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.
|Kim, Woosuk; Le, Thuc M; Wei, Liu et al. (2016) [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. Proc Natl Acad Sci U S A 113:4027-32|
|Faltermeier, Claire M; Drake, Justin M; Clark, Peter M et al. (2016) Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A 113:E172-81|
|Kirkby, Nicholas S; Chan, Melissa V; Zaiss, Anne K et al. (2016) Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-ÎºB and NFAT transcriptional pathways. Proc Natl Acad Sci U S A 113:434-9|
|TavarÃ©, Richard; Escuin-Ordinas, Helena; Mok, Stephen et al. (2016) An Effective Immuno-PET Imaging Method to Monitor CD8-Dependent Responses to Immunotherapy. Cancer Res 76:73-82|
|Atefi, Mohammad; Titz, Bjoern; Tsoi, Jennifer et al. (2016) CRAF R391W is a melanoma driver oncogene. Sci Rep 6:27454|
|Clark, Peter M; Mai, Wilson X; Cloughesy, Timothy F et al. (2016) Emerging Approaches for Targeting Metabolic Vulnerabilities in Malignant Glioma. Curr Neurol Neurosci Rep 16:17|
|Zaiss, Anne K; Foley, Erin M; Lawrence, Roger et al. (2016) Hepatocyte Heparan Sulfate Is Required for Adeno-Associated Virus 2 but Dispensable for Adenovirus 5 Liver Transduction In Vivo. J Virol 90:412-20|
|Barrio, Martin; Czernin, Johannes; Yeh, Michael W et al. (2016) The incidence of thyroid cancer in focal hypermetabolic thyroid lesions: an 18F-FDG PET/CT study in more than 6000 patients. Nucl Med Commun 37:1290-1296|
|Mok, Stephen; Tsoi, Jennifer; Koya, Richard C et al. (2015) Inhibition of colony stimulating factor-1 receptor improves antitumor efficacy of BRAF inhibition. BMC Cancer 15:356|
|Evdokimov, Nikolai M; Clark, Peter M; Flores, Graciela et al. (2015) Development of 2-Deoxy-2-[(18)F]fluororibose for Positron Emission Tomography Imaging Liver Function in Vivo. J Med Chem 58:5538-47|
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