The theme of this proposal is the clinical development of new therapeutic regimens for solid tumors based on modulation of enzymes involved in DNA damage and repair metabolism. Several inhibitors of enzymes involved in DNA damage and repair metabolism have recently entered clinical evaluation and are available for phase I development both as individual cytotoxic agents as well as modulators of established DNA damaging agents. This program brings together a strong interactive team of biochemists, clinical pharmacologists and clinicians to conduct pharmacokinetic and pharmacodynamic guided phase I trials to optimize the use of these new agents. Initial studies will focus on the clinical development of modulators of topoisomerase I and O6-alkylguanine alkyltransferase both as individual agents and in combination with established anticancer drugs whose cytotoxicity is mediated through effects on DNA metabolism. Pharmacokinetic guided phase I trials will be designed to optimize the administration of the topoisomerase I inhibitors 9-aminocamptothecin and topotecan. Novel therapeutic regimens based on combining cisplatinum with inhibitors of topoisomerase directed DNA repair will be developed. Novel strategies based on modulation of O6-alkylguanine alkyltransferase directed DNA repair will be developed to potentiate the cytotoxicity of chloroethylnitrosoureas such as BCNU. Agents which deplete O6-aklylguanine alkyltransferase either through initiation of methyladducts at the O6- position of guanine, for example temozolomide, or through direct inhibition of the enzyme, for example O6-benzylguanine, will be evaluated. Tissue biopsies will be obtained from patients entered on these trials to assess expression of biochemical targets in metastatic cancers and to monitor success of the desired modulation. The strategy developed for these pharmacokinetic and pharmacodynamic guided trials will be followed in the evaluation of new agents that become available for study during the course of this cooperative agreement. Agents which cause cytotoxicity by affecting DNA metabolism or that modulate an enzyme involved in response to DNA damage will be given priority. The identification, design and prioritization of phase I studies for new agents will be based on laboratory evaluation in preclinical models conducted at the CWRU/Ireland Cancer Center and developed in collaboration with staff of the Clinical Trials Evaluation and Development program of the National Cancer Institute.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Fu, P; Hughes, J; Zeng, G et al. (2016) A comparative investigation of methods for longitudinal data with limits of detection through a case study. Stat Methods Med Res 25:153-66
Ahmad, Md Faiz; Huff, Sarah E; Pink, John et al. (2015) Identification of Non-nucleoside Human Ribonucleotide Reductase Modulators. J Med Chem 58:9498-509
Schwandt, Anita; von Gruenigen, Vivian E; Wenham, Robert M et al. (2014) Randomized phase II trial of sorafenib alone or in combination with carboplatin/paclitaxel in women with recurrent platinum sensitive epithelial ovarian, peritoneal, or fallopian tube cancer. Invest New Drugs 32:729-38
Wildey, Gary; Chen, Yanwen; Lent, Ian et al. (2014) Pharmacogenomic approach to identify drug sensitivity in small-cell lung cancer. PLoS One 9:e106784
Kunos, Charles A; Sherertz, Tracy M (2014) Long-Term Disease Control with Triapine-Based Radiochemotherapy for Patients with Stage IB2-IIIB Cervical Cancer. Front Oncol 4:184
Mittal, Kriti; Koon, Henry; Elson, Paul et al. (2014) Dual VEGF/VEGFR inhibition in advanced solid malignancies: clinical effects and pharmacodynamic biomarkers. Cancer Biol Ther 15:975-81
Chee, Cheng Ean; Krishnamurthi, Smitha; Nock, Charles J et al. (2013) Phase II study of dasatinib (BMS-354825) in patients with metastatic adenocarcinoma of the pancreas. Oncologist 18:1091-2
Shibata, Stephen I; Chung, Vincent; Synold, Timothy W et al. (2013) Phase I study of pazopanib in patients with advanced solid tumors and hepatic dysfunction: a National Cancer Institute Organ Dysfunction Working Group study. Clin Cancer Res 19:3631-9
Abrams, Jeffrey S; Mooney, Margaret M; Zwiebel, James A et al. (2013) Implementation of timeline reforms speeds initiation of National Cancer Institute-sponsored trials. J Natl Cancer Inst 105:954-9
Savvides, Panayiotis; Nagaiah, Govardhanan; Lavertu, Pierre et al. (2013) Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. Thyroid 23:600-4

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