses evolved to make only small quantities of this protein.

Five years ago, using a lower-resolution form of electron microscopy in which the protein is visualized in the presence of negative stain, Whelan's team was able to detect at low resolution a structure that looked like a doughnut with three globular domains. Those earlier studies were informative, but the approach could not provide the atomic level of resolution the team ultimately needed.

Advances in electron cryomicroscopy encouraged them to try again. A team from Whelan's lab, working with a group led by Stephen Harrison, Giovanni Armenise - Harvard Professor of Basic Biomedical Science at HMS and a Howard Hughes Medical Institute (HHMI) investigator, was able to collect data from their viral samples that gave them much greater resolution. They also were able to align the images they collected into a three-dimensional model of polymerase protein L.

Into the density map obtained from these studies, members of the team built an atomic model of the polypeptide chain of VSV L protein. Solving this puzzle was a significant challenge and also involved the team of Nikolaus Grigorieff at HHMI's Janelia campus.

The result? An atomic level model of polymerase protein L's structure for VSV, which will form the basis for understanding the L protein of the other viruses in the order.

"The Ebola protein will look the same, the rabies protein will look the same, the other L proteins will look the same," Whelan said. "There will be some subtle differences reflecting the precise nature of amino acids, but we know that they're functionally and structurally the same."

Knowing the structure means scientists can explore how RNA synthesis is working in these viruses.

"It begins to suggest ways that we can perhaps pull apart other proteins that have not been so easy to express, such as the L protein in Ebola," Whelan said. "It doesn't mean we're going to have inhibitors immediately, but this is an important step, I think, towards that longer-term goal."

Source:

Harvard Medical School

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por cyto às 11:37


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