The objectives listed for project 1 in the last grant submission have been successfully addressed during the most recent funding period. The following major accomplishments may be cited as a consequence of the activities of Project 1: (1) DIFFERENTIATION: Since the last grant submission, MSKCC has been a leading center of the development and rational application of all trans-retinoic acid therapy for the treatment of acute promyelocytic leukemia. Studies supported by this program included studies of the pharmacokinetics and metabolism of all trans retinoic acid, its toxicity and its efficacy in the treatment of acute promyelocytic leukemia. (2) DRUG MODULATION AND RESISTANCE: Clinical trials of idarubicin, liposomal doxorubicin and intra hepatic verapamil have been completed. Combination studies of Edatrexate and established chemotherapy agents are continuing. (3) NEW AGENT DEVELOPMENT: A variety of new agents have been tested including edatrexate, lometrexol, deoxyspergualin, topotecan and chloroquinoloxalone sulfonamide. In the next funding period, we will continue our early drug development studies, focused on Phase I and Pharmacology studies of putative differentiation agents, modulation studies and new combination studies. The purpose of project 1 will be to provide Phase I toxicity and pharmacology data on promising new approaches to chemotherapy which can then be applied in a disease specific manner in both projects 2 and 3.
The Specific Aims will be 1) To determine the clinical toxicity and pharmacology of PUTATIVE DIFFERENTIATION INDUCING AGENTS, including a new retinoid LNG 1069, phenylbutyrate, and a new analog of hexamethylene bisacetamide. 2) To conduct a dose escalation study of lobaplatin, a chemotherapy agent which appears to be good candidate for HIGH DOSE THERAPY with growth factor and autologous stem cell support. 3) To determine the effect of RESISTANCE MODULATING AGENTS on the toxicity and pharmacology of established anticancer agents. The modulating agents to be studied include carboxypeptidase G2, and edatrexate leucovorin. 4) To conduct phase I / pharmacology studies of NEW AGENTS AND COMBINATIONS which appear to be synergistic in preclinical studies. These studies will include Phase I studies of the murine/human chimeric antibody HC225 with CDDP, desoxyspergualin and murine antibody cc49, and edatrexate with CDDP / taxol as well as an adaptive control study of 96 h taxol/cddp.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA005826-34
Application #
5206388
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
34
Fiscal Year
1996
Total Cost
Indirect Cost
Tedeschi, Philip M; Vazquez, Alexei; Kerrigan, John E et al. (2015) Mitochondrial Methylenetetrahydrofolate Dehydrogenase (MTHFD2) Overexpression Is Associated with Tumor Cell Proliferation and Is a Novel Target for Drug Development. Mol Cancer Res 13:1361-6
Bell, Melanie L; Kenward, Michael G; Fairclough, Diane L et al. (2013) Differential dropout and bias in randomised controlled trials: when it matters and when it may not. BMJ 346:e8668
Zhou, Ping; Hoffman, James; Landau, Heather et al. (2012) Clonal plasma cell pathophysiology and clinical features of disease are linked to clonal plasma cell expression of cyclin D1 in systemic light-chain amyloidosis. Clin Lymphoma Myeloma Leuk 12:49-58
Rizvi, Naiyer A; Rusch, Valerie; Pao, William et al. (2011) Molecular characteristics predict clinical outcomes: prospective trial correlating response to the EGFR tyrosine kinase inhibitor gefitinib with the presence of sensitizing mutations in the tyrosine binding domain of the EGFR gene. Clin Cancer Res 17:3500-6
Zhao, Binsheng; Oxnard, Geoffrey R; Moskowitz, Chaya S et al. (2010) A pilot study of volume measurement as a method of tumor response evaluation to aid biomarker development. Clin Cancer Res 16:4647-53
Klimek, Virginia M; Fircanis, Sophia; Maslak, Peter et al. (2008) Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes. Clin Cancer Res 14:826-32
Riely, Gregory J; Kris, Mark G; Zhao, Binsheng et al. (2007) Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus. Clin Cancer Res 13:5150-5
Zhao, Binsheng; Schwartz, Lawrence H; Moskowitz, Chaya S et al. (2006) Lung cancer: computerized quantification of tumor response--initial results. Radiology 241:892-8
Maslak, P; Chanel, S; Camacho, L H et al. (2006) Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia 20:212-7
Yankeelov, Thomas E; Rooney, William D; Huang, Wei et al. (2005) Evidence for shutter-speed variation in CR bolus-tracking studies of human pathology. NMR Biomed 18:173-85

Showing the most recent 10 out of 39 publications