Metastatic melanoma has very limited treatment options. However, advances in adoptive cell transfer (ACT) therapy and the development of clinically effective specific inhibitors for BRAF^^??^ oncogenic mutations are providing novel effective therapies for this disease. Over the past 5 years of ICMIC funding we have been testing both the immunotherapy and kinase inhibition approaches in preclinical models and in patients. Molecular imaging technologies have been critical, in both the preclinical mouse model studies and in the clinical investigations, in investigating and understanding the mechanisms of action of these new treatment strategies. For the next 5 years we propose to harnesses the benefits of molecular imaging to guide and evaluate novel therapeutic strategies for patients with metastatic melanoma. Our proposal has two dominant specific aims:
Specific Aim 1. Imaging TCR Engineering Adoptive Cell Transfer Therapy in Humans. We hypothesize that the combined use of nucleoside-based PET probes ([^^FJFLT and [ FjFAC) and PET reporter gene expression (HSV1-sr39tk imaged by [''^FjFHBG) will allow us to determine how best to define and implement ACT therapy based on T cell receptor (TCR) genetically redirected lymphocytes. The combination of small molecule-based PET tracers and PET reporter genes will allow us to determine, by non-invasive monitoring, how TCR transgenic cells adoptively transferred to patients with metastatic melanoma provide immune reconstitution and efficient tumor targeting.
Specific Aim 2. Imaging Combined Therapy with Oncogenic BRAF[V6ooE) Inhibition and Immunotherapy. We hypothesize that the benefits of long term tumor responses with immunotherapy can be merged with the benefits of high frequency tumor responses with targeted small molecule oncogene inhibition. This approach will include the combination of TCR transgenic ACT and the specific BRAF inhibitor PLX4032 in HLA-A2.1 positive patients with BRAF(V600E) mutated melanoma. We will test, in murine models we are developing, if a combination of PET probes will allow the simultaneous study of immune activation (  FJFAC) and tumor responses ([  FjFDG). When properly evolved, we will take this combined therapy/combined imaging approach to the clinic.
Metastatic melanoma is a disease with very limited treatment options. Developing novel therapies for this cancer with a dismal prognosis when using standard of care treatment approaches is of great importance for patient care. This new treatment development will be aided by non-invasive imaging using PET probes.
|Jiao, Jing; Ishikawa, Tomo-O; Dumlao, Darren S et al. (2014) Targeted deletion and lipidomic analysis identify epithelial cell COX-2 as a major driver of chemically induced skin cancer. Mol Cancer Res 12:1677-88|
|Jiao, Jing; Mikulec, Carol; Ishikawa, Tomo-o et al. (2014) Cell-type-specific roles for COX-2 in UVB-induced skin cancer. Carcinogenesis 35:1310-9|
|Shurell, Elizabeth; Tran, Linh M; Nakashima, Jonathan et al. (2014) Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients. BMC Cancer 14:827|
|Mongini, Patricia K A; Kramer, Jill M; Ishikawa, Tomo-O et al. (2014) Candidate chromosome 1 disease susceptibility genes for Sjogren's syndrome xerostomia are narrowed by novel NOD.B10 congenic mice. Clin Immunol 153:79-90|
|Wilks, Moses Q; Knowles, Scott M; Wu, Anna M et al. (2014) Improved modeling of in vivo kinetics of slowly diffusing radiotracers for tumor imaging. J Nucl Med 55:1539-44|
|Schwarzenberg, Johannes; Czernin, Johannes; Cloughesy, Timothy F et al. (2014) Treatment response evaluation using 18F-FDOPA PET in patients with recurrent malignant glioma on bevacizumab therapy. Clin Cancer Res 20:3550-9|
|Wardak, Mirwais; Schiepers, Christiaan; Cloughesy, Timothy F et al. (2014) ¹?F-FLT ???and ¹?F-FDOPA PET kinetics in recurrent brain tumors. Eur J Nucl Med Mol Imaging 41:1199-209|
|Nathanson, David A; Armijo, Amanda L; Tom, Michelle et al. (2014) Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication. J Exp Med 211:473-86|
|Hirata, Kenji; Kobayashi, Kentaro; Wong, Koon-Pong et al. (2014) A semi-automated technique determining the liver standardized uptake value reference for tumor delineation in FDG PET-CT. PLoS One 9:e105682|
|Escuin-Ordinas, Helena; Atefi, Mohammad; Fu, Yong et al. (2014) COX-2 inhibition prevents the appearance of cutaneous squamous cell carcinomas accelerated by BRAF inhibitors. Mol Oncol 8:250-60|
Showing the most recent 10 out of 184 publications