NepaCancer

The human epidermal growth family (HER) of tyrosine kinase receptors underlies the pathogenesis of many types of human cancer. The oncogenic functions of three of the HER proteins can be unleashed through amplification, overexpression, or mutational activation. This has formed the basis for the development of clinically active targeted therapies. However, the third member HER3 is catalytically inactive, not found to be mutated or amplified in cancers, and its role and functions have remained shrouded in mystery. Recent evidence derived primarily from experimental models now seems to implicate HER3 in the pathogenesis of several types of cancer. Furthermore, the failure to recognize the central role of HER3 seems to underlie resistance to epidermal growth factor receptor (EGFR)- or HER2-targeted therapies in some cancers. Structural and biochemical studies have now greatly enhanced our understanding of signaling in the HER family and revealed the previously unrecognized activating functions embodied in the catalytically impaired kinase domain of HER3. This renewed interest and mechanistic basis has fueled the development of new classes of HER3-targeting agents for cancer therapy. However, identifying HER3-dependent tumors presents a formidable challenge and the success of HER3-targeting approaches depends entirely on the development and power of predictive tools. Clin Cancer Res; 16(5); 1373–83

Source:HER3 Comes of Age: New Insights into Its Functions and Role in Signaling, Tumor Biology, and Cancer Therapy

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Source:Is High-Grade Prostate Cancer Easier to Find in Smaller Prostates Because There Is More High-Grade Disease to Find? – Letter

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Purpose: Tumor necrosis factor- (TNF) is a cytokine with potent antitumor activity; however, toxicity and short half-life have limited its utility. Polyethylene glycol (PEG) conjugation of biotherapeutics can decrease immunogenicity while improving bioactivity and half-life. PEGylation of TNF (PEG-TNF) significantly improved half-life and toxicity in mice, resulting in enhanced antitumor activity. This study characterized toxicity, biological effect, and antitumor activity of PEG-TNF in pet dogs with spontaneous cancer.

Experimental Design: A phase I clinical trial enrolled dogs with measurable tumors in which standard therapy had failed or been declined. Physiologic, hematologic, and biochemical parameters were evaluated and tumor biopsies obtained serially. A subset of patients underwent serial dynamic contrast-enhanced magnetic resonance imaging.

Results: Fifteen dogs were enrolled at doses from 20.0 to 30.0 µg/kg. Dose-limiting toxicity at 30.0 µg/kg consisted of vascular leak in one and hypotension/coagulopathy in one, establishing 26.7 µg/kg as the maximum tolerated dose. Mean elimination half-life was 15.3 ± 4.9 hours. Biological activity (transient fever and leukopenia, increased tumor inflammation, and necrosis) was observed at all dosages. A significant increase in tumor blood flow was observed with dynamic contrast-enhanced magnetic resonance imaging. Minor/transient antitumor responses were observed in dogs with melanoma, squamous cell carcinoma, and mammary carcinoma, and a partial response was observed in a dog with angiosarcoma.

Conclusions: Using a clinically relevant, spontaneous large animal model of neoplasia, we have shown that biologically effective doses of PEG-TNF can be administered safely, and that PEG-TNF administration is associated with encouraging biological activity. These results justify the clinical evaluation of PEG-TNF in human cancer. Clin Cancer Res; 16(5); 1498–508

Source:Preclinical Investigation of PEGylated Tumor Necrosis Factor {alpha} in Dogs with Spontaneous Tumors: Phase I Evaluation

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YouTube, in a significant development for millions of deaf Internet users, extended automatic caption capability Thursday to all English-language videos on the video-sharing website.

Source:YouTube extends automatic video captioning

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Debate has simmered for a half-century over why firms pay out cash dividends, siphoning money away from business-building investments and often creating an added tax burden for the shareholders who collect them.

Source:Older investors a springboard for dividends, study says

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Researchers have discovered a key reason why a form of leukemia progresses from its more-treatable chronic phase to a life-threatening phase called blast crisis.

Source:Study identifies key cause of chronic leukemia progression

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