Purpose To assess the efficacy and safety of the anti-VEGF receptor-2 (VEGFR-2) antibody ramucirumab as first-line therapy in patients with advanced hepatocellular carcinoma and explore potential circulating biomarkers. Experimental Design Adults with advanced hepatocellular carcinoma and no prior systemic treatment received ramucirumab 8 mg/kg every two weeks until disease progression or limiting toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR) and overall survival (OS). Circulating biomarkers were evaluated before and after ramucirumab treatment in a subset of patients. Results Forty-two patients received ramucirumab. Median PFS was 4.0 months [95% confidence interval (CI), 2.6–5.7], ORR was 9.5% (95% CI, 2.7–22.6; 4/42 patients had apartial response), and median OS was 12.0 months (95% CI, 6.1–19.7). For patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease, median OS was 4.4 months (95% CI, 0.5–9.0) for patients with Child-Pugh B cirrhosis versus 18.0 months (95% CI, 6.1–23.5) for patients with Child-Pugh A cirrhosis. Treatment-related grade ≥3 toxicities included hypertension (14%), gastrointestinal hemorrhage and infusion-related reactions (7% each), and fatigue (5%). There was one treatment-related death (gastrointestinal hemorrhage). After treatment with ramucirumab, there was an increase in serum VEGF and placental growth factor (PlGF) and a transient decrease in soluble VEGFR-2. Conclusion Ramucirumab monotherapy may confer anticancer activity in advanced hepatocellular carcinoma with an acceptable safety profile. Exploratory biomarker studies showed changes in circulating VEGF, PlGF, and sVEGFR-2 that are consistent with those seen with other anti-VEGF agents.

Programmed cell death (apoptosis) is a normally occurring process used to eliminate unnecessary or potentially harmful cells in multicellular organisms. Recent studies demonstrate that the molecular control of this process is conserved phylogenetically in animals. The dad‐1 gene, which encodes a novel 113 amino acid protein, was originally identified in a mutant hamster cell line (tsBN7) that undergoes apoptosis at restrictive temperature. We have identified a dad‐1 homologue in Caenorhabditis elegans (Ce‐dad‐1) whose predicted product is > 60% identical to vertebrate DAD‐1. A search of the sequence databases indicated that DAD‐1‐like proteins are also expressed in two plant species. Expression of either human dad‐1 or Ce‐dad‐1 under control of a C.elegans heat‐shock‐inducible promoter resulted in a reduction in the number of programmed cell death corpses visible in C.elegans embryos. Extra surviving cells were present in these animals, indicating that both the human and C.elegans dad‐1 genes can suppress developmentally programmed cell death. Ce‐dad‐1 was found to rescue mutant tsBN7 hamster cells from apoptotic death as efficiently as the vertebrate genes. These results suggest that dad‐1, which is necessary for cell survival in a mammalian cell line, is sufficient to suppress some programmed cell death in C.elegans.

The defining structural motif of the inhibitor of apoptosis (iap) protein family is the BIR (baculovirus iap repeat), a highly conserved zinc coordination domain of ϳ70 residues. Although the BIR is required for inhibitor-of-apoptosis (IAP) function, including caspase inhibition, its molecular role in antiapoptotic activity in vivo is unknown. To define the function of the BIRs, we investigated the activity of these structural motifs within Op-IAP, an efficient, virus-derived IAP. We report here that Op-IAP 1-216 , a loss-of-function truncation which contains two BIRs but lacks the C-terminal RING motif, potently interfered with Op-IAP's capacity to block apoptosis induced by diverse stimuli. In contrast, Op-IAP 1-216 had no effect on apoptotic suppression by caspase inhibitor P35. Consistent with a mechanism of dominant inhibition that involves direct interaction be- The iap (inhibitor of apoptosis) genes function in phylogenetically diverse organisms to regulate apoptosis, a genetically programmed suicide response critical to normal development and tissue homeostasis (11,25,32,44). The iap genes are evolutionarily conserved in vertebrates and invertebrates, as well as their viral pathogens (41). As the first discovered members of the iap family (5, 10), baculovirus iap genes function to suppress apoptotic death of the host cell and thereby enhance virus production (reviewed in reference 33). In Drosophila melanogaster, loss of function of the cellular iap designated diap1 causes inappropriate cell death during fly development (18, 49). In mammals, including humans, overexpression of c-iap1, c-iap2, xiap, and survivin is associated with neoplasia (1,2,24,28,29) and genetic lesions in naip are linked to the neurodegenerative disorder spinal muscular atrophy (36). Collectively, this evidence attests to a critical physiological role for viral and cellular IAPs.The baculovirus iap repeat (BIR) is the defining sequence motif of the IAP protein family. Present in one to three tandem copies per protein, the ϳ70-residue BIR is required for antiapoptotic activity (reviewed in references 11, 25, and 32). The BIR possesses a highly conserved C2HC arrangement of Cys and His residues which participates in tetrahedral coordination with Zn and contributes to a novel fold, as indicated by solution structure (21, 38). The BIR is also necessary for IAP interaction with diverse proapoptotic factors, including the invertebrate death inducers Reaper, Grim, Hid, and Doom from Drosophila and vertebrate and invertebrate members of the caspase family of death proteases (12,13,15,23,35,40,45,46,49). How the BIR participates in interactions with these different proteins and thereby contributes to IAP function is unknown. In addition to the BIR, some IAPs possess a C-terminal RING finger motif, a common Zn-binding motif which appears to be distinct in structure and function (reviewed in references 11, 25, and 32).Current evidence suggests that IAPs act at conserved steps in the apoptotic-death pathway (reviewed in references 3, 11, 25, an...

BackgroundThe phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes.Patients and methodsPlasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment.ResultsBiomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers.ConclusionsThe RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing.Clinical trials registrationNCT01183780.

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