Our long-term goal is to advance cure rates for children with malignant solid tumors. The restructured program has an increased focus on developmental therapeutics, testing laboratory driven hypotheses developed from non-mammalian and mammalian experimental systems, in unique xenograft models of childhood cancers, with subsequent design of clinical trials that simulate schedules and systemic exposures found optimal in these models. This approach has been validated through our clinical project, where camptothecins, drugs that target DNA topoisomerase I, have demonstrated very significant activity in Phase I/II trials in pediatric patients. In this application we propose studies that will lead to a greater understanding of sensitivity or resistance to topoisomerase inhibitors, and will start of integrate cytotoxic agents with inhibitors of signal transduction pathways. Project 23 continues studies of mTOR signaling in growth, and survival of tumor cells. Studies will explore the therapeutic strategy of combining the mTOR inhibitor CCI-779, a rapamycin ester, in combination with IGF-I receptor antagonists and cytotoxic agents. Project 24 builds on the finding that hypomorphic alleles of genes that regulate cell cycle checkpoints in yeast confer dramatic hypersensitivity to camptothecin and rapamycin. Human homologues will be cloned, their function defined and their role in determining drug sensitivity in mammalian cells determined. Project 25 will focus on how know DNA damage response pathways determine cellular fate to camptothecins, and how hypoxia induced stress influences p53-directed cell fate. Project 26 will focus on how hypoxia or nutritional stress influences cellular sensitivity to topoisomerase II-targeted drugs and DNA cross-linking drugs through the unfolded protein response pathway. Project 27 builds on results showing that ZD1839 (an ErbB1 inhibitor) potently inhibits ABC transporters (BCRP/MRP4) that confer resistance to camptothecin drugs. The role of ZD1839 in reversing drug resistance, and altering the pharmacology of clinically used camptothecins will be explored. Project 10 comprises Phase I and II clinical trials with topotecan and irinotecan each of which is based on our laboratory and preclinical data. These protocols are supported by pharmacokinetic, and pharmacogenomic studies that ensure optimal systemic exposure, and biological studies designed to increase our understanding of parameters that determine therapeutic efficacy of camptothecin-based topoisomerase I inhibitors used alone or in combination. We will also evaluate the rapamycin ester, CCI-779, alone or in combination with vincristine, to test whether mTOR-targeted therapy will have therapeutic significance in children with solid malignancies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA023099-26
Application #
6784612
Study Section
Subcommittee G - Education (NCI)
Program Officer
Wu, Roy S
Project Start
1978-08-01
Project End
2007-06-30
Budget Start
2004-07-26
Budget End
2005-06-30
Support Year
26
Fiscal Year
2004
Total Cost
$1,604,058
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Dowless, Michele; Lowery, Caitlin D; Shackleford, Terry et al. (2018) Abemaciclib Is Active in Preclinical Models of Ewing Sarcoma via Multipronged Regulation of Cell Cycle, DNA Methylation, and Interferon Pathway Signaling. Clin Cancer Res 24:6028-6039
Bishop, Michael W; Advani, Shailesh M; Villarroel, Milena et al. (2018) Health-Related Quality of Life and Survival Outcomes of Pediatric Patients With Nonmetastatic Osteosarcoma Treated in Countries With Different Resources. J Glob Oncol :1-11
Wang, Tingting; Liu, Lingling; Chen, Xuyong et al. (2018) MYCN drives glutaminolysis in neuroblastoma and confers sensitivity to an ROS augmenting agent. Cell Death Dis 9:220
Feng, Helin; Tillman, Heather; Wu, Gang et al. (2018) Frequent epigenetic alterations in polycomb repressive complex 2 in osteosarcoma cell lines. Oncotarget 9:27087-27091
Hu, Dongli; Jablonowski, Carolyn; Cheng, Pei-Hsin et al. (2018) KDM5A Regulates a Translational Program that Controls p53 Protein Expression. iScience 9:84-100
Power-Hays, Alexandra; Friedrich, Paola; Fernandez, Gretchen et al. (2017) Delivery of radiation therapy in resource-limited settings: A pilot quality assessment study. Pediatr Blood Cancer 64:
Brennan, Rachel C; Qaddoumi, Ibrahim; Mao, Shenghua et al. (2017) Ocular Salvage and Vision Preservation Using a Topotecan-Based Regimen for Advanced Intraocular Retinoblastoma. J Clin Oncol 35:72-77
Yu, Peter Y; Gardner, Heather L; Roberts, Ryan et al. (2017) Target specificity, in vivo pharmacokinetics, and efficacy of the putative STAT3 inhibitor LY5 in osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. PLoS One 12:e0181885
Yang, Jun; Milasta, Sandra; Hu, Dongli et al. (2017) Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox. Cancer Res 77:4626-4638
Brennan, Rachel C; Qaddoumi, Ibrahim; Billups, Catherine A et al. (2016) Patients with retinoblastoma and chromosome 13q deletions have increased chemotherapy-related toxicities. Pediatr Blood Cancer 63:1954-8

Showing the most recent 10 out of 814 publications