Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin

Background: Trastuzumab has revolutionized treatment of HER2+ breast cancer. Globally accessible alternatives are a critical need. We evaluated Myl-1401O, a proposed trastuzumab biosimilar, as treatment for HER2+ metastatic breast cancer (MBC), based on physicochemical analyses, nonclinical, pharmacokinetic and pharmacodynamic studies*. Methods: Heritage is a double-blind, randomized clinical trial designed to evaluate comparative efficacy and safety of Myl-1401O vs Herceptin. Eligible patients (pts) had ..

Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation

Overexpression of the type II transmembrane serine protease matriptase is a highly consistent feature of human epithelial tumors. Here we show that matriptase possesses a strong oncogenic potential when unopposed by its endogenous inhibitor, HAI-1. Modest orthotopic overexpression of matriptase in the skin of transgenic mice caused spontaneous squamous cell carcinoma and dramatically potentiated carcinogen-induced tumor formation. Matriptase-induced malignant conversion was preceded by progressive interfollicular hyperplasia, dysplasia, follicular transdifferentiation, fibrosis, and dermal inflammation. Furthermore, matriptase induced activation of the pro-tumorigenic PI3K–Akt signaling pathway. This activation was frequently accompanied by H-ras or K-ras mutations in carcinogen-induced tumors, whereas matriptase-induced spontaneous carcinoma formation occurred independently of ras activation. Increasing epidermal HAI-1 expression completely negated the oncogenic effects of matriptase. The data implicate dysregulated matriptase expression in malignant epithelial transformation

Molecular analysis of anoikis resistance in oral cavity squamous cell carcinoma

Oral Cavity Squamous Cell Carcinoma (OSCC) is one of the leading causes of cancer deaths worldwide and most of these deaths result from local-regional recurrence and metastases. Evasion of apoptosis is an important hallmark of cancer development and progression, and previous studies have shown that evasion of anoikis, or detachment-induced apoptosis, correlates with a more aggressive phenotype of carcinoma cells in OSCC. To elucidate the cytogenetic and molecular characteristics of anoikis resistance, we generated several cell lines and clones that displayed this cellular phenotype. To test the hypothesis that chromosomal alterations may underlie this phenotypic transformation, we used karyotype analysis to observe changes in the chromosomal structure of anoikis-sensitive and anoikis-resistant cell lines. We further hypothesized that a unique pattern of gene expression was induced by cell-detachment of anoikis-resistant cell lines and cDNA microarray analysis was performed using a panel of anoikis-resistant oral cancer cell lines grown under attached and detached growth conditions. We identified S100P, KLK6 and CTNNAL1 as genes whose expression levels were differentially regulated in the anoikis-resistant cell lines compared to the anoikis-sensitive cells under detached conditions. These results were verified using real-time RT-PCR. The anoikis-resistant phenotype of squamous cell carcinoma has a distinct genetic expression pattern that is marked by chromosomal alterations that may contribute to differential expression of genes involved in diverse cellular functions. Therapies targeting these potential mediators of anoikis resistance may prove to be beneficial in the treatment of metastatic squamous cell carcinoma