This translational research project will develop quantitative imaging bionnarkers for assessing therapeutic response in Sarcoma using advanced quantitative imaging approaches in PET and MRl.
In Specific Aim #1, dynamic contrast enhanced (DCE) and diffusion weighted (DW) MRl will be evaluated in a multi-center clinical trial of patients with soft tissue sarcoma ofthe extremities receiving neoadjuvant chemotherapy prior to surgical resection. DCE- and DW-MRI imaging will be performed prior to and at the conclusion of chemotherapy to evaluate the correlation between treatment response assessed with MRl parameters (permeability, perfusion, and diffusion) and tumor histopathology obtained from surgical resection. Exploratory analysis will also be performed to compare imaging and pathologic response with clinical outcome.
In Specific Aim #2, two novel PET apoptosis probes (18F-ML-10 and 1241-Diannexin) will be evaluated and compared to existing PET probes for glucose metabolism (FDG) and cellular proliferation (FLT). Similar strategies will be employed in Specific Aim #3 to evaluate hwo novel PET probes for angiogenesis (i8F-FPP(RgD) and 892R-beYaci?Ufnat)). Preclinical microPET/CT imaQlno studiQS will bQ performed in several sarcoma mouse models using the comprehensive panel of PET probes in longitudinal treatment studies of various therapeutic agents. Correlations with tumor histopathology will be performed to validate the imaging assessments. In addition, DCE and DW MRl imaging will be performed in the same studies to compare the more specific PET assessments of metabolism, proliferation, angiogenesis, and apopotosis with the MRl perfusion and diffusion measurements that are more clinically available. This will further refine and validate the interpretation of MRl imaging response measured in Specific Aim #1 as well develop more specific PET imaging probes for future clinical trials. Together, the Specific Aims of this proposal will advance bi-directional translational research that enhances the knowledge of clinical MRl biomarkers for assessing early drug response in sarcoma therapy (bedside to bench) as well as develop novel PET imaging agents that are translatable to clinical trials and patient care (bench to bedside).

Public Health Relevance

This project will develop new imaging approaches using MRl and PET to non-invasively measure various aspects of tumor biology and pathophysiology in response to conventional and experimental chemotherapies. This will enable a powerful set of tools to evaluate treatment efficacy and ultimately improve the development of new drugs and clinical management of sarcoma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA168512-03
Application #
8725491
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
3
Fiscal Year
2014
Total Cost
$267,525
Indirect Cost
$9,602
Name
Sarc
Department
Type
DUNS #
186146911
City
Ann Arbor
State
MI
Country
United States
Zip Code
48106
Feng, Yong; Sassi, Slim; Shen, Jacson K et al. (2015) Targeting CDK11 in osteosarcoma cells using the CRISPR-Cas9 system. J Orthop Res 33:199-207
Monument, Michael J; Johnson, Kirsten M; McIlvaine, Elizabeth et al. (2014) Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group. PLoS One 9:e104378
Choy, Edwin; Butrynski, James E; Harmon, David C et al. (2014) Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 14:813
Kernstine, Kemp H; Moon, James; Kraut, Michael J et al. (2014) Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-Intergroup Trial S0220. Ann Thorac Surg 98:402-10
Sankar, Savita; Theisen, Emily R; Bearss, Jared et al. (2014) Reversible LSD1 inhibition interferes with global EWS/ETS transcriptional activity and impedes Ewing sarcoma tumor growth. Clin Cancer Res 20:4584-97
Zhang, Pingyu; Garnett, Jeannine; Creighton, Chad J et al. (2014) EZH2-miR-30d-KPNB1 pathway regulates malignant peripheral nerve sheath tumour cell survival and tumourigenesis. J Pathol 232:308-18
Sioletic, Stefano; Czaplinski, Jeffrey; Hu, Lan et al. (2014) c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas. J Pathol 234:190-202
Chen, Eleanor Y; DeRan, Michael T; Ignatius, Myron S et al. (2014) Glycogen synthase kinase 3 inhibitors induce the canonical WNT/?-catenin pathway to suppress growth and self-renewal in embryonal rhabdomyosarcoma. Proc Natl Acad Sci U S A 111:5349-54
Krook, Melanie A; Nicholls, Lauren A; Scannell, Christopher A et al. (2014) Stress-induced CXCR4 promotes migration and invasion of ewing sarcoma. Mol Cancer Res 12:953-64
Jia, Bin; Choy, Edwin; Cote, Gregory et al. (2014) Cyclin-dependent kinase 11 (CDK11) is crucial in the growth of liposarcoma cells. Cancer Lett 342:104-12

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