) The primary focus of the Developmental Therapeutics Program at Case Western Reserve University (CWRU)/University Hospitals Ireland Cancer Center (UHICC) has been to incorporate both pharmacokinetic and pharmacodynamic clinically assessable endpoints on which to base therapeutic intervention in all phase I clinical trials. It is anticipated that with more rational administration of cytotoxic chemotherapy that is mechanistically based the therapeutic ratio will be enhanced. For the p a s t several years, an interactive and multi-disciplinary team of investigators at our institution has effectively and creatively designed a variety of phase I clinical studies. Which are mechanistically-based. Recent efforts have explored the biochemical modulation of enzymes involved in DNA damage and repair metabolism, including principally, O-alkylguanine DNA alkyltransferase (AGT) and topoisomerase I. It is the intent of this application to continue to build on this strong clinical translational research theme and, more importantly, to provide a resource for the cooperative evaluation of scientifically directed phase I trials of anti-cancer agents in collaboration with the CTEP. Four areas of active interest have been identified by our program for phase I drug development as part of this cooperative agreement: 1) develop therapeutic regimens based on the biochemical modulation of the DNA repair enzyme (AGT) using a variety of agents including O benzylguanine (OBG), BCNU, temozolomide, and SarCNU; 2) i n i t i ate the first clinical trials of the photosensitizer silicon phthalocyanine Pc 4 - photodynamic therapy (PDT), a compound discovered at our institution; 3) translate promising strategies based in laboratory programs involving poly (ADP-ribose) polymerase (PARP) and NAD depletion, modulation of alkylating agent sensitivity by glucose-regulated protein GRP78, and topisomerase I into clinical trials; and finally 4) continue to employ the strategy of pharmacokinetic and pharmacodynamic-guided correlative studies in the evaluation of new agents that become available for study during the course of this cooperative agreement. A unique and important component of these studies is to continue to obtain sequential visceral CT-guided tumor biopsies for translational laboratory correlative studies. 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/UHICC and developed in collaboration with CTEP.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RLB-7 (O1))
Program Officer
Jensen, Leeann T
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 59 publications