PAKs (p21 activated kinases) are an important class of Rho effectors which contain a Cdc42-Rac1 interaction and binding (CRIB) and a flanking auto-inhibitory domain (AID) which binds the C-terminal catalytic domain. The group II kinases PAK4 and PAK5 are considered significant therapeutic targets in cancer. Among human cancer cell lines we find PAK5 protein levels are much lower than those of PAK4, even in NCI-H446 which has the highest PAK5 mRNA expression among 317 lines screened. Although these two kinases are evolutionarily and structurally related, it has never been established why PAK4 is inactive while PAK5 has high basal activity. Experimentally, the AID of PAK5 is functionally indistinguishable from that of PAK4, pointing to other regions being responsible for higher activity of PAK5. Gel filtration indicates PAK4 is a monomer but PAK5 is dimeric. The central region of PAK5 (residues 109-420) is shown here to promote self-association, and an elevated activity, but has no effect on activation loop Ser602 phosphorylation. These residues allow PAK5 to form characteristic puncta in cells, and removing sequences involved in oligomerization suppresses kinase activity. Our model suggests PAK5 self-association interferes with AID binding to the catalytic domain, thus maintaining its high activity. Further, our model explains the observation that PAK5(1-180) inhibits PAK5in vitro.
©2016 The Author(s).

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On April 21, 2016 Helocyte, Inc. a majority-owned subsidiary of Fortress Biotech, Inc. (NASDAQ: FBIO) focused on the acquisition, development and commercialization of novel immunotherapies for the prevention and treatment of cancer and infectious disease (and in particular, cytomegalovirus or "CMV"), reported several corporate and clinical milestones (Press release, Fortress Biotech, APR 21, 2016, View Source;FID=1500083994 [SID:1234511213]).

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In June 2015, Helocyte’s Board of Directors appointed Frank Taffy as President and Chief Executive Officer (and in December 2015, as an additional member of the Board). Mr. Taffy has more than fifteen years of experience in life sciences corporate development and business operations. He identified the Helocyte programs and co-founded the company during his role as Entrepreneur in Residence at Fortress Biotech. Mr. Taffy previously held the positions of Head (Senior Director) of Business Affairs at Forest Laboratories (now Allergan) and Director of Corporate Development at Life Technologies (now Thermo Fisher Scientific), where he also held Board positions on behalf of the company. Mr. Taffy began his career as Counsel for Intellectual Property at Procter & Gamble. He holds a J.D. from Syracuse University College of Law and a B.A. in biochemistry from the University of North Texas.

In June 2015, a Phase 2 study of Helocyte’s PepVax opened for enrollment. The randomized, placebo-controlled, multicenter trial will evaluate the potential of PepVax to reduce the frequency of CMV events in 96 recipients of allogeneic hematopoietic stem cell transplant. The study is supported by funding from the National Cancer Institute. For additional information on the Phase 2 study of PepVax, please visit: View Source

In November 2015, a Phase 2 study of Helocyte’s universal Triplex opened for enrollment. The randomized, placebo-controlled, multicenter trial will evaluate the potential of Triplex to reduce the frequency of CMV events in 115 recipients of allogeneic hematopoietic stem cell transplant. The study is also supported by funding from the National Cancer Institute. For additional information on the Phase 2 study of Triplex, please visit: View Source

In November 2015, the results of a Phase 1 study of Triplex were selected for presentation at the 57th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper). Triplex is the first CMV immunotherapy that uses a recombinant Modified Vaccinia Ankara (MVA) vector incorporating multiple CMV response antigens. The Phase 1 study demonstrated the safety and marked immunogenicity of Triplex. The complete text of the ASH (Free ASH Whitepaper) abstract can be accessed at: View Source

In December 2015, the results of a Phase 1b study of PepVax were published in The Lancet Haematology. PepVax was observed to be well-tolerated, immunogenic and highly effective in controlling CMV in patients. To our knowledge, PepVax is the first immunotherapy to demonstrate proof of concept for CMV control in the post-transplant setting. PepVax further demonstrated the unexpected clinical outcomes of reduced relapse and increased survival (from underlying cancer). The full text of the Lancet publication can be accessed at: http://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(15)00246-X/abstract.

Among the various types of diseases, cancer remains one of the most leading causes of mortality that people are always suffering from and fighting with. So far, the effective cancer treatment demands accurate medical diagnosis, precise surgery, expensive medicine administration, which leads to a significant burden on patients, their families, and the whole national healthcare system around the world. In order to increase the therapeutic efficiency and minimize side effects in cancer treatment, various kinds of stimuli-responsive drug delivery systems and bioimaging platforms have been extensively developed within the past decades. Among them, the strategy of photoactivated approach has attracted considerable research interest because light enables the precise control, in a highly spatial and temporal manner, the release of drug molecules as well as the activation of bioimaging agents. In general, several appropriate photoresponsive systems, which are normally sensitive to ultraviolet (UV) or visible light irradiation to undergo the multiple reaction pathways such as photocleavage and photoisomerization strategy etc. have been mainly involved in the light activated cancer therapies. Considering the potential issues of poor tissue penetration and high photoctotoxicity of short wavelength light, the recently emerged therapies based on long-wavelength irradiation, e.g., near-infrared (NIR) light (700-1000 nm), have displayed distinct advantages in biomedical applications. The light irradiation at NIR window indicates minimized photodamage, deep penetration, and low autofluorescence in living cells and tissues, which are of clinical importance in the desired diagnosis and therapy. In this review article, we introduce the recent advances in light-activated drug release and biological imaging mainly for anticancer treatment. Various types of strategies such as photocage, photo-induced isomerization, optical upconversion, and photothermal release by which different wavelength ranges of light can play the important roles in the controlled therapeutic or imaging agents delivery, and activation will be systemically discussed. In addition, the challenges and future perspectives for photo-based cancer theranostics will be also summarized. For further resources related to this article, please visit the WIREs website.
© 2016 Wiley Periodicals, Inc.

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On April 21, 2016 – Medtronic (NYSE: MDT) reported the launch of the new BarrxTM 360 Express radiofrequency ablation (RFA) balloon catheter, which can help in the treatment of Barrett’s esophagus (Press release, Medtronic, APR 21, 2016, View Source;p=RssLanding&cat=news&id=2159148 [SID:1234511214]).

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The Barrx 360 Express catheter, with its self-adjusting circumferential RFA catheter, lets gastroenterologists and surgeons provide RFA treatment more easily and efficiently. RFA therapy removes diseased tissue while minimizing injury1 to healthy esophageal tissue. This treatment has been shown to reduce the risk of Barrett’s esophagus with low grade dysplasia — a precancerous condition that causes abnormal cell growth in the esophagus, progressing to high grade dysplasia or esophageal adenocarcinoma, a type of cancer — by approximately 90%.2

Esophageal cancer is the fastest-growing cancer in the U.S., having increased sixfold since the 1970s, outpacing breast cancer, prostate cancer and melanoma.3 Barrett’s esophagus, which affects more than 12 million American adults, develops as a result of chronic injury from gastroesophageal reflux disease (GERD).1,4

The new design helps physicians lower procedural time by up to 20 percent 2,5 by reducing procedural steps and enhanced ease-of-use features, including the ability to custom fit the device to various esophagus diameter sizes. With this tool, physicians are able to ablate Barrett’s tissue more efficiently. Using RFA to treat dysplastic Barrett’s tissue has been shown to reduce the risk for progression to high-grade dysplasia and esophageal adenocarcinoma,2,6 the most common type of esophageal cancer in the U.S.
"The biggest advantage of the Barrx 360 Express catheter is that it’s easier to use because of the larger, longer and adjustable balloon size," said Anthony Infantolino, MD, AGAF, FACG, FACP, of Thomas Jefferson University Hospital in Philadelphia. "These new features provide for a reduction in surgery time2,5 and the number of catheters required during RFA procedures, allowing me to concentrate on increasing the quality of the procedure."

"In reducing the progression of dysplastic Barrett’s esophagus to esophageal cancer, the launch of the Barrx 360 Express RFA balloon catheter underscores our commitment to patients," said Vafa Jamali, president, Early Technologies business in the Medtronic Minimally Invasive Therapies Group. "We believe patients and physicians will benefit from the easier-to-use technology of the Barrx 360 Express catheter, which provides a more precise delivery of RF energy to the targeted area."
The company is currently launching the Barrx 360 Express RFA balloon catheter in the United States. The catheter is also expected to be available in the EU, Australia and New Zealand in 2016.

BarrxTM 360 Express radiofrequency ablation (RFA) balloon catheter
Click the image for a larger image.

On April 20, 2016 Genmab A/S (Nasdaq Copenhagen: GEN) reported that two daratumumab abstracts have been accepted for presentation at the 2016 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, June 3 — 7 (Press release, Genmab, APR 20, 2016, View Source [SID:1234511144]). The titles of the abstracts are available on the ASCO (Free ASCO Whitepaper) website at www.asco.org via ASCO (Free ASCO Whitepaper)’s iPlanner. With the exception of the daratumumab Phase III Castor study data, which has been designated as a late breaking abstract by ASCO (Free ASCO Whitepaper), the full abstracts are scheduled to be published on the ASCO (Free ASCO Whitepaper) website on May 18 at 5:00PM EDT.

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Daratumumab Phase III Castor Study Data
Safety and efficacy data from the Phase III study of daratumumab in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma will be presented in the Plenary Session at the ASCO (Free ASCO Whitepaper) meeting on June 5. A total of 498 patients with relapsed or refractory multiple myeloma were enrolled in the study. The study met the primary endpoint of improving progression free survival (PFS); Hazard Ratio (HR) = 0.39, p<0.0001. The median PFS for patients treated with daratumumab has not been reached, compared to median PFS of 7.2 months for patients who did not receive daratumumab.

Daratumumab showed a manageable safety profile in the study consistent with the reported safety profile of monotherapy and background bortezomib/dexamethasone therapy.

As announced on March 30, 2016 an Independent Data Monitoring Committee recommended stopping the study as the primary endpoint had been reached at the time of the pre-specified interim analysis. Patients originally assigned to the bortezomib plus dexamethasone treatment group will be offered the option of receiving daratumumab following confirmed disease progression. Patients continue to be monitored for safety and overall survival.

Abstract details: Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study— Abstract # LBA4, Oral presentation, Sunday, June 5 at 3:10PM-3:25PM CDT

This abstract has been designated a late breaking abstract and the embargo will be lifted on Sunday, June 5 at 6:30AM CDT.
"ASCO is one of the premier medical conferences of the year and we are very pleased that highly impressive data with one of our key programs, daratumumab, will be presented again this year," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

List of Further Abstracts to Be Presented

Daratumumab
An open-label, dose-escalation Phase 1b study of subcutaneous daratumumab with recombinant human hyaluronidase in patients with relapsed or refractory multiple myeloma (PAVO) — Abstract # 333b, Trials in progress poster presentation, Monday, June 6 at 8:00AM -11.30AM CDT
The study described in this abstract is ongoing.

About DARZALEX (daratumumab)
DARZALEX (daratumumab) injection for intravenous infusion is indicated in the United States for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.1 DARZALEX is the first monoclonal antibody (mAb) to receive U.S. Food and Drug Administration (FDA) approval to treat multiple myeloma. For more information, visit www.DARZALEX.com.

Daratumumab is a human IgG1k monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through programmed cell death, or apoptosis,1,2 and multiple immune-mediated mechanisms, including complement-dependent cytotoxicity,1,2 antibody-dependent cellular phagocytosis3,4 and antibody-dependent cellular cytotoxicity.1,2 In addition, daratumumab therapy results in a reduction of immune-suppressive myeloid derived suppressor cells (MDSCs) and subsets of regulatory T cells (Tregs) and B cells (Bregs), all of which express CD38. These reductions in MDSCs, Tregs and Bregs were accompanied by increases in CD4+ and CD8+ T cell numbers in both the peripheral blood and bone marrow.1

Daratumumab is being developed by Janssen Biotech, Inc. under an exclusive worldwide license to develop, manufacture and commercialize daratumumab from Genmab. Five Phase III clinical studies with daratumumab in relapsed and frontline settings are currently ongoing, and additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma, non-Hodgkin’s lymphoma and a solid tumor indication.