The theme of our program continues to be the integration of basic laboratory studies, animal model evaluation, and clinical trials to develop improved treatment for childhood solid tumors. The program is tightly focused on new and innovative approaches to improving cytotoxic therapy, and integrating signaling inhibitors with cytotoxic therapies. The theme of the program, developmental therapeutics for solid tumors, incorporates basic studies of how cellular stress (growth factor signaling hypoxia, DNA damage) impacts on drug sensitivity in solid tumors. Emphasis has been placed on the identification of pathways upstream and downstream of DNA damage that may be targets for new therapy, and on growth factor receptors that are involved in angiogenesis and in survival of cells treated with cytotoxic agents. We have structured the program to encompass objectives that can be accomplished within this cycle of support, and objectives that, realistically, could take longer to fulfill, but that may represent radically new approaches to curative therapy. Project 1 continues therapeutic studies of IGF-IR/Akt/mTOR inhibitors, and the role of IGF-IR signaling in childhood cancers. Project 2 extends studies that have demonstrated mTOR signaling regulates cellular response to DNA damage, and mutation frequency. Project 3 continues studies that demonstrate activation of the unfolded protein response (UPR) modulates cell sensitivity to cytotoxic agents, and will examine UPR activation in clinical tumors. Project 4 will elucidate how antiangiogenic agents may modulate the pharmacology of cytotoxic agents (ABC transporters) and provide new insights into clinically relevant ways to evaluate and monitor specific changes in tumor vascularity based on noninvasive assessments of changes in tumor blood flow/vasculature (through MRI and ultrasonography). These studies will allow building detailed pharmacokinetic and pharmacodynamic models that will assist in design of our clinical studies. Project 5 will continue novel Phase l/ll trials to test ideas emanating from the preclinical projects. We will continue to optimize therapy with topotecan and irinotecan, and initiate trials of irinotecan with rapamycin. Our trials will explore novel anti-angiogenic therapies, and investigate the single agent activity of small molecule or antibody therapy targeted to the IGF-I receptor alone or combined with rapamycin. Our intent remains to advance preclinical information to the design of clinical trials, and extend these to cooperative groups.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA023099-33
Application #
8117111
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Program Officer
Timmer, William C
Project Start
1998-07-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
33
Fiscal Year
2011
Total Cost
$2,230,285
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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
Yang, Jun; Milasta, Sandra; Hu, Dongli et al. (2017) Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox. Cancer Res 77:4626-4638
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
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
Talleur, Aimee C; Navid, Fariba; Spunt, Sheri L et al. (2016) Limited Margin Radiation Therapy for Children and Young Adults With Ewing Sarcoma Achieves High Rates of Local Tumor Control. Int J Radiat Oncol Biol Phys 96:119-26
Hurley, Caitlin; McCarville, M Beth; Shulkin, Barry L et al. (2016) Comparison of (18) F-FDG-PET-CT and Bone Scintigraphy for Evaluation of Osseous Metastases in Newly Diagnosed and Recurrent Osteosarcoma. Pediatr Blood Cancer 63:1381-6
Nebane, N Miranda; Coric, Tatjana; McKellip, Sara et al. (2016) Acoustic Droplet Ejection Technology and Its Application in High-Throughput RNA Interference Screening. J Lab Autom 21:198-203
D'Oto, Alexandra; Tian, Qing-Wu; Davidoff, Andrew M et al. (2016) Histone demethylases and their roles in cancer epigenetics. J Med Oncol Ther 1:34-40
Zhai, Yali; Kuick, Rork; Tipton, Courtney et al. (2016) Arid1a inactivation in an Apc- and Pten-defective mouse ovarian cancer model enhances epithelial differentiation and prolongs survival. J Pathol 238:21-30

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