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Toledo R.A.,Cancer Therapy and Research Center
Endocrinology and Metabolism Clinics of North America | Year: 2017

Genomic studies conducted by different centers have uncovered various new genes mutated in pheochromocytomas and paragangliomas (PPGLs) at germline, mosaic, and/or somatic levels, greatly expanding our knowledge of the genetic events occurring in these tumors. The current review focuses on very newly findings and discusses the previously not recognized role of MERTK, MET, fibroblast growth factor receptor 1, and H3F3A genes in syndromic and nonsyndromic PPGLs. These 4 new genes were selected because, although their association with PPGLs is very recent, mounting evidence was generated that rapidly consolidated the prominence of these genes in the molecular pathogenesis of PPGLs. © 2017 Elsevier Inc.


News Article | February 15, 2017
Site: www.marketwired.com

MOUNTAIN VIEW, CA--(Marketwired - February 13, 2017) - Amunix Operating Inc., a privately held biotechnology company and developer of a broad portfolio of biopharmaceuticals based on its novel XTEN® polymer half-life extension technology, XTEN drug-conjugate delivery technology and bispecific T-cell engager (ProTIA) pro-drug cancer therapeutics platforms, announced that it has appointed Frederick Hausheer, MD, FACP, as its Chief Medical Officer. Dr. Hausheer brings more than 25 years' experience in global oncology drug development, translational medicine, and drug discovery in commercial and academic settings to Amunix. Volker Schellenberger, Ph.D., President and Chief Executive Officer, said, "We are extremely pleased to have Fred join the Amunix management team. He brings exceptionally broad product development leadership and clinical expertise to the organization. His deep clinical experience in the oncology field will be especially valuable in the support of our ProTIA oncology platform. I look forward to working with Fred to accelerate the advancement of our clinical pipeline." Dr. Hausheer said, "It is a great privilege to be joining Amunix. I am exceedingly impressed with the technology, the Amunix team and the progress that has been made with the company's ProTIA T-cell engager cancer targeting platform which has broad potential to serve as a novel important therapeutic option over current cancer treatment regimens. I am excited about the prospects for advancing the pipeline of ProTIA platform products into patients and beyond. I believe that Amunix' innovative technologies will be an important advance for immuno-oncology drugs to improve patient outcomes." Over the course of his career, Dr. Hausheer has helped secure over $750 million in financial transactions involving capital raising, joint ventures, strategic alliances and licensing of compounds for partnership opportunities. He is experienced in trial design and execution, and involved in numerous regulatory interactions for drugs spanning from pre-IND and Phase I-III development in the United States, Europe, Asia/PAC and other territories. As founder, Chairman, CEO and President of BioNumerik from 1992-2015, he led the discovery and development of two novel oncologic therapeutics from laboratory through global Phase III development. In addition, he co-founded and served as Chairman of KI Pharma from 2005-2013, a joint venture between BioNumerik Pharmaceuticals, Inc. and ASKA Pharmaceutical Co., with a focus on development and commercialization of oncology products in Japan. Prior to joining industry, Dr. Hausheer was an Associate Professor of Medical Oncology and Associate Director Drug Development and Chief, Molecular Design at the University Texas Health Science Center and Cancer Therapy and Research Center and performed oncology drug research as a Senior Scientist at the National Cancer Institute. Dr. Hausheer completed his graduate training in Physiology and Biophysics at the University of Illinois-Champagne. He obtained his MD and completed his Internal Medicine residency at the University of Missouri School of Medicine, followed by completion of Medical Oncology fellowship training and joining the faculty at Johns Hopkins, where he focused on development of novel experimental therapeutics and pharmacology. He currently holds adjunct professorships at the University of Missouri in Internal Medicine and Oncology and The Johns Hopkins Oncology Center in Medical Oncology. He is board certified in Internal Medicine and Medical Oncology. Dr. Hausheer has published over 200 articles, abstracts and book chapters, and is an inventor or co-inventor on more than 400 issued/allowed United States and international patents. He has served as a board member to JP Morgan Chase, the Whittaker Institute for BioMedical Engineering at Johns Hopkins, the National Cancer Institute's (NCI) Experimental Therapeutics Study Section I, and the NCI Institutional Review Board. Amunix, based in Mountain View, CA, is a privately held biotechnology company focused on the discovery and development of biologics with improved in vivo half-lives. Amunix' half-life extension technology is based on XTEN -- hydrophilic, unstructured, biodegradable proteins that impart a number of favorable properties upon the molecules to which they are attached. XTEN can be recombinantly fused or chemically conjugated to peptides, proteins, and other pharmaceuticals. In addition to the advantages of reduced dosing frequency, XTENylation also stabilizes plasma drug concentrations, which often results in increased efficacy as well as reduced side effects. Two genetically fused XTENylated products have been tested clinically. VRS-859 (exenatide-XTEN) has been tested through Phase I in the treatment of diabetes and VRS-317 (human growth hormone-XTEN) is currently in Phase III testing. Amunix is also working with additional partners, including Eli Lilly, Bioverativ, Roche, Janssen, Naia and other undisclosed companies in a wide range of therapeutic areas. Amunix is developing an internal pipeline of ProTIA (Protease Triggered Immune Activator) immuno-oncology therapeutics. ProTIAs are bispecific molecules that bind tumor antigens and T cells. ProTIAs are administered as long-acting prodrugs that can be activated in the tumor environment by tumor-associated proteases. Amunix is actively seeking partnerships for applications of its XTEN technology and its ProTIA platform. For additional information about the company, please visit www.amunix.com.


Rohena C.C.,University of Texas Health Science Center at San Antonio | Mooberry S.L.,University of Texas Health Science Center at San Antonio | Mooberry S.L.,Cancer Therapy and Research Center
Natural Product Reports | Year: 2014

Covering: late 2008 to August 2013 Nature has yielded numerous classes of chemically distinct microtubule stabilizers. Several of these, including paclitaxel (Taxol) and docetaxel (Taxotere), are important drugs used in the treatment of cancer. New microtubule stabilizers and novel formulations of these agents continue to provide advances in cancer therapy. In this review we cover recent progress in the chemistry and biology of these diverse microtubule stabilizers focusing on the wide range of organisms that produce these compounds, their mechanisms of inhibiting microtubule-dependent processes, mechanisms of drug resistance, and their interactions with tubulin including their distinct binding sites and modes. A new potential role for microtubule stabilizers in neurodegenerative diseases is reviewed. © 2014 The Royal Society of Chemistry.


Scott L.M.,University of Queensland | Rebel V.I.,Cancer Therapy and Research Center | Rebel V.I.,University of Texas Health Science Center at San Antonio
Journal of the National Cancer Institute | Year: 2013

The application of next-generation sequencing technologies to interrogate the genome of human hematologic malignancies is providing promising insights into their molecular etiology and into the pathogenesis of seemingly unrelated malignancies. Among the somatic mutations identified by this approach are ones that target components of the spliceosome, a ribonucleoprotein complex responsible for the posttranscriptional processing of primary transcripts to form mature messenger RNA species. These mutations were initially detected in patients with chronic lymphocytic leukemia or a myelodysplastic syndrome, but can also occur at relatively high frequency in some solid tumors, including uveal malignant melanoma, adenocarcinoma of the lung, and estrogen receptor-positive breast cancers. Their presence in a variety of malignancies suggests that the spliceosomal mutations may play a fundamental role in defining the malignant phenotype. The development and testing of drugs that eliminate cells bearing a spliceosomal mutation, or normalize their altered transcript splicing patterns, are therefore a priority. Here, we summarize the effects of spliceosome-associated mutations on transcript processing in vitro and in vivo, and their impact on disease initiation and/or progression and patient outcome. Moreover, we discuss the therapeutic potential of compounds already known to target splicing factor 3B subunit 1 (SF3B1), an essential component of the spliceosome that is frequently mutated. © The Author 2013. Published by Oxford University Press.


Barontini M.,Hospital Of Ninos R Gutierrez | Dahia P.L.M.,Cancer Therapy and Research Center
Best Practice and Research: Clinical Endocrinology and Metabolism | Year: 2010

von Hippel-Lindau disease (VHL) disease increases susceptibility to several malignancies, including renal cell carcinoma, haemangioblastomas of the central nervous system or retina and phaeochromocytomas. The VHL tumour suppressor gene, responsible for the disease, encodes for a major regulator of the hypoxic response by targeting the transcription factor hypoxia inducible factor (HIF) for degradation. In this review, we present a synopsis of clinical features of the disease and emphasise unique aspects of VHL syndrome in the paediatric population. Genotype-phenotype associations based on the risk of phaeochromocytoma have pointed to the existence of additional, HIF-independent functions of VHL that remain underexplored. We also examine the progress on these pleiotropic roles of VHL, which contribute to explain clinical features of VHL disease. These advances have important translational implications and are likely to offer a new host of therapeutic options to individuals affected by the disease in the future. © 2010 Elsevier Ltd. All rights reserved.


Butler M.O.,Cancer Therapy and Research Center | Butler M.O.,University of Toronto | Hirano N.,Cancer Therapy and Research Center | Hirano N.,University of Toronto
Immunological Reviews | Year: 2014

Adoptive T-cell therapy, where anti-tumor T cells are first prepared in vitro, is attractive since it facilitates the delivery of essential signals to selected subsets of anti-tumor T cells without unfavorable immunoregulatory issues that exist in tumor-bearing hosts. Recent clinical trials have demonstrated that anti-tumor adoptive T-cell therapy, i.e. infusion of tumor-specific T cells, can induce clinically relevant and sustained responses in patients with advanced cancer. The goal of adoptive cell therapy is to establish anti-tumor immunologic memory, which can result in life-long rejection of tumor cells in patients. To achieve this goal, during the process of in vitro expansion, T-cell grafts used in adoptive T-cell therapy must be appropriately educated and equipped with the capacity to accomplish multiple, essential tasks. Adoptively transferred T cells must be endowed, prior to infusion, with the ability to efficiently engraft, expand, persist, and traffic to tumor in vivo. As a strategy to consistently generate T-cell grafts with these capabilities, artificial antigen-presenting cells have been developed to deliver the proper signals necessary to T cells to enable optimal adoptive cell therapy. © 2013 John Wiley & Sons A/S.


Li Q.,Cancer Therapy and Research Center
Frontiers in bioscience (Landmark edition) | Year: 2013

Type III interferons (IFNs), a new type IFN family consisting of 3 IFN-lambdas, have been identified through a homology search. They include IFN-lambda1, IFN-lambda2 and IFN-lambda3, which are also named as interleukin (IL)-29, IL-28A and IL-28B, respectively. The receptor complex of IFN-lambdas is composed of the IL-10 receptor beta (IL-10Rbeta) and a novel IL-28 receptor alpha (IL-28Ralpha). The signal transductions of type III IFNs seem to be similar to those of type I IFNs. Both type I and III IFNs activate Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and transcribe a number of IFN-associated genes. Various types of viruses induce expressions of type III IFNs as well as type I IFNs; however, the biological functions of type III IFNs could be distinct from those of type I IFNs partly because of the tissue-restricted expression of the type III receptor complexes. In this review, we encapsulate recent understandings about type III IFNs in particular the anti-tumor effects, and discuss possible mechanisms and a potential use for cancer therapy.


Curiel T.J.,Cancer Therapy and Research Center
Drug Resistance Updates | Year: 2012

Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct for other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic agents, capitalization on other immune properties of MDR positive cells, or conditional immunotoxins expressed under MDR control. Additional insights into the immunogenic potential of some cytotoxic agents can also be brought to bear on these strategies. This review will highlight key concepts in cancer immunotherapy and illustrate immune principles and strategies that have been or could be used to help destroy MDR positive tumor cells, either alone or in rational combinations. © 2012 Elsevier Ltd.


Zhang B.,Cancer Therapy and Research Center
Cancer Research | Year: 2010

The promise of cancer immunotherapy has not been translated into clinical successes, in large part because of tumor-associated immune suppression that blocks effective antitumor immunity. Recent findings show a tumor-induced immunosuppressive mechanism, whereby tumor-derived CD73 functions as an ecto-enzyme to produce extracellular adenosine, which promotes tumor growth by limiting antitumor T-cell immunity via adenosine receptor signaling. Results with small molecule inhibitors, or monoclonal antibodies targeting CD73 in murine tumor models, suggest that targeted CD73 therapy is an important alternative and realistic approach to effective control of tumor growth. In particular, it helps T-cell-based therapy by enhancing the adaptive immune response machinery, which may increase the function of tumor-infiltrating T lymphocytes, and subsequently lead to improved survival in cancer patients. ©2010 AACR.


Carew J.S.,Cancer Therapy and Research Center | Kelly K.R.,Cancer Therapy and Research Center | Nawrocki S.T.,Cancer Therapy and Research Center
Cancer Management and Research | Year: 2012

Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Numerous preclinical studies have demonstrated that inhibition of autophagy enhances the activity of a broad array of anticancer agents. Thus, targeting autophagy may be a global anticancer strategy that may improve the efficacy of many standard of care agents. These results have led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. In this review, we summarize the anticancer agents that have been reported to modulate autophagy and discuss new developments in autophagy inhibition as an anticancer strategy. © 2012 Mazzotti etal, publisher and licensee Dove Medical Press Ltd.

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