Balanced expression of proteases and their inhibitors is one prerequisite of tissue homeostasis. Metastatic spread of tumor cells through the organism depends on proteolytic activity and is the death determinant for cancer patients. Paradoxically, increased expression of tissue inhibitor of metalloproteinases-1 (TIMP-1), a natural inhibitor of several endometalloproteinases, including matrix metalloproteinases and a disintegrin and metalloproteinase-10 (ADAM-10), in cancer patients is negatively correlated with their survival, although TIMP-1 itself inhibits invasion of some tumor cells. Here, we show that elevated stromal expression of TIMP-1 promotes liver metastasis in two independent tumor models by inducing the hepatocyte growth factor (HGF) signaling pathway and expression of several metastasis-associated genes, including HGF and HGF-activating proteases, in the liver. We also found in an in vitro assay that suppression of ADAM-10 is in principle able to prevent shedding of cMet, which may be one explanation for the increase of cell-associated HGF receptor cMet in livers with elevated TIMP-1. Similar TIMP-1-associated changes in gene expression were detected in livers of patients with metastatic colorectal cancer. The newly identified role of TIMP-1 to create a prometastatic niche may also explain the TIMP-1 paradoxon. [Cancer Res 2007;67(18):8615-23]

mTOR-inhibitor treatment either alone or in combination with CNIs reduces significantly the CMV incidence after organ transplantation. With the use of an mTOR-inhibitor, CMV prophylaxis may be dispensible.

SummaryCytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti-HCMV drug in development, acting via a novel mechanism of action. In this proof-ofconcept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14-day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open-label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV-DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti-CMV drug.

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