Gerner E.W.,Arizona Cancer Center
Cancer Prevention Research | Year: 2010
Ornithine decarboxylase has a relatively long history as a target for cancer chemoprevention and chemotherapy. Plym Forshell et al. report new evidence (beginning on p. 140 in this issue of the journal) indicating that spermidine synthase, a fellow enzyme of ornithine decarboxylase in polyamine metabolism, is transactivated in part by the MYC gene and is a potential target for chemoprevention of B-cell lymphomas. ©2010 AACR.
Brownlee C.W.,Arizona Cancer Center |
Rogers G.C.,Arizona Cancer Center
Cellular and Molecular Life Sciences | Year: 2013
Centrosomes are organelles involved in generating and organizing the interphase microtubule cytoskeleton, mitotic spindles and cilia. At the centrosome core are a pair of centrioles, structures that act as the duplicating elements of this organelle. Centrioles function to recruit and organize pericentriolar material which nucleates microtubules. While centrioles are relatively simple in construction, the mechanics of centriole biogenesis remain an important yet poorly understood process. More mysterious still are the regulatory mechanisms that oversee centriole assembly. The fidelity of centriole duplication is critical as defects in either the assembly or number of centrioles promote aneuploidy, primary microcephaly, birth defects, ciliopathies and tumorigenesis. In addition, some pathogens employ mechanisms to promote centriole overduplication to the detriment of the host cell. This review summarizes our current understanding of this important topic, highlighting the need for further study if new therapeutics are to be developed to treat diseases arising from defects of centrosome duplication. © 2012 Springer Basel AG.
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.
Weiss G.J.,Arizona Cancer Center
PloS one | Year: 2013
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.
Zhang D.D.,University of Arizona |
Zhang D.D.,Arizona Cancer Center
Antioxidants and Redox Signaling | Year: 2013
The targeted activation of nuclear factor erythroid-derived-2-like 2 (Nrf2) to alleviate symptoms of chronic kidney disease has recently garnered much attention. Unfortunately, the greatest clinical success to date, bardoxolone, failed in phase III clinical trial for unspecified safety reasons. The present letter to the editor discusses the clinical development of bardoxolone and explores potential reasons for the ultimate withdrawal from clinical trials. In particular, was the correct clinical indication pursued and would improved specificity have mitigated the safety concerns? Ultimately, it is concluded that the right clinical indication and heightened specificity will lead to successful Nrf2-based therapies. Therefore, the bardoxolone clinical results do not dampen enthusiasm for Nrf2-based therapies; rather it illuminates the clinical potential of the Nrf2 pathway as a drug target. Antioxid. Redox Signal. 19, 517-518. © Copyright 2013, Mary Ann Liebert, Inc. 2013.
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.
Li H.-Y.,University of Arizona |
Li H.-Y.,Arizona Cancer Center
Organic Letters | Year: 2014
An expeditious one-pot, ligand-free, Pd(OAc)2-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines was developed under microwave irradiation. With the high availability of commercial reagents and great efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines analogues. © 2014 American Chemical Society.
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.