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The Mechanisms and Managements of Hormone-Therapy Resistance in Breast and Prostate Cancers
Endocrine-Related Cancer (2005) 12 511–532 REVIEW The mechanisms and managements of hormone-therapy resistance in breast and prostate cancers K-M Rau1,2*, H-Y Kang3,4*, T-L Cha1,5,6, S A Miller1 and M-C Hung1 1Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA 2Department of Hematology-Oncology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 3Graduate Institute of Clinical Medical Sciences, Chang Gung University, Kaohsiung, Taiwan 4The Center for Menopause and Reproductive Medicine Research, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Kaohsiung, Taiwan 5Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA 6Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (Requests for offprints should be addressed to M-C Hung; Email: [email protected]) *(K-M Rau and H-Y Kang contributed equally to this work) Abstract Breast and prostate cancer are the most well-characterized cancers of the type that have their development and growth controlled by the endocrine system. These cancers are the leading causes of cancer death in women and men, respectively, in the United States. Being hormone-dependent tumors, antihormone therapies usually are effective in prevention and treatment. However, the emergence of resistance is common, especially for locally advanced tumors and metastatic tumors, in which case resistance is predictable. The phenotypes of these resistant tumors include receptor- positive, ligand-dependent; receptor-positive, ligand-independent; and receptor-negative, ligand- independent. The underlying mechanisms of these phenotypes are complicated, involving not only sex hormones and sex hormone receptors, but also several growth factors and growth factor re- ceptors, with different signaling pathways existing alone or together, and with each pathway possibly linking to one another. -
Preclinical Toxicology – Points to Consider in Program Design
To view this booklet online, please visit PacificBioLabs.com. Preclinical Toxicology – Points To Consider in Program Design PACIFIC BIOLABS – YOUR PARTNER FOR PRECLINICAL SAFETY TESTING As The Service Leader in Bioscience Testing, Pacific BioLabs (PBL) strives to help our clients deliver safe and effective pharmaceuticals to the patients who need them. Well designed and executed preclinical studies are critical to the success of any drug development program. They must reliably assess the safety of a new drug entity, laying the groundwork for clinical trials and ultimately, regulatory approval. Pacific BioLabs interacts closely with our clients, providing quality nonclinical testing results to meet regulatory requirements and guide your drug development decisions. As part of our commitment to clients, we have prepared a pair of publications that will assist you in planning your preclinical testing program. This publication, Preclinical Toxicology – Points to Consider in Program Design, gives an overview of the drug development process, describes the contents of a typical Common Technical Document, shows the relative timing of various studies required for a successful IND and NDA, and presents advice on selecting and working with contract toxicology labs and other CROs. PBL’s companion publication, Preclinical Toxicology – Guidance for Industry – ICH Guidances, is available on our website at PacificBioLabs.com. It presents two major ICH guidance documents that directly address safety testing of new pharmaceuticals: Guidance M3 – Nonclincal Safety Studies for the Conduct of Human Clinical Trials for Pharmaceutical and Guidance S6 – Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. The FDA website http://www.fda.gov/cder/guidance contains these two documents along with a variety of other references on regulatory expectations for the nonclinical development of NCEs. -
Research and Development in the Pharmaceutical Industry
Research and Development in the Pharmaceutical Industry APRIL | 2021 At a Glance This report examines research and development (R&D) by the pharmaceutical industry. Spending on R&D and Its Results. Spending on R&D and the introduction of new drugs have both increased in the past two decades. • In 2019, the pharmaceutical industry spent $83 billion dollars on R&D. Adjusted for inflation, that amount is about 10 times what the industry spent per year in the 1980s. • Between 2010 and 2019, the number of new drugs approved for sale increased by 60 percent compared with the previous decade, with a peak of 59 new drugs approved in 2018. Factors Influencing R&D Spending. The amount of money that drug companies devote to R&D is determined by the amount of revenue they expect to earn from a new drug, the expected cost of developing that drug, and policies that influence the supply of and demand for drugs. • The expected lifetime global revenues of a new drug depends on the prices that companies expect to charge for the drug in different markets around the world, the volume of sales they anticipate at those prices, and the likelihood the drug-development effort will succeed. • The expected cost to develop a new drug—including capital costs and expenditures on drugs that fail to reach the market—has been estimated to range from less than $1 billion to more than $2 billion. • The federal government influences the amount of private spending on R&D through programs (such as Medicare) that increase the demand for prescription drugs, through policies (such as spending for basic research and regulations on what must be demonstrated in clinical trials) that affect the supply of new drugs, and through policies (such as recommendations for vaccines) that affect both supply and demand. -
Drug Discovery and Preclinical Development
Drug Discovery and Preclinical Development Neal G . Simon , Ph . D. Professor Department of Biological Sciences Disclaimer “Those wh o h ave k nowl ed ge, d on’t predi ct . Those who predict, don’t have knowledge.” Lao Tzu, 6th Century BC Chinese Poet Discovery and Preclinical Development I. Background II. The R&D Landscape III. ItidTftiInnovation and Transformation IV. The Preclinical Development Process V. Case Study: Stress-related Affective Disorders Serendipity or Good Science: Building Opportunity Hoffman Osterhof I. Background Drug Development Process Biopharmaceutical Drug Development: Attrition Drug FDA Large Scale Discovery Pre-Clinical Clinical Trials Review Manufacturing / Phase IV Phase I Phase III 20-100 1000-5000 Volunteers Volunteers 10,000 bmitted 1 FDA Com- bmitted 250 Compounds 5 Compounds uu pound uu AdApproved s Drug NDA S NDA IND S Phase II 100-500 Volunteers 5 years 1.5 years 6 years 2 years 2 years Quelle: Burrell Report Biotechnology Industry 2006 Capitalized Cost Estimates per New Molecule *All R&D costs (basic research and preclinical development) prior to initiation of clinical testing ** Based on a 5-year shift and prior growth rates for the preclinical and clinical periods. DiMasi and Grabowski (2007) II. The Research & Developppment Landscape R&D Expenditures and Return on Investment: A Declining Function Phrma (2005); Tufts CSDD (2005) R&D Expenditures 1992-2004 and FDA Approvals Hu et al (2007) NIH Budget by Area Pharmaceutical Industry: Diminishing Returns “That is why the business model is under threat: the ability to devise new molecules through R&D and bring them to market is not keeping up with what ’s being lost to generic manufacturers on the other end. -
Anticancer Activity of Bicalutamide-Loaded PLGA Nanoparticles in Prostate Cancers
EXPERIMENTAL AND THERAPEUTIC MEDICINE 10: 2305-2310, 2015 Anticancer activity of bicalutamide-loaded PLGA nanoparticles in prostate cancers JUN GUO1*, SHU-HONG WU2*, WEI-GUO REN3, XIN-LI WANG4 and AI-QING YANG5 1Department of Urology, The Affiliated Hospital of Taishan Medical University, Taian, Shandong 271000; 2Department of Urology, Feicheng Kuangye Central Hospital, Feicheng, Shandong 271608; 3Department of Urology, Rugao Boai Hospital, Nantong, Jiangsu 226500; 4Department of Pathology, The Affiliated Hospital of Taishan Medical University;5 Department of Pathology, The First People's Hospital of Taian, Taian, Shandong 271000, P.R. China Received October 6, 2014; Accepted August 26, 2015 DOI: 10.3892/etm.2015.2796 Abstract. Prostate cancer is the most commonly diagnosed Introduction non-cutaneous malignancy in men in western and most devel- oping countries. Bicalutamide (BLT) is an antineoplastic Men in Western countries and developing nations are hormonal agent primarily used in the treatment of locally frequently diagnosed with cancers of the prostate gland (1). advanced and metastatic prostate cancers. In the present study, Statistically, prostate cancer has overtaken heart diseases and the aim was to develop a nanotechnology-based delivery lung disorders in old people as a cause of mortality. According system to target prostate cancer cells. This involved the to estimates, >200,000 new cases of prostate cancer were development of a BLT-loaded poly(D,L-lactide-co-glycolide) reported with >30,000 mortalities during the year 2013 (2,3). PLGA (PLGA-BLT) nanoparticulate system in an attempt to A similar or higher number of cases has been projected for the improve the therapeutic efficacy of BLT in prostate cancer and year 2014 (4). -
Raloxifene for the Treatment of Triple Negative Breast Cancer
Raloxifene for the Treatment of Triple Negative Breast Cancer Julian Dzeyk A Thesis Submitted for the Degree of Master of Science At the University of Otago, Dunedin, New Zealand Submitted on February 29th 2012 Acknowledgments I would like to sincerely thank Associate Professor Rhonda Rosengren for giving me the opportunity to work on this project as well as her help and guidance throughout the entire time. I want to greatly thank Dr Sebastien Taurin for teaching me the majority of techniques used in this study, as well as for always being there to discuss my endless questions and thoughts. I have learned a lot from you. Thank you for your continuous help. I would like to thank Babasaheb Yadav for his help and for always bringing a smile or laugh into the lab. You made the ECCO 2011 conference in Stockholm a trip to remember! Thank you. I would also like to thank Mhairi Nimick for her help around the lab, especially for tumor slicing when I had my back problems. To everyone else in the department and especially my fellow MSc students, thank you for the help and the good times. I would also like to thank my family in Germany who have always supported me in my plans and future goals and have always provided me with constructive feedback and ideas. To my dearest Steffi, thank you for your love, and your honest and continuous support. You have been a relentless source of motivation and inspiration. To Andrea and Bernard, thank you for your continuous support, your patience, your constructive criticism, your help, and most of all your love. -
In Vitro and in Silico Analyses of the Inhibition of Human Aldehyde Oxidase By
JPET Fast Forward. Published on July 9, 2019 as DOI: 10.1124/jpet.119.259267 This article has not been copyedited and formatted. The final version may differ from this version. JPET #259267 In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues Shiyan Chen, Karl Austin-Muttitt, Linghua Harris Zhang, Jonathan G.L. Mullins, and Aik Jiang Lau Downloaded from Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore jpet.aspetjournals.org (S.C., A.J.L.); Institute of Life Science, Swansea University Medical School, United Kingdom (K.A-M, J.G.L.M.); NanoBioTec, LLC., Whippany, New Jersey, U.S.A. (L.H.Z.); at ASPET Journals on September 29, 2021 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (A.J.L.) 1 JPET Fast Forward. Published on July 9, 2019 as DOI: 10.1124/jpet.119.259267 This article has not been copyedited and formatted. The final version may differ from this version. JPET #259267 Running Title In Vitro and In Silico Analyses of AOX Inhibition by SERMs Corresponding author: Dr. Aik Jiang Lau Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543. Downloaded from Tel.: 65-6601 3470, Fax: 65-6779 1554; E-mail: [email protected] jpet.aspetjournals.org Number of text pages: 35 Number of tables: 4 Number of figures: 8 at ASPET Journals on September 29, 2021 Number of references 60 Number of words in Abstract (maximum -
Medication Use for the Risk Reduction of Primary Breast Cancer in Women: a Systematic Review for the U.S
Evidence Synthesis Number 180 Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov Contract No. HHSA-290-2015-00009-I, Task Order No. 7 Prepared by: Pacific Northwest Evidence-Based Practice Center Oregon Health & Science University Mail Code: BICC 3181 SW Sam Jackson Park Road Portland, OR 97239 www.ohsu.edu/epc Investigators: Heidi D. Nelson, MD, MPH Rongwei Fu, PhD Bernadette Zakher, MBBS Marian McDonagh, PharmD Miranda Pappas, MA L.B. Miller, BA Lucy Stillman, BS AHRQ Publication No. 19-05249-EF-1 January 2019 This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (HHSA-290-2015-00009-I, Task Order No. 7). The findings and conclusions in this document are those of the authors, who are responsible for its contents, and do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. -
WO 2009/137104 Al
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 12 November 2009 (12.11.2009) WO 2009/137104 Al (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/137 (2006.01) A61K 31/5685 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/138 (2006.01) A61P 35/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A61K 31/4196 (2006.01) CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, PCT/US2009/002885 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, 7 May 2009 (07.05.2009) NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, (25) Filing Language: English UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/127,025 9 May 2008 (09.05.2008) US GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, (71) Applicant (for all designated States except US): RA¬ TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, DIUS HEALTH, INC. -
Receptor Af®Nity and Potency of Non-Steroidal Antiandrogens: Translation of Preclinical ®Ndings Into Clinical Activity
Prostate Cancer and Prostatic Diseases (1998) 1, 307±314 ß 1998 Stockton Press All rights reserved 1365±7852/98 $12.00 http://www.stockton-press.co.uk/pcan Review Receptor af®nity and potency of non-steroidal antiandrogens: translation of preclinical ®ndings into clinical activity GJCM Kolvenbag1, BJA Furr2 & GRP Blackledge3 1Medical Affairs, Zeneca Pharmaceuticals, Wilmington, DE, USA; 2Therapeutic Research Department, and 3Medical Research Department, Zeneca Pharmaceuticals, Alderley Park, Maccles®eld, Cheshire, UK The non-steroidal antiandrogens ¯utamide (Eulexin1), nilutamide (Anandron1) and bicalutamide (Casodex1) are widely used in the treatment of advanced prostate cancer, particularly in combination with castration. The naturally occurring ligand 5a-DHT has higher binding af®nity at the androgen receptor than the non-steroidal antiandrogens. Bicalutamide has an af®nity two to four times higher than 2-hydroxy¯utamide, the active metabolite of ¯utamide, and around two times higher than nilutamide for wild-type rat and human prostate androgen receptors. Animal studies have indicated that bicalutamide also exhi- bits greater potency in reducing seminal vesicle and ventral prostate weights and inhibiting prostate tumour growth than ¯utamide. Although preclinical data can give an indication of the likely clinical activity, clinical studies are required to determine effective, well-tolerated dosing regimens. As components of combined androgen blockade (CAB), controlled studies have shown survival bene®ts of ¯utamide plus a luteinising hormone-releasing hormone analogue (LHRH-A) over LHRH-A alone, and for nilutamide plus orchiectomy over orchiectomy alone. Other studies have failed to show such survival bene®ts, including those comparing ¯utamide plus orchiectomy with orchiectomy alone, and nilutamide plus LHRH-A with LHRH-A alone. -
(12) Patent Application Publication (10) Pub. No.: US 2009/0226431 A1 Habib (43) Pub
US 20090226431A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0226431 A1 Habib (43) Pub. Date: Sep. 10, 2009 (54) TREATMENT OF CANCER AND OTHER Publication Classification DISEASES (51) Int. Cl. A 6LX 3/575 (2006.01) (76)76) InventorInventor: Nabilabil Habib,Habib. Beirut (LB(LB) C07J 9/00 (2006.01) Correspondence Address: A 6LX 39/395 (2006.01) 101 FEDERAL STREET A6IP 29/00 (2006.01) A6IP35/00 (2006.01) (21) Appl. No.: 12/085,892 A6IP37/00 (2006.01) 1-1. (52) U.S. Cl. ...................... 424/133.1:552/551; 514/182: (22) PCT Filed: Nov.30, 2006 514/171 (86). PCT No.: PCT/US2O06/045665 (57) ABSTRACT .."St. Mar. 6, 2009 The present invention relates to a novel compound (e.g., 24-ethyl-cholestane-3B.5C,6C.-triol), its production, its use, and to methods of treating neoplasms and other tumors as Related U.S. Application Data well as other diseases including hypercholesterolemia, (60) Provisional application No. 60/741,725, filed on Dec. autoimmune diseases, viral diseases (e.g., hepatitis B, hepa 2, 2005. titis C, or HIV), and diabetes. F2: . - 2 . : F2z "..., . Cz: ".. .. 2. , tie - . 2 2. , "Sphagoshgelin , , re Cls Phosphatidiglethanolamine * - 2 .- . t - r y ... CBs .. A . - . Patent Application Publication Sep. 10, 2009 Sheet 1 of 16 US 2009/0226431 A1 E. e'' . Phosphatidylcholine. " . Ez'.. C.2 . Phosphatidylserias. * . - A. z' C. w E. a...2 .". is 2 - - " - B 2. Sphingoshgelin . Cls Phosphatidglethanglamine Figure 1 Patent Application Publication Sep. 10, 2009 Sheet 2 of 16 US 2009/0226431 A1 Chile Phosphater Glycerol Phosphatidylcholine E. -
Establishing a Preclinical Multidisciplinary Board for Brain Tumors Birgit V
Published OnlineFirst January 4, 2018; DOI: 10.1158/1078-0432.CCR-17-2168 Cancer Therapy: Preclinical Clinical Cancer Research Establishing a Preclinical Multidisciplinary Board for Brain Tumors Birgit V. Nimmervoll1, Nidal Boulos2, Brandon Bianski3, Jason Dapper4, Michael DeCuypere5, Anang Shelat6, Sabrina Terranova1, Hope E. Terhune4, Amar Gajjar7, Yogesh T. Patel8, Burgess B. Freeman9, Arzu Onar-Thomas10, Clinton F. Stewart11, Martine F. Roussel12, R. Kipling Guy6,13, Thomas E. Merchant3, Christopher Calabrese14, Karen D. Wright15, and Richard J. Gilbertson1 Abstract Purpose: Curing all children with brain tumors will require an Results: Mouse models displayed distinct patterns of response understanding of how each subtype responds to conventional to surgery, irradiation, and chemotherapy that varied with tumor treatments and how best to combine existing and novel therapies. subtype. Repurposing screens identified 3-hour infusions of It is extremely challenging to acquire this knowledge in the clinic gemcitabine as a relatively nontoxic and efficacious treatment of alone, especially among patients with rare tumors. Therefore, we SEP and CPC. Combination neurosurgery, fractionated irradia- developed a preclinical brain tumor platform to test combina- tion, and gemcitabine proved significantly more effective than tions of conventional and novel therapies in a manner that closely surgery and irradiation alone, curing one half of all animals with recapitulates clinic trials. aggressive forms of SEP. Experimental Design: A multidisciplinary team was established Conclusions: We report a comprehensive preclinical trial to design and conduct neurosurgical, fractionated radiotherapy platform to assess the therapeutic activity of conventional and chemotherapy studies, alone or in combination, in accurate and novel treatments among rare brain tumor subtypes.