DESCRIPTION (provided by applicant): Brain cancer is the second leading cause of death in children under age 15 and in young adults up to age 34. Malignant glioma, the most common type of the primary brain tumors, remains largely incurable despite intensive multimodality treatments including surgical resection, irradiation and chemotherapy. There is a definite need for the development of novel therapeutic (e.g., targeted therapy) and diagnostic agents for this dreadful disease. The long-term goal of this proposed research is to develop clinically useful dual imaging and therapeutic targeting agents for glioblastoma. Integrins are potential targets for tumor imaging and therapy. Integrin 1321 is the major intergrin isotype expressed on the surface of glioma cells. Through screening "one-bead one- compound" (OBOC) combinatorial peptide libraries with a whole cell binding approach, we recently identified several cyclic peptide ligands against 1321 integrin. Modification of these peptides led to identification of a more potent peptide ligand, LXY1 (cyclic cdGLG- Hyp-Nc, Hyp=hydroxyproline), against malignant human glioblastoma A-172 and U- 87MG cell lines. In vivo optical imaging showed high tumor uptake in both subcutaneous and orthotopic U-87MG xenografts in mice. In this proposed research, we plan to use OBOC combinatorial library approaches to further optimize the lead compound LXY1. Highly potent and specific ligands will be selected to evaluate for in vivo tumor targeting and biodistribution studies in both subcutaneous and orthotopic U-87MG xenografts in mice, first using optical imaging and later microPET imaging. Because 64Cu is suitable for both PET imaging and radiotherapy, we hypothesize that fully optimized LXY1 derivatives for glioblastoma binding, when conjugated to a metal chelator CB-TE2A and labeled with 64Cu can be developed into new cancer-targeted PET imaging and radiotherapeutic agents for glioblastoma. Therapeutic effects of 64Cu-CB-TE2A-peptide are beyond the scope of this current R21 proposal. If successful, efficient and sensitive PET imaging agents can be used for early detection and diagnosis of glioblastoma, as well as a surrogate marker or end point for tumor response in therapeutic trials. PUBLIC HEALTH RELEVANCE: In this proposed research, highly potent and specific glioblastoma cell binding-peptides will be identified by focused one-bead one-compound library approaches. Such peptides, when radiolabeled with 64Cu, can be developed into clinically useful dual PET imaging and radiotherapeutic targeting agents for glioblastoma. MicroPET will be used to evaluate the cancer targeting potential of the peptides for glioblastoma in an orthotopic and subcutaneous xenograft mice model.
|Effective start/end date||7/1/08 → 6/30/11|
- National Institutes of Health: $171,000.00
- National Institutes of Health: $205,200.00