While the cytoplasmic phase of the hepadnavirus replication cycle is well understood, very little is known about the nuclear phase. In contrast to retroviruses, proviral integration is not required for hepadnavirus replication; however, some of the viral DNAs in the nucleus are diverted into an integration pathway. Under certain conditions these integrations function as carcinogenic agents. In order to study the integration process, we have utilized LMH-D2 cells, which replicate wild-type duck hepatitis B virus (DHBV), to develop the first protocol to detect and characterize integrations of DHBV originating from episomal viral DNAs. Contrary to expectations, our results showed that stable new integrations are readily detectable in subclones of LMH-D2 cells. Complete characterization of one integration revealed a single-genome-length integrant with the structure of double-stranded linear (DSL) DHBV DNAs which are produced by in situ priming during viral replication. The integration contained a terminal redundancy of 6 bp from the r region of the virus DNA minus strand as well as a direct repeat of 70 bp of cellular DNA. On the basis of the structure of the integrant and the cellular DNA target site, we propose a molecular model for the integration mechanism that has some similarities to that of retroviruses. Identification of DSL hepadnavirus DNA integration suggests the possibility that modified DSL viral DNAs may be the precursors to a class of simple, unrearranged hepadnavirus integrations.

#1157 Background: In breast cancer patients with metastatic bone disease (MBD), an osteolytic process releases factors that sustain tumor cell survival and proliferation. Cathepsin (Cat) K inhibition suppresses osteolysis in preclinical models of MBD. This study assessed the efficacy and safety of odanacatib, a potent and reversible selective Cat K inhibitor, in reducing markers of bone resorption in women with breast cancer and MBD depending on concomitant anti-neoplastic treatment.
 Materials and Methods: Women with breast cancer and MBD were randomized (double-blind) to oral odanacatib 5 mg daily for 4 weeks or IV zoledronic acid (ZA) 4 mg given once at study initiation. Bone resorption was assessed by urinary N-telopeptide of type I collagen corrected for creatinine (uNTx). A post-hoc analysis of the influence of concomitant therapy (chemotherapy vs hormone therapy) on study medication effects on uNTx was also conducted. Adverse events (AE) were monitored throughout the 4-week study and up to 14 days after last dose.
 Results: 43 patients (mean age 60 yrs) received odanacatib (n=29) or ZA (n=14); 40 patients completed all 4 weeks of treatment. 12 (41%) and 17 (59%) patients on odanacatib and 6 (46%) and 7 (54%) patients on ZA received chemotherapy or hormone therapy, respectively; one patient was on both co-therapies and one patient on ZA was not on concomitant therapy. Results for the effect of study medication on uNTx as well as the effects of concomitant therapy on each treatment group are shown in the table; results for the full analysis set were similar. The most common reported AEs were nausea, vomiting, headache, and bone pain, and generally not attributed to study drug.
 Conclusions: In women with breast cancer and MBD, the Cat K inhibitor, odanacatib, suppressed markers of bone resorption after 4 weeks of treatment. Mean uNTx was decreased in both treatment groups. The effect on biomarkers observed in this study was seen irrespective of concomitant anti-neoplastic treatment. Odanacatib was generally safe and well tolerated. These results suggest that Cat K inhibition is a potentially important, novel therapeutic approach for treating MBD.
 
 Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1157.