Arizona Cancer Center

Tucson, AZ, United States

Arizona Cancer Center

Tucson, AZ, United States
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News Article | May 8, 2017

PHOENIX, Ariz. -- May 8, 2017 -- Dr. Daniel Von Hoff -- Distinguished Professor, Physician-In-Chief, and Director of Molecular Medicine at the Translational Genomics Research Institute (TGen) -- will receive a gold medal for excellence in clinical medicine from his alma mater, Columbia University. Columbia University College of Physicians and Surgeons Alumni Association will present the award May 13 in New York City to Dr. Von Hoff, a world-renowned expert in new therapies for patients with cancer. "This medal represents the highest honor which the Alumni Association can bestow in recognition of your outstanding accomplishments," said Dr. Kenneth A. Forde, chair of the P&S Alumni Association Honors and Awards Committee, which represents some of the nation's most accomplished medical professionals. This year marks the 250th anniversary of P&S, and its founding as the first medical school in Colonial America to award an Medical Doctorate degree. "This recognition is especially gratifying as it is being presented by notable fellow graduates of my medical school, and I am deeply humbled and appreciative to be counted among those devoted to the welfare of patients," said Dr. Von Hoff, who has been instrumental in developing numerous new cancer treatments. He also is a Senior Consultant-Clinical Investigations for City of Hope, Chief Scientific Officer at HonorHealth Research Institute, and Professor of Medicine at Mayo Clinic. Dr. Von Hoff currently co-leads an international Stand Up To Cancer (SU2C) Pancreatic Cancer Dream Team, developing new treatments for this disease. It is one of three SU2C Dream Team grants awarded to TGen. He graduated cum laude from Carroll University (1969), and received his M.D. from Columbia University College of Physicians and Surgeons (1973). He completed his internship and residency in internal medicine at the University of California, San Francisco, then completed a medical oncology fellowship at the National Cancer Institute. Dr. Von Hoff is a past director of the University of Arizona's Arizona Cancer Center. He also is a past board member and president of the American Association for Cancer Research (AACR), a Fellow of the AACR, and recipient of the distinguished AACR Richard and Hinda Rosenthal Memorial Award. In addition, he is a past board member of the American Association of Clinical Oncology (ASCO) and winner of its prestigious David A. Karnofsky Memorial Award for outstanding contributions to patient care and treatment. He served a six-year term on President Bush's National Cancer Advisory Board (2004-10); is a recipient of the Wallace A. Reed M.D. Award, recognizing his accomplishments in advancing innovative cancer treatments, from the Arizona Medical Association; and received the Award of Excellence from the Hope Funds for Cancer Research, for his work in the clinical development of many new cancer treatments. Dr. Von Hoff and his colleagues have conducted early clinical investigations of many new cancer agents, including: gemcitabine, docetaxel, paclitaxel, topotecan, irinotecan, nanoliposomal irinotecan, fludarabine, mitoxantrone, dexrazoxane, nab-paclitaxel, vismodegib, and others. These treatments are helping many patients with breast, ovarian, prostate, colon, leukemia, advanced basal cell and pancreatic cancers. Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is focused on helping patients with neurological disorders, cancer, and diabetes, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. TGen is allied with City of Hope, a world-renowned independent research and cancer and diabetes treatment center. This precision medicine alliance enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. For more information, visit: http://www. . Follow TGen on Facebook, LinkedIn and Twitter @TGen.

Mantyh P.W.,Arizona Cancer Center
European Journal of Neuroscience | Year: 2014

Disorders of the skeleton are one of the most common causes of chronic pain and long-term physical disability in the world. Chronic skeletal pain is caused by a remarkably diverse group of conditions including trauma-induced fracture, osteoarthritis, osteoporosis, low back pain, orthopedic procedures, celiac disease, sickle cell disease and bone cancer. While these disorders are diverse, what they share in common is that when chronic skeletal pain occurs in these disorders, there are currently few therapies that can fully control the pain without significant unwanted side effects. In this review we focus on recent advances in our knowledge concerning the unique population of primary afferent sensory nerve fibers that innervate the skeleton, the nociceptive and neuropathic mechanisms that are involved in driving skeletal pain, and the neurochemical and structural changes that can occur in sensory and sympathetic nerve fibers and the CNS in chronic skeletal pain. We also discuss therapies targeting nerve growth factor or sclerostin for treating skeletal pain. These therapies have provided unique insight into the factors that drive skeletal pain and the structural decline that occurs in the aging skeleton. We conclude by discussing how these advances have changed our understanding and potentially the therapeutic options for treating and/or preventing chronic pain in the injured, diseased and aged skeleton. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Balasubramanian S.,University of Cambridge | Balasubramanian S.,Cancer Research UK Research Institute | Hurley L.H.,University of Arizona | Hurley L.H.,Arizona Cancer Center | Neidle S.,University of London
Nature Reviews Drug Discovery | Year: 2011

G-quadruplexes are four-stranded DNA structures that are over-represented in gene promoter regions and are viewed as emerging therapeutic targets in oncology, as transcriptional repression of oncogenes through stabilization of these structures could be a novel anticancer strategy. Many gene promoter G-quadruplexes have physicochemical properties and structural characteristics that might make them druggable, and their structural diversity suggests that a high degree of selectivity might be possible. Here, we describe the evidence for G-quadruplexes in gene promoters and discuss their potential as therapeutic targets, as well as progress in the development of strategies to harness this potential through intervention with small-molecule ligands. © 2011 Macmillan Publishers Limited. All rights reserved.

Gonzalez V.,University of Arizona | Hurley L.H.,University of Arizona | Hurley L.H.,Arizona Cancer Center
Annual Review of Pharmacology and Toxicology | Year: 2010

c-MYC is an important regulator of a wide array of cellular processes necessary for normal cell growth and differentiation, and its dysregulation is one of the hallmarks of many cancers. Consequently, understanding c-MYC transcriptional activation is critical for understanding developmental and cancer biology, as well as for the development of new anticancer drugs. The nuclease hypersensitive element (NHE) III1 region of the c-MYC promoter has been shown to be particularly important in regulating c-MYC expression. Specifically, the formation of a G-quadruplex structure appears to promote repression of c-MYC transcription. This review focuses on what is known about the formation of a G-quadruplex in the NHE III1 region of the c-MYC promoter, as well as on those factors that are known to modulate its formation. Last, we discuss the development of small molecules that stabilize or induce the formation of G-quadruplex structures and could potentially be used as anticancer agents. Copyright © 2010 by Annual Reviews. All rights reserved.

Bookman M.A.,Arizona Cancer Center
Annals of Oncology | Year: 2010

Advanced-stage epithelial ovarian cancer is generally managed with cytoreductive surgery and chemotherapy consisting of carboplatin and paclitaxel, achieving clinical complete remission in the majority of patients. However, most tumors recur, and are associated with progressive chemotherapy resistance. Techniques to optimize chemotherapy have included intraperitoneal administration and weekly scheduling of paclitaxel. Efforts to improve on the long-term results of primary therapy through addition of a third cytotoxic agent have not been successful, including extended maintenance, as well as strategies to overcome chemotherapy resistance. Limited data emerging from phase III trials using bevacizumab suggest some advantage in progression-free survival, particularly in the maintenance setting, and further data are awaited. At present, primary therapy with carboplatin and paclitaxel remains a well-tolerated standard regimen, including the option of weekly paclitaxel dosing, intraperitoneal delivery and neoadjuvant therapy in selected patients. Emerging biological paradigms will hopefully contribute to individualized treatment options in the future. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

New anticancer agents that target a single cell surface receptor, up-regulated or amplified gene product, or mutated gene, have met with some success in treating advanced cancers. However, patients' tumors still eventually progress on these therapies. If it were possible to identify a larger number of targetable vulnerabilities in an individual's tumor, multiple targets could be exploited with the use of specific therapeutic agents, thus possibly giving the patient viable therapeutic alternatives. In this exploratory study, we used next-generation sequencing technologies (NGS) including whole genome sequencing (WGS), and where feasible, whole transcriptome sequencing (WTS) to identify genomic events and associated expression changes in advanced cancer patients. WGS on paired tumor and normal samples from nine advanced cancer patients and WTS on six of these patients' tumors was completed. One patient's treatment was based on targets and pathways identified by NGS and the patient had a short-lived PET/CT response with a significant reduction in his tumor-related pain. To design treatment plans based on information garnered from NGS, several challenges were encountered: NGS reporting delays, communication of results to out-of-state participants and their treating oncologists, and chain of custody handling for fresh biopsy samples for Clinical Laboratory Improvement Amendments (CLIA) target validation. While the initial effort was a slower process than anticipated due to a variety of issues, we demonstrate the feasibility of using NGS in advanced cancer patients so that treatments for patients with progressing tumors may be improved.

Rana S.,Arizona Cancer Center
Journal of applied clinical medical physics / American College of Medical Physics | Year: 2014

The Radiation Therapy Oncology Group (RTOG) 0813 protocol requires the use of dose calculation algorithms with tissue heterogeneity corrections to compute dose on stereotactic body radiation therapy (SBRT) non-small cell lung cancer (NSCLC) plans. A new photon dose calculation algorithm called Acuros XB (AXB) has recently been implemented in the Eclipse treatment planning system (TPS). The main purpose of this study was to compare the dosimetric results of AXB with that of anisotropic analytical algorithm (AAA) for RTOG 0813 parameters. Additionally, phantom study was done to evaluate the dose prediction accuracy of AXB and AAA beyond low-density medium of different thicknesses by comparing the calculated results with the measurements. For the RTOG dosimetric study, 14 clinically approved SBRT NSCLC cases were included. The planning target volume (PTV) ranged from 3.2-43.0 cc. RapidArc treatment plans were generated in the Eclipse TPS following RTOG 0813 dosimetric criteria, and treatment plans were calculated using AAA with heterogeneity correction (AAA plans). All the AAA plans were then recalculated using AXB with heterogeneity correction (AXB plans) for identical beam parameters and same number of monitor units. The AAA and AXB plans were compared for following RTOG 0813 parameters: ratio of prescription isodose volume to PTV (R100%), ratio of 50% prescription isodose volume to PTV (R50%), maximal dose 2 cm from the PTV in any direction as a percentage of prescription dose (D2cm), and the percentage of ipsilateral lung receiving dose equal to or larger than 20 Gy (V20). The phantom study showed that the results of AXB had better agreement with the measurements, and the difference ranged from -1.7% to 2.8%. The AAA results showed larger disagreement with the measurements, with differences from 4.1% to 12.5% for field size 5 × 5cm2 and from 1.4% to 6.8% for field size 10 × 10 cm2. The results from the RTOG SBRT lung cases showed that, on average, the AXB plans produced lower values for R100%, R50%, and D2cm by 4.96%, 1.15%, and 1.60%, respectively, but higher V20 of ipsilateral lung by 1.09% when compared with AAA plans. In the set of AAA plans, minor deviation was seen for R100% (six cases), R50% (nine cases), D2cm (four cases), and V20 (one case). Similarly, the AXB plans also showed minor deviation for R100% (one case), R50% (eight cases), D2cm (three cases), and V20 (one case). The dosimetric results presented in the current study show that both the AXB and AAA can meet the RTOG 0813 dosimetric criteria.

Jaramillo M.C.,University of Arizona | Zhang D.D.,University of Arizona | Zhang D.D.,Arizona Cancer Center
Genes and Development | Year: 2013

The Nrf2 (nuclear factor erythroid 2 [NF-E2]-related factor 2 [Nrf2])-Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1) signaling pathway is one of the most important cell defense and survival pathways. Nrf2 can protect cells and tissues from a variety of toxicants and carcinogens by increasing the expression of a number of cytoprotective genes. As a result, several Nrf2 activators are currently being tested as chemopreventive compounds in clinical trials. Just as Nrf2 protects normal cells, studies have shown that Nrf2 may also protect cancer cells from chemotherapeutic agents and facilitate cancer progression. Nrf2 is aberrantly accumulated in many types of cancer, and its expression is associated with a poor prognosis in patients. In addition, Nrf2 expression is induced during the course of drug resistance. Collectively, these studies suggest that Nrf2 contributes to both intrinsic and acquired chemoresistance. This discovery has opened up a broad spectrum of research geared toward a better understanding of the role of Nrf2 in cancer. This review provides an overview of (1) the Nrf2-Keap1 signaling pathway, (2) the dual role of Nrf2 in cancer, (3) the molecular basis of Nrf2 activation in cancer cells, and (4) the challenges in the development of Nrf2-based drugs for chemoprevention and chemotherapy. © 2013 Jaramillo and Zhang.

Bunch T.A.,Arizona Cancer Center
Journal of Biological Chemistry | Year: 2010

Integrin αIIbβ3 affinity regulation by talin binding to the cytoplasmic tail of β3 is a generally accepted model for explaining activation of this integrin in Chinese hamster ovary cells and human platelets. Most of the evidence for this model comes from the use of multivalent ligands. This raises the possibility that the activation being measured is that of increased clustering of the integrin rather than affinity. Using a newly developed assay that probes integrins on the surface of cells with only monovalent ligands prior to fixation, I do not find increases in affinity of αIIbβ3 integrins by talin head fragments in Chinese hamster ovary cells, nor do I observe affinity increases in human platelets stimulated with thrombin. Binding to a multivalent ligand does increase in both of these cases. This assay does report affinity increases induced by either Mn2+, a cytoplasmic domain mutant (D723R) in the cytoplasmic domain of β3, or preincubation with a peptide ligand. These results reconcile the previously observed differences between talin effects on integrin activation in Drosophila and fertebrate systems and suggest new models for talin regulation of integrin activity in human platelets. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Centuori S.M.,Arizona Cancer Center
Digestive diseases and sciences | Year: 2014

A high-fat diet coincides with increased levels of bile acids. This increase in bile acids, particularly deoxycholic acid (DCA), has been strongly associated with the development of colon cancer. Conversely, ursodeoxycholic acid (UDCA) may have chemopreventive properties. Although structurally similar, DCA and UDCA present different biological and pathological effects in colon cancer progression. The differential regulation of cancer by these two bile acids is not yet fully understood. However, one possible explanation for their diverging effects is their ability to differentially regulate signaling pathways involved in the multistep progression of colon cancer, such as the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway. This review will examine the biological effects of DCA and UDCA on colon cancer development, as well as the diverging effects of these bile acids on the oncogenic signaling pathways that play a role in colon cancer development, with a particular emphasis on bile acid regulation of the EGFR-MAPK pathway.

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