On April 08, 2016 PharmaCyte Biotech, Inc. (OTCQB:PMCB), a clinical stage biotechnology company focused on developing targeted treatments for cancer and diabetes using its signature live-cell encapsulation technology, Cell-in-a-Box, reported that the encapsulation facility located in Bangkok, Thailand, that will be used to encapsulate the live cells used for PharmaCyte’s pancreatic cancer therapy has recently been inspected by the Food and Drug Administration of Thailand (Thai FDA) (Press release, PharmaCyte Biotech, APR 8, 2016, View Source [SID:1234510768]). In its report on that inspection, the Thai FDA stated that, "The facility is built according to the pre-approved floor plan and is now deemed suitable for the manufacture of pharmaceutical products."

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PharmaCyte Biotech’s Chief Executive Officer, Kenneth L. Waggoner, commented, "We are very pleased that our partner, Austrianova, has received a positive opinion from the Thai FDA for Austrianova’s live-cell encapsulation facility. This is an important milestone in the development of PharmaCyte’s treatment for pancreatic cancer and a pre-requisite for our upcoming pancreatic cancer clinical trial."

The main role of the Thai FDA is to protect consumer’s health, especially, to ensure safety, quality and efficacy of health products within its purview. These products include: foods, drugs, psychotropic substances, narcotics, medical devices, volatile substances, cosmetics and hazardous substances. It is an absolute requirement that the construction and operation of Austrianova’s live-cell encapsulation facility be in accordance with both Thai national legislation as well as international agreements.

PharmaCyte’s product for pancreatic cancer will be manufactured in Austrianova’s facility in Bangkok. It consists of live human cells that have been genetically engineered to convert the anticancer prodrug ifosfamide into its "cancer-killing" form and then encapsulated using the Cell-in-a-Box encapsulation technology. In PharmaCyte’s upcoming clinical trial, these encapsulated live cells will be used with low doses of ifosfamide (one third the normal dose) as a "consolidation therapy" with the current standard of care for advanced pancreatic cancer when a patient no longer benefits from first line therapy. PharmaCyte’s therapy will be compared with the combination of the anticancer drug capecitabine plus radiation in patients with locally advanced, non-metastatic, inoperable pancreatic cancer whose tumors are stable or progressing after 4-6 cycles of treatment with either the combination of Abraxane plus gemcitabine or the four-drug combination known as FOLFIRINOX.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. Tumor necrosis factor-Related Apoptosis-Inducing Ligand (TRAIL) directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein,we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3′-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR’s role in affecting TRAIL apoptotic-resistance. NanoString{trade mark, serif} analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in anti-apoptotic processes. Taken together, these data extend HuR’s role as a key regulator of TRAIL-induced apoptosis.
Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAILPage-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients.
Copyright ©2016, American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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The design of efficacious and cost-effective therapeutic vaccines against cancer remains both a research priority and a challenge. For more than a decade, our laboratory has been involved in the development of synthetic peptide-based anti-cancer therapeutic vaccines. We first dedicated our efforts in the identification and validation of peptide epitopes for both CD8 and CD4 T cells from tumor-associated antigens (TAAs). Because of suboptimal immune responses and lack of therapeutic benefit of peptide vaccines containing these epitopes, we have focused our recent efforts in optimizing peptide vaccinations in mouse tumor models using numerous TAA epitopes. In this focused research review, we describe how after taking lessons from the immune system’s way of dealing with acute viral infections, we have designed peptide vaccination strategies capable of generating very high numbers of therapeutically effective CD8 T cells. We also discuss some of the remaining challenges to translate these findings into the clinical setting.

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On April 8, 2016 Delcath Systems, Inc. (NASDAQ: DCTH), a specialty pharmaceutical and medical device company focused on the treatment of primary and metastatic liver cancers, reported that the Hacettepe University Clinic in Ankara, Turkey has been activated as a treatment center for the Delcath Hepatic CHEMOSAT Delivery System (CHEMOSAT) for the treatment of cancers of the liver (Press release, Delcath Systems, APR 8, 2016, View Source;p=RssLanding&cat=news&id=2155549 [SID:1234510558]). Hacettepe University Clinic successfully completed its first CHEMOSAT treatments in March, and the center represents the first CHEMOSAT commercial location to be activated outside of the European Union.

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"We are especially pleased to be expanding access to CHEMOSAT to benefit the thousands of patients in Turkey suffering with these life-threatening cancers of the liver for which there are limited treatment options," said Dr. Jennifer K. Simpson, Ph.D., MSN, CRNP, President and Chief Executive Office of Delcath. "With its high level of clinical expertise, we believe that Hacettepe University can serve as an important hub for CHEMOSAT treatment to patients in Turkey and throughout the region. We are selectively evaluating other markets in the wider European region in order to continue our geographic expansion and the steady growth in clinical adoption of CHEMOSAT as a treatment for patients with cancers of the liver."

p53 tumor suppressor maintains genomic stability, typically acting through cell-cycle arrest, senescence, and apoptosis. We discovered a function of p53 in preventing conflicts between transcription and replication, independent of its canonical roles. p53 deficiency sensitizes cells to Topoisomerase (Topo) II inhibitors, resulting in DNA damage arising spontaneously during replication. Topoisomerase IIα (TOP2A)-DNA complexes preferentially accumulate in isogenic p53 mutant or knockout cells, reflecting an increased recruitment of TOP2A to regulate DNA topology. We propose that p53 acts to prevent DNA topological stress originating from transcription during the S phase and, therefore, promotes normal replication fork progression. Consequently, replication fork progression is impaired in the absence of p53, which is reversed by transcription inhibition. Pharmacologic inhibition of transcription also attenuates DNA damage and decreases Topo-II-DNA complexes, restoring cell viability in p53-deficient cells. Together, our results demonstrate a function of p53 that may underlie its role in tumor suppression.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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