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11 - Predictive toxicology approaches for small molecule oncology drugs

from II - INTEGRATED APPROACHES OF PREDICTIVE TOXICOLOGY

Published online by Cambridge University Press:  06 December 2010

By
Timothy J. Maziasz ,
Vivek J. Kadambi  and
Carl L. Alden
Edited by
Jinghai J. Xu  and
Laszlo Urban
Jinghai J. Xu
Affiliation:
Merck Research Laboratory, New Jersey
Laszlo Urban
Affiliation:
Novartis Institutes for Biomedical Research, Massachusetts
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Summary

CANCER AS A WORLDWIDE DISEASE

Oncology therapeutic research and development represents the greatest opportunity today for pharmaceutical companies to significantly affect morbidity and mortality in the developed world. More than 12 million new cancer cases emerged worldwide in 2007. In 2009, approximately 560,000 people were projected to die from malignancies in the United States. According to the World Cancer Center Report 2008, cancer is destined to become the leading cause of death on the planet by 2010. The number of new cancer cases per year is predicted to triple by the year 2030, which represents 20 million to 26 million new cases and 13 million to 17 million additional deaths annually. Of equal significance is the number of new drugs undergoing testing for treatment of various forms of cancer. As of April 2009, 831 drugs and vaccines were in clinical development, which is a 32 percent increase over the number of oncologic agents in development in April 2008.

This daunting unmet medical need, coupled with the rapid demise of the majority of cancer patients, requires that oncology drug development follow a much different paradigm than that used for the development of drugs for non-life-threatening diseases. The challenges of oncology drug development are underscored by the fact that phase 1 clinical trials commonly include patients with nonresponsive late-stage disease and a mean life expectancy of 3 to 5 months; patients treated with oncology drugs targeted against solid metastatic tumor disease (excluding a few cancers, such as hormone-dependent metastatic prostate cancer), typically have a mean life expectancy of only 1 to 2 years.

Type
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Information
Predictive Toxicology in Drug Safety , pp. 204 - 229
Publisher: Cambridge University Press
Print publication year: 2010

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References

Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59(4):225–249.CrossRefGoogle ScholarPubMed
Boyle, P, Levin, B., ed. 2008. World Cancer Report 2008. Lyon Cedex: World Health Organization. www.who.int. Accessed February 2009.
Christel, MD. From pipeline to market: Pipelines bulk up as industry shakes up R&D, a surge in clinical projects spurs hope. R&D Directions. 2009;15:12–89.Google Scholar
,PhRMA. (2009). Pharmaceutical Industry report: industry profile 2009. www.phrma.org. Accessed February 2009.
DiMasi, JA, Grabowski, HG. Economics of new oncology drug development. J Clin Oncol. 2007;25(2):209–216.CrossRefGoogle ScholarPubMed
Griffith, J, Hardman, LEL, Gilman, AG. Goodman & Gilman's The Pharmacological Basis of Therapeutics. (Section IX, Table IX-1) 10th ed. McGraw-Hill Professional United States of America,;2001.Google Scholar
Gibbs, JB. Mechanism-based target identification and drug discovery in cancer research. Science. 2000;287(5460):1969–1973.CrossRefGoogle ScholarPubMed
Saijo, N, Tamura, T, Nishio, K. Problems in the development of target-based drugs. Cancer Chemother Pharmacol. 2000;46(Suppl):S43–45.CrossRefGoogle ScholarPubMed
Saijo, N. What are the reasons for negative phase III trials of molecular-target-based drugs?Cancer Sci. 2004;95(10):772–776.CrossRefGoogle ScholarPubMed
Haystead, TA. The purinome, a complex mix of drug and toxicity targets. Curr Top Med Chem. 2006;6(11):1117–1127.CrossRefGoogle ScholarPubMed
Knapp, M, Bellamacina, C, Murray, JM, et al. Targeting cancer: The challenges and successes of structure-based drug design against the human purinome. Curr Top Med Chem. 2006;6(11):1129–1159.CrossRefGoogle ScholarPubMed
Iglehart, JD, Silver, DP. Synthetic lethality – A new direction in cancer-drug development. N Engl J Med. 2009;361(2):189–191.CrossRefGoogle ScholarPubMed
Rosa, DD, Ismael, G, Lago, LD, et al. Molecular-targeted therapies: Lessons from years of clinical development. Cancer Treat Rev. 2008;34(1):61–80.CrossRefGoogle ScholarPubMed
Marchetti, S, Schellens, JH. The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials. Br J Cancer. 2007;97(5):577–581.CrossRefGoogle ScholarPubMed
Kola, I, Landis, J. Can the pharmaceutical industry reduce attrition rates?Nat Rev Drug Discov. 2004;3(8):711–715.CrossRefGoogle ScholarPubMed
Walker, I, Newell, H. Do molecularly targeted agents in oncology have reduced attrition rates?Nat Rev Drug Discov. 2009;8(1):15–16.CrossRefGoogle ScholarPubMed
Sasseville, VG, Lane, JH, Kadambi, VJ, et al. Testing paradigm for prediction of development-limiting barriers and human drug toxicity. Chem Biol Interact. 2004;150(1):9–25.CrossRefGoogle ScholarPubMed
Kramer, JA, Sagartz, JE, Morris, DL. The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates. Nat Rev Drug Discov. 2007;6(8):636–649.CrossRefGoogle ScholarPubMed
Smith, DA, Schmid, EF. Drug withdrawals and the lessons within. Curr Opin Drug Discov Devel. 2006;9(1):38–46.Google Scholar
Liebler, DC, Guengerich, FP. Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov. 2005;4(5):410–420.CrossRefGoogle ScholarPubMed
Hughes, JD, Blagg, J, Price, DA, et al. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg Med Chem Lett. 2008;18(17):4872–4875.CrossRefGoogle ScholarPubMed
Shanholtz, C. Acute life-threatening toxicity of cancer treatment. Crit Care Clin. 2001;17(3):483–502.CrossRefGoogle ScholarPubMed
Supko, JG, Hickman, RL, Grever, MR, et al. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother Pharmacol. 1995;36(4):305–315.CrossRefGoogle ScholarPubMed
Campillos, M, Kuhn, M, Gavin, AC, et al. Drug target identification using side-effect similarity. Science. 2008;321(5886):263–266.CrossRefGoogle ScholarPubMed
Lang, W, Caldwell, GW, Li, J, et al. Biotransformation of geldanamycin and 17-allylamino-17-demethoxygeldanamycin by human liver microsomes: Reductive versus oxidative metabolism and implications. Drug Metab Dispos. 2007;35(1):21–29.CrossRefGoogle ScholarPubMed
Nowakowski, GS, McCollum, AK, Ames, MM, et al. A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer. Clin Cancer Res. 2006;12(20 Pt 1):6087–6093.CrossRefGoogle ScholarPubMed
Guner, OF. Pharmacophore Perception, Development, and Use in Drug Design (IuI Biotechnology Series 2). (See Preface). International University Line; La Jolla, CA, 2000.
Smith, DA, Johnson, , Park, BK. Editorial overview: Safety of drugs can never be absolute. Curr Opin Drug Discov Devel. 2006;9(1):26–28.Google ScholarPubMed
Houck, KA, Kavlock, RJ. Understanding mechanisms of toxicity: Insights from drug discovery research. Toxicol Appl Pharmacol. 2008;227(2):163–178.CrossRefGoogle ScholarPubMed
Zambrowicz, BP, Sands, AT. Knockouts model the 100 best-selling drugs – Will they model the next 100?Nat Rev Drug Discov. 2003;2(1):38–51.CrossRefGoogle ScholarPubMed
Ryffel, B. Impact of knockout mice in toxicology. Crit Rev Toxicol. Mar 1997;27(2):135–154.CrossRefGoogle ScholarPubMed
Bolon, B. Genetically engineered animals in drug discovery and development: a maturing resource for toxicologic research. Basic Clin Pharmacol Toxicol. 2004;95(4):154–161.CrossRefGoogle ScholarPubMed
Lesko, LJ, Rowland, M, Peck, CC, et al. Optimizing the science of drug development: Opportunities for better candidate selection and accelerated evaluation in humans. Pharm Res. 2000;17(11):1335–1344.CrossRefGoogle ScholarPubMed
Caldwell, GW, Ritchie, DM, Masucci, JA, et al. The new pre-preclinical paradigm: Compound optimization in early and late phase drug discovery. Curr Top Med Chem. 2001;1(5):353–366.CrossRefGoogle ScholarPubMed
Atterwill, CK, Wing, MG. In vitro preclinical lead optimisation technologies (PLOTs) in pharmaceutical development. Toxicol Lett. 2002;127(1–3):143–151.CrossRefGoogle Scholar
Merlot, C. In silico methods for early toxicity assessment. Curr Opin Drug Discov Devel. 2008;11(1):80–85.Google ScholarPubMed
Wallace, KB. Mitochondrial off targets of drug therapy. Trends Pharmacol Sci. 2008;29(7):361–366.CrossRefGoogle ScholarPubMed
Aronov, AM. Tuning out of hERG. Curr Opin Drug Discov Devel. 2008;11(1):128–140.Google ScholarPubMed
Ng, R, Better, N, Green, MD. Anticancer agents and cardiotoxicity. Semin Oncol. 2006;33(1):2–14.CrossRefGoogle ScholarPubMed
Davies, SP, Reddy, H, Caivano, M, et al. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000;351(Pt 1):95–105.CrossRefGoogle ScholarPubMed
Fedorov, O, Marsden, B, Pogacic, V, et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA. 2007;104(51):20523–20528.CrossRefGoogle ScholarPubMed
Goldstein, DM, Gray, NS, Zarrinkar, PP. High-throughput kinase profiling as a platform for drug discovery. Nat Rev Drug Discov. 2008;7(5):391–397.CrossRefGoogle ScholarPubMed
Karaman, MW, Herrgard, S, Treiber, DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–132.CrossRefGoogle ScholarPubMed
Overington, JP, Al-Lazikani, B, Hopkins, AL. How many drug targets are there?Nat Rev Drug Discov. 2006;5(12):993–996.CrossRefGoogle Scholar
Castoldi, RE, Pennella, G, Saturno, GS, et al. Assessing and managing toxicities induced by kinase inhibitors. Curr Opin Drug Discov Devel. 2007;10(1):53–57.Google ScholarPubMed
Marshall, J. Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer. 2006;107(6):1207–1218.CrossRefGoogle ScholarPubMed
Lacouture, ME. Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006;6(10):803–812.CrossRefGoogle ScholarPubMed
Larkin, JM, Eisen, T. Kinase inhibitors in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol. 2006;60(3):216–226.CrossRefGoogle ScholarPubMed
Illanes, O, Anderson, S, Niesman, M, et al. Retinal and peripheral nerve toxicity induced by the administration of a pan-cyclin dependent kinase (cdk) inhibitor in mice. Toxicol Pathol. 2006;34(3):243–248.CrossRefGoogle ScholarPubMed
Kerkela, R, Grazette, L, Yacobi, R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12(8):908–916.CrossRefGoogle ScholarPubMed
Clark, JW, Eder, JP, Ryan, D, et al. Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43–9006, in patients with advanced, refractory solid tumors. Clin Cancer Res. 2005;11(15):5472–5480.CrossRefGoogle ScholarPubMed
Ramiro-Ibanez, F, Trajkovic, D, Jessen, B. Gastric and pancreatic lesions in rats treated with a pan-CDK inhibitor. Toxicol Pathol. 2005;33(7):784–791.CrossRefGoogle ScholarPubMed
Patyna, S, Arrigoni, C, Terron, A, et al. Nonclinical safety evaluation of sunitinib: A potent inhibitor of VEGF, PDGF, KIT, FLT3, and RET receptors. Toxicol Pathol. 2008;36(7):905–916.CrossRefGoogle ScholarPubMed
Balani, SK, Miwa, GT, Gan, LS, et al. Strategy of utilizing in vitro and in vivo ADME tools for lead optimization and drug candidate selection. Curr Top Med Chem. 2005;5(11):1033–1038.CrossRefGoogle ScholarPubMed
Leeson, PD, Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat Rev Drug Discov. 2007;6(11):881–890.CrossRefGoogle ScholarPubMed
Tomaszewski, JE. Multi-species toxicology approaches for oncology drugs: the US perspective. Eur J Cancer. 2004;40(6):907–913.CrossRefGoogle ScholarPubMed
Lab, Jackson (2009). The Jackson Lab Mice Database. jaxmice.jax.org/strain. Accessed February 2009
Dorato, MA, Engelhardt, JA. The no-observed-adverse-effect-level in drug safety evaluations: use, issues, and definition(s). Regul Toxicol Pharmacol. 2005;42(3):265–274.CrossRefGoogle Scholar
Lewis, RW, Billington, R, Debryune, E, et al. Recognition of adverse and nonadverse effects in toxicity studies. Toxicol Pathol. 2002;30(1):66–74.CrossRefGoogle ScholarPubMed
Newell, DR, Silvester, J, McDowell, C, et al. The Cancer Research UK experience of pre-clinical toxicology studies to support early clinical trials with novel cancer therapies. Eur J Cancer. 2004;40(6):899–906.CrossRefGoogle ScholarPubMed
Paulson, SK, Maziasz, TJ . Role of metabolism and pharmacokinetics in the development of celecoxib. In: Krishna, R, ed. Applications of Pharmacokinetics Principles in Drug DeliveryKluwer Academic/Plenum, New York, NY: 2003.Google Scholar
Hsieh, FY, Tengstrand, E, Lee, JW, et al. Drug safety evaluation through biomarker analysis – A toxicity study in the cynomolgus monkey using an antibody-cytotoxic conjugate against ovarian cancer. Toxicol Appl Pharmacol. 2007;224(1):12–18.CrossRefGoogle ScholarPubMed
O'Connell, D, Roblin, D. Translational research in the pharmaceutical industry: From bench to bedside. Drug Discov Today. 2006;11(17–18):833–838.CrossRefGoogle ScholarPubMed
Yamamoto, DS, Viale, PH. Cyclooxygenase-2: From arthritis treatment to new indications for the prevention and treatment of cancer. Clin J Oncol Nurs. 2003;7(1):21–29.CrossRefGoogle ScholarPubMed
Loerzel, VW, Dow, KH. Cardiac toxicity related to cancer treatment. Clin J Oncol Nurs. 2003;7(5):557–562.CrossRefGoogle ScholarPubMed
Force, T, Krause, DS, Etten, RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7(5):332–344.CrossRefGoogle ScholarPubMed
Simbre, VC, Duffy, SA, Dadlani, GH, et al. Cardiotoxicity of cancer chemotherapy: implications for children. Paediatr Drugs. 2005;7(3):187–202.CrossRefGoogle ScholarPubMed
Young, JL, Jr., Ries, LG, Silverberg, E, et al. Cancer incidence, survival, and mortality for children younger than age 15 years. Cancer. 1986;58(Suppl 2):598–602.3.0.CO;2-C>CrossRefGoogle ScholarPubMed
,U.S. Department of Health and Human Services, Food & Drug Administration, Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research. Guidance for industry: Pediatric Oncology Studies in Response to a Written Request. Rockville, MD; 2000.Google Scholar

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