iNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to radiotherapy, chemotherapy, or a combination of these modalities, and surgery remains the only curative intervention for localized disease. Although cancer-associated fibroblasts (CAF) are abundant in PDAC tumors, the effects of radiotherapy on CAFs and the response of PDAC cells to radiotherapy are unknown. Using patient samples and orthotopic PDAC biological models, we showed that radiotherapy increased inducible nitric oxide synthase (iNOS) in the tumor tissues. Mechanistic in vitro studies showed that, although undetectable in radiotherapy-activated tumor cells, iNOS expression and nitric oxide (NO) secretion were significantly increased in CAFs secretome following radiotherapy. Culture of PDAC cells with conditioned media from radiotherapy-activated CAFs increased iNOS/NO signaling in tumor cells through NF-κB, which, in turn, elevated the release of inflammatory cytokines by the tumor cells. Increased NO after radiotherapy in PDAC contributed to an acidic microenvironment that was detectable using the radiolabeled pH (low) insertion peptide (pHLIP). In murine orthotopic PDAC models, pancreatic tumor growth was delayed when iNOS inhibition was combined with radiotherapy. These data show the important role that iNOS/NO signaling plays in the effectiveness of radiotherapy to treat PDAC tumors. SIGNIFICANCE: A radiolabeled pH-targeted peptide can be used as a PET imaging tool to assess therapy response within PDAC and blocking iNOS/NO signaling may improve radiotherapy outcomes.

Imaging of human epidermal growth factor receptors for patient selection and response monitoring - From PET imaging and beyond.

The Human Epidermal Growth Factor Receptor (ErbB/HER) family - EGFR/HER1, ErbB-2/HER2, ErbB-3/HER3, and ErbB-4/HER4 - play a key role in tumor development. Moreover, positive status of HER2 and specific mutations of EGFR are necessary to initiate HER2 directed and EGFR mutation directed therapies. The status of these receptors is usually determined by assaying biopsy specimens of tumor tissues; however, tissue samples are insufficient to account for the complex dynamics and heterogeneity involved in HER status. Molecular imaging of receptors of the HER family have undergone much development, and some show promise for facilitating patient selection for HER therapy and monitoring of treatment response. This review provides a general overview of HER family expression and signaling in tumor tissue and more importantly discusses the available EGFR, HER2 and HER3 molecular imaging modalities, highlighting their use not only for selecting patients for receptor-targeted therapy, but also for monitoring therapeutic response. Additionally, the design and the biological evaluation of HER-specific imaging probes using different cancer models and clinical data are discussed.