The premise behind this grant application is that impeccable characterization and understanding of a systemically administered new antineoplastic agent's pharmacology and effect on molecular targets in cancer should allow better clinical utilization of that agent. Determination of clinical toxicities and maximum tolerated dose (MTD) of an agent is no longer sufficient. Ideally, early clinical trials of an investigational agent should define pharmacokinetic (PK) disposition and metabolism, with correlation to pharmacodynamic (PD) manifestations at molecular, cellular, and clinical levels. With this abiding philosophy and hypothesis, performance of scientifically directed phase I trials of promising novel anti-cancer agents available through the National Cancer Institute is warranted. Integrating information regarding the mechanism of action and effect on molecular targets with development of biomarkers in phase I trials is the strategy that will be pursued with the following objectives to : define the toxicities of new antineoplastic agents in patients with advanced cancer;re-define (as necessary)the toxicities and PK of existing anticancer agents administered in combination with molecularly targeted agents, colony stimulating factors and other toxicity-ameliorating agents that may facilitate the exploration of more effective doses and schedules;provide information on the absorption, distribution, metabolism, and elimination of antitumor agents;define treatment regimens for use in phase II trials;establish, based on clinical and pharmacologic characteristics, appropriate phase II doses in special patient populations (e.g., patients with impaired organ function;heavily pretreated patients or geriatric patient populations), explore PK and PD differences based on sex, race, or ethnic group;obtain preliminary information on PK/PD correlations that can then be extended in phase II trials;incorporate basic laboratory and correlative science studies, when possible and appropriate, to enhance the understanding of the biochemical and/or biological mechanisms of drug actions;study the PK and the PD impact of drugs on specific metabolic pathways and molecular targets using non-invasive techniques such as magnetic resonance spectroscopy and nuclear imaging with radio-labeled drugs;and integrate pharmacogenomic studies to characterize differences in relevant drug metabolizing enzymes and drug targets related to toxicity and efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01CA099168-10S1
Application #
8628948
Study Section
Special Emphasis Panel (ZCA1-SRRB-K (O1))
Program Officer
Ivy, S Percy
Project Start
2003-03-18
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$254,109
Indirect Cost
$85,385
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lin, Fan; de Gooijer, Mark C; Roig, Eloy Moreno et al. (2014) ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res 20:2703-13
Gharpure, Santosh J; Nanda, Laxmi Narayan; Shukla, Manoj Kumar (2014) Donor-acceptor substituted cyclopropane to butanolide and butenolide natural products: enantiospecific first total synthesis of (+)-hydroxyancepsenolide. Org Lett 16:6424-7
Tawbi, Hussein (2014) Matching wits with melanoma brain metastases: from biology to therapeutics. Clin Cancer Res 20:5346-8
Kiesel, Brian F; Parise, Robert A; Tjornelund, Jette et al. (2013) LC-MS/MS assay for the quantitation of the HDAC inhibitor belinostat and five major metabolites in human plasma. J Pharm Biomed Anal 81-82:89-98
Gojo, Ivana; Tan, Ming; Fang, Hong-Bin et al. (2013) Translational phase I trial of vorinostat (suberoylanilide hydroxamic acid) combined with cytarabine and etoposide in patients with relapsed, refractory, or high-risk acute myeloid leukemia. Clin Cancer Res 19:1838-51
Choi, Serah; Bakkenist, Christopher J (2013) Brd4 shields chromatin from ATM kinase signaling storms. Sci Signal 6:pe30
Magge, D; Zureikat, A H; Bartlett, D L et al. (2013) A phase I trial of isolated hepatic perfusion (IHP) using 5-FU and oxaliplatin in patients with unresectable isolated liver metastases from colorectal cancer. Ann Surg Oncol 20:2180-7
Stearns, Vered; Jacobs, Lisa K; Fackler, Maryjo et al. (2013) Biomarker modulation following short-term vorinostat in women with newly diagnosed primary breast cancer. Clin Cancer Res 19:4008-16
Parise, Robert A; Beumer, Jan H; Clausen, Dana M et al. (2013) Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice. Cancer Chemother Pharmacol 72:1195-204
Beumer, J H (2013) Without therapeutic drug monitoring, there is no personalized cancer care. Clin Pharmacol Ther 93:228-30

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