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Puma Biotechnology Announces Publication of Abstracts on Neratinib for the AACR Annual Meeting 2016

On March 18, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported publication of abstracts on neratinib for the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Puma Biotechnology, MAR 18, 2016, View Source [SID:1234510445]). The AACR (Free AACR Whitepaper) Annual Meeting will be held at the Ernest N. Morial Convention Center in New Orleans from April 16 to April 20.

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Sun, Apr 17, 1:00 – 5:00 p.m. CDT – Abstract 298, Section 16, Poster Board 9: Amplification of mutant ERBB2 drives resistance to the irreversible kinase inhibitor neratinib in ERBB2-mutated breast cancer patients.
FJ Carmona, D Hyman, G Ulaner, J Erinjeri, N Bouvier, H Won, R Cutler, A Alani, M Berger, J Baselga, M Scaltriti.

Tue, Apr 19, 8:00 a.m. – 12:00 p.m. CDT – Abstract 3140, Section 22, Poster Board 7: Differential clonal selection in tumor tissue and cell-free DNA from a neratinib-treated refractory breast cancer patient harboring an activating ERBB2 (HER2) mutation.
L Joenson, CW Yde, O Østrup, M Mau-Sørensen, FC Nielsen, U Lassen

Wed, Apr 20, 8:00 a.m. – 12:00 p.m. CDT – Abstract 4760, Poster Board 11: Efficacy of EGFR/HER2 duel-kinase inhibitors in PDX models harboring known and novel HER2-mutations.
MJ Wick, M Farley, T Vaught, J Meade, M Glassman, A Moriarty, AW Tolcher, D Rasco, A Patnaik, KP Papadopoulos

The abstracts are available online at: View Source;DetailItemID=363#.Vusrr-IrKUk.

OMNIS PHARMA AND MAGNIS THERAPEUTICS MERGE TO FORM VYRIAD, A CLINICAL-STAGE ONCOLYTIC IMMUNOVIROTHERAPY DEVELOPMENT COMPANY

On March 18, 2016 Omnis Pharma, Inc. and Magnis Therapeutics, LLC, reported their strategic merger to form Vyriad, a clinical-stage oncolytic immunovirotherapy development company (Press release, Omnis Pharmaceuticals, MAR 18, 2016, http://www.vyriad.com/2016/03/18/omnis-pharma-magnis-therapeutics-merge-form-vyriad-clinical-stage-oncolytic-immunovirotherapy-development-company-combined-entity-aims-leader-oncolytic-virotherapy-discov/ [SID:1234509779]). The combined companies’ product development pipeline encompasses multiple clinical-stage and late preclinical-stage products targeting a broad range of human cancer indications, including a Phase 1 development program partnered with a large pharmaceutical company. Financial details of the transaction were not disclosed.

"I am delighted to announce the completion of this merger, which consolidates two leading oncolytic platforms, a broad intellectual property portfolio, a strong collaborative research and development network, and a vibrant clinical-stage product pipeline that spans the cancer spectrum," said Stephen J. Russell, MD, PhD, President and CEO of Vyriad. "Given our broad clinical and advanced preclinical portfolio, product development engine, and scientific capabilities, I firmly believe that Vyriad is on course to become the leading oncolytic virotherapy company creating powerful new immunotherapies for patients with cancer."

The combined company results in:

A robust pipeline encompassing eight oncolytic virotherapies in clinical development and seven in late-stage preclinical development: Vyriad’s lead programs include Phase 2 product candidates in ovarian cancer and multiple myeloma, and Phase 1 programs in glioblastoma, mesothelioma, head and neck cancer, blood cancers, endometrial cancer, hematologic malignancies, and gastrointestinal cancer. The company’s seven pre-IND programs include initiatives that pair oncolytic vaccines with other cancer immunotherapy approaches such as checkpoint inhibitors, as well as other forms of cancer therapy such as chemotherapy.

Validated, industry-leading oncolytic virotherapy platforms: Vyriad unites vesicular stomatitis virus (VSV) and measles virus platforms licensed from Mayo Clinic, the University of Miami, and Yale University School of Medicine following more than 15 years of intensive research to identify the most promising oncolytic viruses based on selectivity, mechanism of action, and potency. In 2014, Vyriad’s Oncolytic Measles virus demonstrated successful treatment of a patient with multiple myeloma who had previously undergone 10 years of unsuccessful treatment and exhausted all traditional treatment options, and who remains disease-free two years following treatment.

Electrophilic Oxidation and [1,2]-Rearrangement of the Biindole Core of Birinapant.

Birinapant/TL32711 (1) is a bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins and was designed to mimic AVPI, the N-terminal tetrapeptide of the second mitochondria-derived activator of caspases (Smac/DIABLO). Birinapant bound to the BIR3 domains of cIAP1, cIAP2, and XIAP with K i values of 1, 36, and 45 nM, respectively. Birinapant-mediated activation of cIAP1 resulted in cIAP1 autoubiquitylation and degradation and correlated with inhibition of TNF-mediated NF-κB activation, induction of tumor cell death in vitro, and tumor regression in vivo. Birinapant is being evaluated in Phase 1/2 trials for the treatment of cancer and hepatitis B virus (HBV) infection. After one year at accelerated storage conditions, a formulation of 1 afforded four degradants in &gt;0.1% abundance by HPLC analysis. The primary degradants (2 and 3) were formed via oxidation of the biindole core, while the secondary degradants (5 and 6) arose via [1,2]-rearrangement of 3 and 2, respectively. Forced degradation conditions were developed, which allowed the isolation of 2 and 3 in multigram quantities. Novel deuterated analogues of 1 were prepared to determine the site of oxidation, and NMR experiments confirmed the chemical structures of 5 and 6. The de novo synthesis of 2, 3, 5, and 6 confirmed these experimental findings.

A RNA-DNA Hybrid Aptamer for Nanoparticle-Based Prostate Tumor Targeted Drug Delivery.

The side effects of radio- and chemo-therapy pose long-term challenges on a cancer patient’s health. It is, therefore, highly desirable to develop more effective therapies that can specifically target carcinoma cells without damaging normal and healthy cells. Tremendous efforts have been made in the past to develop targeted drug delivery systems for solid cancer treatment. In this study, a new aptamer, A10-3-J1, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), was designed. A super paramagnetic iron oxide nanoparticle-aptamer-doxorubicin (SPIO-Apt-Dox) was fabricated and employed as a targeted drug delivery platform for cancer therapy. This DNA RNA hybridized aptamer antitumor agent was able to enhance the cytotoxicity of targeted cells while minimizing collateral damage to non-targeted cells. This SPIO-Apt-Dox nanoparticle has specificity to PSMA⁺ prostate cancer cells. Aptamer inhibited nonspecific uptake of membrane-permeable doxorubic to the non-target cells, leading to reduced untargeted cytotoxicity and endocytic uptake while enhancing targeted cytotoxicity and endocytic uptake. The experimental results indicate that the drug delivery platform can yield statistically significant effectiveness being more cytotoxic to the targeted cells as opposed to the non-targeted cells.

Hypoxia-inducible factor 1-mediated characteristic features of cancer cells for tumor radioresistance.

Tumor hypoxia has been attracting increasing attention in the fields of radiation biology and oncology since Thomlinson and Gray detected hypoxic cells in malignant solid tumors and showed that they exert a negative impact on the outcome of radiation therapy. This unfavorable influence has, at least partly, been attributed to cancer cells acquiring a radioresistant phenotype through the activation of the transcription factor, hypoxia-inducible factor 1 (HIF-1). On the other hand, accumulating evidence has recently revealed that, even though HIF-1 is recognized as an important regulator of cellular adaptive responses to hypoxia, it may not become active and induce tumor radioresistance under hypoxic conditions only. The mechanisms by which HIF-1 is activated in cancer cells not only under hypoxic conditions, but also under normoxic conditions, through cancer-specific genetic alterations and the resultant imbalance in intermediate metabolites have been summarized herein. The relevance of the HIF-1-mediated characteristic features of cancer cells, such as the production of antioxidants through reprogramming of the glucose metabolic pathway and cell cycle regulation, for tumor radioresistance has also been reviewed.
© The Author 2016. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.