DOCSLIB.ORG

1111111111111111111In11111

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1111111111111111111In11111 1111111111111111111in11111uumu (12) United States Patent (1o) Patent No.: US 8,679,835 B2 Hlatky (45) Date of Patent: Mar. 25, 2014 (54) TUMOR-INITIATING CELLS AND METHODS (56) References Cited OF USE U.S. PATENT DOCUMENTS (75) Inventor: Lynn Hlatky, Boston, MA (US) 2002/0102230 Al 8/2002 Wang et al. 2004/0142333 Al 7/2004 Lu et al. (73) Assignee: GeneSys Research Institute, Brighton, MA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Chakraborty (Cancer Research. 2000; 60:2512-2519).* Kirsten Walen (In Vitro Cell. Dev. Biol.-Animal; Jun. 2004; 40: patent is extended or adjusted under 35 150-158).* U.S.C. 154(b) by 0 days. Fridman et al. (Oncogene. 2003; 22: 9030-9040).* Chen et al. (Experimental Neurology. 2006; 198: 129-135).* (21) Appl. No.: 12/495,417 International Search Report dated Nov. 25, 2009, corresponding to related application PCT/US09/03924. (22) Filed: Jun. 30, 2009 Duelli et al., "Cell Fusion: Ahidden enemy?" Cancer Cell, May 2003, vol. 3, pp. 445-448. (65) Prior Publication Data Terada et al., "Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion", Nature, vol. 416, Apr. 4, 2002, pp. US 2010/0162419 Al Jun. 24, 2010 542-545. Related U.S. Application Data * cited by examiner (60) Provisional application No. 61/133,497, filed on Jun. 30, 2008. Primary Examiner Scott Long (74) Attorney, Agent, or Firm Edwards Wildman Palmer (51) Int. Cl. LLP; David G. Conlin; Richard B. Emmons A 01 67100 (2006.01) C12N 5112 (2006.01) (57) ABSTRACT C12N 5102 (2006.01) Provided herein are an isolated or enriched population of C12Q 1102 (2006.01) tumor initiating cells derived from normal cells, cells suscep- A61K39100 (2006.01) tible to neoplasia, or neoplastic cells. Methods of use of the (52) U.S. Cl. cells for screening for anti -hyperproliferative agents, and use USPC ............. 435/346; 435/325; 435/378; 435/29; of the cells for animal models of hyperproliferative disorders 435/377; 424/277.1 including metastatic cancer, diagnostic methods, and thera- (58) Field of Classification Search peutic methods are provided. None See application file for complete search history. 51 Claims, 20 Drawing Sheets U.S. Patent Mar. 25, 2014 Sheet 1 of 20 US 8,679,835 B2 a MLF—MLF LLC—LLC LF Figure U.S. Patent Mar. 25, 2014 Sheet 2 of 20 US 8,679,835 B2 .a ~j C .1: 1 1pl Four continu ed U.S. Patent Mar. 25, 2014 Sheet 3 of 20 US 8,679,835 B2 (58,8%) 60.[ 24,8% 114,7% ,e-540- 30, ------------------------------ 0 20.- --------------------------------- 10 0 MLF LLC MLF-&4LFp25 .0% ti No lwiwt 24 hr Figure I continued U.S. Patent Mar. 25, 2014 Sheet 4 of 20 US 8,679,835 B2 mall R-R 10 MEN-H* . ............ 0• ..... ..................... I m U.S. Patent Mar. 25,2014 Sheet 5 of 20 US 8,679,835 B2 MU-MU P-1 MLF-MLF p7 MLF-MLF p 17 LLC Figure '0' U.S. Patent Mar. 25, 2014 Sheet 6 of 20 US 8,679,835 B2 26 ~9 P 9 -9 9 Z Ns ssz .............. W9 .......... 0 - ------------------------------- 0 vt -- -------------------------------- - - - - ------------------------- (eultu) --MnIOA IOW-rJ- .................................... .................................... .............. .... ....... ....... --------------------------- Irlt co ------------------------------- (D L- Z3 U.S. Patent Mar. 25, 2014 Sheet 7 of 20 US 8,679,835 B2 05 w LO U.S. Patent Mar. 25,2014 Sheet 8 of 20 US 8,679,835 B2 -a \~ Q Q~ 44 <-~ <,, <Z <-Z- ALF-.,MLF Figure 6 U.S. Patent Mar. 25, 2014 Sheet 9 of 20 US 8,679,835 B2 U.S. Patent Mar. 25, 2014 Sheet 10 of 20 US 8,679,835 B2 d li4.1 -W ." Kf as 1W 4 0 0 U- AALF LLC k-LF4&F Figure 6 continued U.S. Patent Mar. 25, 2014 Sheet 11 of 20 US 8,679,835 B2 0 E E to poloeful Soo U.S. Patent Mar. 25, 2014 Sheet 12 of 20 US 8,679,835 B2 lj 1, 1 S, , L. 1, , , , , " t. 4k! t, , CA D cli Crl a ~ 1. Ili N 7, T, J, T, 7 L4 71 4 k,-, J, s j p" a'.. ~;. pn ! rot ~. i a w "j, ~ j3 e- D~ 171 r t, r P 1 J, 1~ J, C) (0 to tn LL C\j co to u 1= . co 'T C) C: -0 C) . cy) E 0 ~ww) awnlOA a 0 U.S. Patent Mar. 25, 2014 Sheet 13 of 20 US 8,679,835 B2 1 00 0 0 V 4): C 4, 'N era C? ' 1 AC'S 0 &10 0 110 t~0r ;r LL. LL LL UL u—l UL. C~ 0 U. LL j C> E Q) E CV 0 (,L,uw..) atun-10A JOWnl U.S. Patent Mar. 25, 2014 Sheet 14 of 20 US 8,679,835 B2 0 :E 0 E 0 N 0 1. C 0 4) -E ~ 0 M iz < 0 CD a 0 (SAeo) awl LL U.S. Patent Mar. 25, 2014 Sheet 15 of 20 US 8,679,835 B2 Q ON, 00 LL U.S. Patent Mar. 25, 2014 Sheet 16 of 20 US 8,679,835 B2 '' S is im .............. .. ... ........................... ......... ... ....................... ...... ....... .. ;.N W.10 iz U.S. Patent Mar. 25, 2014 Sheet 17 of 20 US 8,679,835 B2 CD T 4.e%as. U.S. Patent Mar. 25, 2014 Sheet 18 of 20 US 8,679,835 B2 A PSA-1HO Figure 11 U.S. Patent Mar. 25,2014 Sheet 19 of 20 US 8,679,835 B2 (D (D 0 0 U.S. Patent Mar. 25, 2014 Sheet 20 of 20 US 8,679,835 B2 2 3 I ............. ................. .................... ........ ;gi zpp Figure 11 continued US 8,679,835 B2 2 TUMOR-INITIATING CELLS AND METHODS Many cancers will eventually recur, and these recurrences can OF USE be fatal. This observation has given rise to the hypothesis that cancer may originate in a small population of cancer stem CROSS-REFERENCE TO RELATED cells that are responsible for the growth of tumors and that are APPLICATION 5 resistant to conventional cancer therapies. Cancer stem cells are believed to be quite rare, and have been difficult to isolate. This application claims the benefit of U.S. Provisional Methods for generating cells that are capable of initiating Application No. 61/133,497, filed on Jun. 30, 2008, the entire tumors and isolated populations of such cells are required for contents of which are incorporated herein by reference. the identification of novel anti-neoplastic agents that are use- 10 ful not only as chemotherapeutic s, but that can prevent cancer STATEMENT OF RIGHTS TO INVENTIONS relapse by targeting tumor-initiating cells that are capable of MADE UNDER FEDERALLY SPONSORED regenerating a tumor when anti-cancer therapy is completed. RESEARCH SUMMARY OF THE INVENTION The work was supported by in part, by NASA grant 15 NNJ06HA28G. The Government has certain rights in the The invention provides tumor-initiating cell compositions, invention. methods for producing a tumor-initiating cell, the use of such cells for the identification of agents useful for the treatment or BACKGROUND OF THE INVENTION prevention of neoplasia and neoplasia relapse following che- 20 motherapy or radiation therapy, as well as anti-neoplasia vac- Thirty years of investigations into the molecular genetics cines, and for the treatment of diseases and disorders associ- and signaling of cancer cells have revealed cancer to be a ated with a deficiency in cell number. genetic disease. The prevailing carcinogenesis paradigm The invention provides an isolated cell selected for having asserts that cancer originates from a single cell which, undergone at least one spontaneous cell-cell fusion, or a through a series of well-defined mutations and selected clonal 25 descendant of said cell, wherein said cell is self-renewing. expansions, ultimately transforms into a cancer cell. Intense Such cells can be used for the methods taught herein. study has identified three critical gene classes which contrib- The invention further provides a tumor-initiating cell ute to the carcinogenesis process: oncogenes, tumor-suppres- selected as having undergone spontaneous cell-cell fusion or sor genes and DNA repair genes, sometimes referred to as a descendant of said cell. Tumor-initiating cells of the inven- stability genes. Beyond the abnormal regulation of these clas- 30 tion give rise to a neoplasia in vitro or in vivo under suitable sic cancer genes, a number of additional processes which are growth conditions. Further, the tumor initiating cells of the common across cancer types have been identified as hall- invention exhibit one or more characteristic features as dem- marks of the disease. These include sustained angiogenesis, onstrated herein. These characteristics include, but are not tissue invasion and metastasis, and unlimited replicative limited to, aneuploidy, increased cellular proliferation rate capacity. Cancer cells also exhibit genomic instability, where 35 relative to a corresponding reference cell, periodically the progeny of cancer cells express increasing levels of chro- increased expression of VEGF, k-ras, myc, MMP-9, CD44 or mosomal aberrations and allelic imbalance. Genomic insta- Bcl-2 relative to a corresponding reference cell, periodically bility generates the vast genotypic and phenotypic diversity reduced expression of CDKn2A and p53 relative to a corre- found in all tumors, and it is the major obstacle in cancer sponding reference cell, formation of a colony in soft agar in treatment. 40 vitro, and formation of a tumor in vivo. Despite these major inroads into elucidating the carcino- The tumor initiating cells of the invention can be generated genesis process, there still remain large gaps in scientists' by the spontaneous fusion between a neoplastic cell and a understanding of how mutations actually drive cell transfor- neoplastic cell, a non-neoplastic cell and a neoplastic cell, or mation and the subsequent cancer progression.
Load more

Recommended publications
  • Thesis Was Carried out at the K
    Experimental modeling and novel therapeutic strategies in melanoma brain metastasis Terje Sundstrøm Dissertation for the degree of philosophiae doctor (PhD) University of Bergen, Norway 2015 Dissertation date: June 9th 2015 LIST OF ABBREVIATIONS 3D 3-dimensional 5-ALA 5-aminolevulinic acid AAAS American Association for the Advancement of Science ACT Adoptive cell transfer ADC Apparent diffusion coefficient AJCC American Joint Committee on Cancer AKT Protein kinase B ALK Anaplastic lymphoma kinase APC Antigen-presenting cell APOE Apolipoprotein-E ATP Adenosine triphosphate B7-H3 B7 homolog 3 BBB Blood-brain barrier BCL2A1 Bcl-2-related protein A1 bFGF Basic fibroblast growth factor BLI Bioluminescence imaging BRAF Serine/threonine-protein kinase B-raf BRMS1 Breast cancer metastasis-suppressor 1 BTB Blood-tumor barrier CI (Mitochondrial) Complex I CC22 Chemokine (C-C motif) ligand 22 CD44v6 CD44 splicing variant 6 CDK4 Cyclin-dependent kinase 4 CDKN2A p16INK4A inhibitor of CDK4 cMAP Connectivity Map CNS Central nervous system COT Serine/threonine kinase Cot CRAF RAF proto-oncogene serine/threonine-protein kinase CT Computed tomography CTLA4 Cytotoxic T-lymphocyte-associated protein 4 CXCR4 C-X-C chemokine receptor type 4 2 Da Dalton (unit) DNA Deoxyribonucleic acid DWI Diffusion weighted imaging ECM Extracranial metastases EDNRB Endothelin receptor B EFSA European Foods Safety Authority EGFR Epidermal growth factor receptor ER Estrogen receptor ERBB2 Receptor tyrosine-protein kinase erbB-2 ERK Extracellular signal-regulated kinase ET3 Endothelin-3
    [Show full text]
  • Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer
    Author Manuscript Published OnlineFirst on November 21, 2016; DOI: 10.1158/0008-5472.CAN-16-1901 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Systematic drug screening identifies tractable targeted combination therapies in triple-negative breast cancer Vikram B Wali1,3, Casey G Langdon2, Matthew A Held2, James T Platt1, Gauri A Patwardhan1, Anton Safonov1, Bilge Aktas1, Lajos Pusztai1,3, David F Stern2,3,Christos Hatzis1,3 1 Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA 2 Department of Pathology, Yale School of Medicine, Yale University, New Haven, Connecticut, USA 3 Yale Cancer Center, New Haven Connecticut, USA Corresponding authors: Christos Hatzis, Ph.D. or Vikram B Wali, Ph.D. Section of Medical Oncology Yale School of Medicine Yale University 333 Cedar Street PO Box 208032 New Haven, CT 06520 [email protected] [email protected] Running Title: Novel Combination Therapies in Triple Negative Breast Cancer CONFLICTS OF INTEREST Authors have no conflict of interest to disclose. 1 Downloaded from cancerres.aacrjournals.org on October 6, 2021. © 2016 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 21, 2016; DOI: 10.1158/0008-5472.CAN-16-1901 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. ABSTRACT Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation.
    [Show full text]
  • Mitochondrial Reprogramming in Tumor Progression and Therapy M
    Published OnlineFirst December 9, 2015; DOI: 10.1158/1078-0432.CCR-15-0460 Molecular Pathways Clinical Cancer Research Molecular Pathways: Mitochondrial Reprogramming in Tumor Progression and Therapy M. Cecilia Caino and Dario C. Altieri Abstract Small-molecule inhibitors of the phosphoinositide 3-kinase mitochondrial Hsp90s in preclinical development (gamitrinib) (PI3K), Akt, and mTOR pathway currently in the clinic produce a prevents adaptive mitochondrial reprogramming and shows paradoxical reactivation of the pathway they are intended to potent antitumor activity in vitro and in vivo. Other therapeutic suppress. Furthermore, fresh experimental evidence with PI3K strategies to target mitochondria for cancer therapy include antagonists in melanoma, glioblastoma, and prostate cancer small-molecule inhibitors of mutant isocitrate dehydrogenase shows that mitochondrial metabolism drives an elaborate process (IDH) IDH1 (AG-120) and IDH2 (AG-221), which opened new of tumor adaptation culminating with drug resistance and met- therapeutic prospects for patients with high-risk acute myelog- astatic competency. This is centered on reprogramming of mito- enous leukemia (AML). A second approach of mitochondrial chondrial functions to promote improved cell survival and to fuel therapeutics focuses on agents that elevate toxic ROS levels from the machinery of cell motility and invasion. Key players in these a leaky electron transport chain; nevertheless, the clinical expe- responses are molecular chaperones of the Hsp90 family com- rience with these compounds, including a quinone derivative, partmentalized in mitochondria, which suppress apoptosis via ARQ 501, and a copper chelator, elesclomol (STA-4783) is phosphorylation of the pore component, Cyclophilin D, and limited. In light of this evidence, we discuss how best to target enable the subcellular repositioning of active mitochondria to a resurgence of mitochondrial bioenergetics for cancer therapy.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix
    United States International Trade Commission Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix USITC Publication 4208 December 2010 U.S. International Trade Commission COMMISSIONERS Deanna Tanner Okun, Chairman Irving A. Williamson, Vice Chairman Charlotte R. Lane Daniel R. Pearson Shara L. Aranoff Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement Changes to the Pharmaceutical Appendix Publication 4208 December 2010 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 15, 2010, set forth at the end of this publication, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the United States International Trade Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement changes to the Pharmaceutical Appendix, effective on January 1, 2011. Table 1 International Nonproprietary Name (INN) products proposed for addition to the Pharmaceutical Appendix to the Harmonized Tariff Schedule INN CAS Number Abagovomab 792921-10-9 Aclidinium Bromide 320345-99-1 Aderbasib 791828-58-5 Adipiplon 840486-93-3 Adoprazine 222551-17-9 Afimoxifene 68392-35-8 Aflibercept 862111-32-8 Agatolimod
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Gene Regulatory Network Analysis with Drug Sensitivity Reveals Synergistic
    www.nature.com/scientificreports OPEN Gene regulatory network analysis with drug sensitivity reveals synergistic efects of combinatory chemotherapy in gastric cancer Jeong Hoon Lee1, Yu Rang Park 2, Minsun Jung 3 & Sun Gyo Lim 4* The combination of docetaxel, cisplatin, and fuorouracil (DCF) is highly synergistic in advanced gastric cancer. We aimed to explain these synergistic efects at the molecular level. Thus, we constructed a weighted correlation network using the diferentially expressed genes between Stage I and IV gastric cancer based on The Cancer Genome Atlas (TCGA), and three modules were derived. Next, we investigated the correlation between the eigengene of the expression of the gene network modules and the chemotherapeutic drug response to DCF from the Genomics of Drug Sensitivity in Cancer (GDSC) database. The three modules were associated with functions related to cell migration, angiogenesis, and the immune response. The eigengenes of the three modules had a high correlation with DCF (−0.41, −0.40, and −0.15). The eigengenes of the three modules tended to increase as the stage increased. Advanced gastric cancer was afected by the interaction the among modules with three functions, namely cell migration, angiogenesis, and the immune response, all of which are related to metastasis. The weighted correlation network analysis model proved the complementary efects of DCF at the molecular level and thus, could be used as a unique methodology to determine the optimal combination of chemotherapy drugs for patients with gastric cancer. Although its incidence is decreasing in some parts of the world, gastric cancer is still the fourth most common cancer worldwide1,2.
    [Show full text]
  • ROS and the DNA Damage Response in Cancer T Upadhyayula Sai Srinivasa,1, Bryce W.Q
    Redox Biology 25 (2019) 101084 Contents lists available at ScienceDirect Redox Biology journal homepage: www.elsevier.com/locate/redox ROS and the DNA damage response in cancer T Upadhyayula Sai Srinivasa,1, Bryce W.Q. Tana,1, Balamurugan A. Vellayappanb, ⁎ Anand D. Jeyasekharana,c, a Cancer Science Institute of Singapore, National University of Singapore, Singapore b Department of Radiation Oncology, National University Hospital, Singapore c Department of Haematology-Oncology, National University Hospital, Singapore ARTICLE INFO ABSTRACT Keywords: Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can Reactive Oxygen Species induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical ROS evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. DNA damage response Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA DDR damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to Chemotherapy the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed Radiotherapy success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance. 1. Introduction to the DNA damage response and ROS collectively termed as the DNA damage response (DDR) is activated. This response includes DNA damage recognition, activation of check- 1.1.
    [Show full text]
  • Clinical Trial Outcomes for Cancer Drug Combinations Can Be Predicted
    Clinical trial outcomes for cancer drug combinations can be predicted using cancer cell line monotherapy screens and a model of independent drug action Alexander Ling and R. Stephanie Huang Experimental and Clinical Pharmacology, University of Minnesota MSI Research Exhibition, 2020 Introduction In vitro validation of IDACombo Clinical validation of IDACombo In many cancer settings, it is evident that combination drug therapies show We utilized three high-throughput cancer cell line drug combination screens to Figure 4. Trial selection Figure 5. Clinical trial validation results increased efficacy compared to monotherapies. However, it is infeasible to validate whether or not IDACombo’s predicted drug combination efficacies match pipeline for clinical show accurate efficacy predictions for trials experimentally evaluate the vast number of possible drug combinations when with measured drug combination efficacies. For each screen, IDACombo was validation. Flowchart in previously untreated patients but not for designing new therapies. To overcome this problem, many computational used to predict drug combination efficacies using the monotherapy data from the detailing how completed, trials in previously treated patients. methods have been developed to estimate drug combination efficacy prior to screen, and then these predictions were compared to the measured drug phase III cancer clinical trials IDACombo’s predicted powers for PFS/TTP experimental testing using existing pre-clinical datasets. These methods have combination efficacies also available in each screen (Figure 2). were selected for the clinical correctly classify 88.5% of clinical trials in which focused on estimating drug synergy and additivity, but they have so far shown trial validation analysis. patients had not received cancer drug treatment limited potential to be translated to independent pre-clinical datasets or to clinical NCI-ALMANAC7 Searches of ClinicalTrials.gov prior to trial entry (Figure 5A), with >85% drug development.1,2 A B C and PubMed.gov were sensitivity and specificity.
    [Show full text]
  • Formerly STA-4783) at AACR-NCI-EORTC International Conference
    Synta Presents New Data on Elesclomol (Formerly STA-4783) at AACR-NCI-EORTC International Conference October 25, 2007 LEXINGTON, Mass.--(BUSINESS WIRE)--Oct. 25, 2007--Synta Pharmaceuticals Corp., (NASDAQ: SNTA) announced it presented new preclinical data on elesclomol (formerly STA-4783) at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics sponsored by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI) and the European Organization for Research and Treatment of Cancer (EORTC), in San Francisco, CA. Data presented at the conference confirmed that the primary mechanism of action of elesclomol is through the induction of reactive oxygen species (ROS) and provided details of the sequence of events by which programmed cell death (apoptosis) is induced. The results presented at the conference also provided evidence that elesclomol enhances the efficacy of several leading first-line cancer agents including Rituxan(R), Gemzar(R), and Taxotere(R), with minimal additional toxicity. Finally, the results showed that elesclomol has single agent anti-tumor activity. "Oxidative stress induction by elesclomol represents a novel and promising anti-cancer strategy," said James Barsoum, Ph.D., Senior Vice President of Research at Synta Pharmaceuticals. "Cancer cells operate at a much higher level of oxidative stress than normal cells. By causing the level of ROS in cancer cells to exceed sustainable levels, elesclomol selectively induces apoptosis in cancer cells, with minimal effects on normal cells. The elevation of ROS also appears to sensitize cancer cells to killing by other agents acting through the mitochondrial apoptosis pathway." "Taken together, the encouraging results presented at the conference on mechanism and combination activity provide continuing evidence that oxidative stress induction has broad potential application across multiple tumor types and in combination with widely used anti-cancer agents," said Dr.
    [Show full text]
  • Regulation of the Oxidative Stress Response by Arid1a
    The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2015 REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A Suet Yan Kwan Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Oncology Commons Recommended Citation Kwan, Suet Yan, "REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A" (2015). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 608. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/608 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. REGULATION OF THE OXIDATIVE STRESS RESPONSE BY ARID1A By Suet Yan Kwan, BSc APPROVED: ______________________________ Kwong-Kwok Wong, Ph.D. Advisory Professor ______________________________ Russell Broaddus, M.D., Ph.D. ______________________________ Joya Chandra, Ph.D.
    [Show full text]
  • Thesis Title Goes Here
    Development and Application of High-Throughput Chemical Genomic Screens for Functional Studies of Cancer Therapeutics by Kahlin Cheung-Ong A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Molecular Genetics University of Toronto © Copyright by Kahlin Cheung-Ong 2013 Development and Application of High-Throughput Chemical Genomic Screens for Functional Studies of Cancer Therapeutics Kahlin Cheung-Ong Doctor of Philosophy Department of Molecular Genetics University of Toronto 2013 Abstract Chemotherapeutic agents act by targeting rapidly dividing cancer cells. The full extent of their cellular mechanisms, which is essential to balance efficacy and toxicity, is often unclear. In addition, the use of many anticancer drugs is limited by dose-limiting toxicities as well as the development of drug resistance. The work presented in this thesis aims to address the basic biology that underlies these issues through the development and application of chemical genomic tools to probe mechanisms of current and novel anticancer compounds. Chemical genomic screens in the yeast Saccharomyces cerevisiae have been used to successfully identify targets and pathways related to a compound‟s mode of action. I applied these screens to examine the mode of action of potential anticancer drugs: a class of platinum-acridine compounds and the apoptosis-inducing compound elesclomol. By analogy to the yeast screens, I developed an RNAi-mediated chemical genomic screen in human cells which has the potential to reveal novel targets and drug mechanisms. This screen was applied to further understand doxorubicin‟s mode of action. In parallel with the loss-of-function assays, our lab developed a human ORF overexpression screen in human cells.
    [Show full text]
  • Supportive Oncology
    Utku_v1_A4_book_01_2011 14/12/2011 15:10 Page 228 Supportive Oncology The End of Cytotoxics? Nalân Utku Private Lecturer, Institute for Medical Immunology, Charité University Hospital Berlin Abstract Cytotoxic drugs were the first form of cancer chemotherapy to be established, but they can have quite severe side effects. Cytotoxics attack all rapidly dividing cells, including healthy cells and cancer cells. They can therefore cause side effects such as loss of hair, damage to the skin and mucosa, and damage to bone marrow, affecting the immune system. For this reason, the focus of some cancer research has moved from cytotoxics to targeted therapeutics, including monoclonal antibodies. Monoclonal antibodies can be very effective in patients who express the appropriate target; however, not all patients do, and some develop resistance. Monoclonal antibodies, like other biologicals, are also very costly. All is not lost for cytotoxics. Because they have been around for so long, there is an abundance of data on their modes of action. Based on these data, researchers have developed newer cytotoxics that are more effective and have fewer side effects, and approaches that deliver cytotoxics more safely or target them to tumours. Keywords Antigens, cancer, cytotoxics, drug delivery, monoclonal antibodies, targeting Disclosure: Nalân Utku is Managing Director of CellAct Pharma GmbH, a biotech company focused on the development of innovative therapeutics. Received: 5 May 2011 Accepted: 6 September 2011 Citation: European Oncology & Haematology, 2011;7(4):228–33 DOI: 10.17925/EOH.2011.07.04.228 Correspondence: Nalân Utku, Institut für Medizinische Immunologie, Charité Universitätsmedizin Berlin, Campus Virchow-Clinikum, Augustenburger Platz 1, 13353 Berlin, Germany.
    [Show full text]