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Patients with pancreatic ductal adenocarcinoma (PDAC) do not benefit from immune checkpoint blockade (ICB) along the PD-1/PD-L1 axis. Variable PD-L1 expression in PDAC indicates a potential access issue of PD-L1-targeted therapy. To monitor target engagement of PD-L1-targeted therapy, we generated a PD-L1-targeted PET tracer labeled with zirconium-89 ( 89 Zr). As the MAPK signaling pathway (MEK and ERK) is known to modulate PD-L1 expression in other tumor types, we used [ 89 Zr]Zr-DFO-anti-PD-L1 as a tool to noninvasively assess whether manipulation of the MAPK signaling cascade could be leveraged to modulate PD-L1 expression and thereby immunotherapeutic outcomes in PDAC. In this study, we observed that the inhibition of MEK or ERK is sufficient to increase PD-L1 expression, which we hypothesized could be leveraged for anti-PD-L1 immune checkpoint therapy. We found that the combination of ERK inhibition and anti-PD-L1 therapy corresponded with a significant improvement of overall survival in a syngeneic mouse model of PDAC. Furthermore, IHC analysis indicates that the survival benefit may be CD8 + T-cell mediated. The therapeutic and molecular imaging tool kit developed could be exploited to better structure clinical trials and address the therapeutic gaps in challenging malignancies such as PDAC., (©2021 American Association for Cancer Research.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, with a 5-year survival rate of less than 10%. Physicians often rely on biopsy or CT to guide treatment decisions, but these techniques fail to reliably measure the actions of therapeutic agents in PDAC. KRAS mutations are present in >90% of PDAC and are connected to many signaling pathways through its oncogenic cascade, including extracellular regulated kinase (ERK) and MYC. A key downstream event of MYC is transferrin receptor (TfR), which has been identified as a biomarker for cancer therapeutics and imaging., Experimental Design: In this study, we aimed to test whether zirconium-89 transferrin ([ 89 Zr]Zr-Tf) could measure changes in MYC depending on KRAS status of PDAC, and assess target engagement of anti-MYC and anti-ERK-targeted therapies., Results: Mice bearing iKras*p53* tumors showed significantly higher ( P < 0.05) uptake of [ 89 Zr]Zr-Tf in mice withdrawn from inducible oncogenic KRAS. A therapy study with JQ1 showed a statistically significant decrease ( P < 0.05) of [ 89 Zr]Zr-Tf uptake in drug versus vehicle-treated mice bearing Capan-2 and Suit-2 xenografts. IHC analysis of resected PDAC tumors reflects the data observed via PET imaging and radiotracer biodistribution., Conclusions: Our study demonstrates that [ 89 Zr]Zr-Tf is a valuable tool to noninvasively assess oncogene status and target engagement of small-molecule inhibitors downstream of oncogenic KRAS, allowing a quantitative assessment of drug delivery., (©2018 American Association for Cancer Research.)

Sixty-two anxious patients were treated under double-blind conditions for 4 weeks with either clorazepate or lorazepam. Two-thirds of each treatment group were then switched abruptly to placebo for 2 weeks, while one-third continued to receive active medication. Two major findings were obtained. About 70% of the patients maintained improvement during the 2-week placebo period. Some patients, however, experienced rebound anxiety, which appeared to be more intense and occurred earlier when placebo was substituted for a benzodiazepine with a short half-life (lorazepam) than for one with a long half-life (clorazepate). The clinical relevance of these findings is discussed.