Glioblastomas commonly (40%) exhibit epidermal growth factor receptor (EGFR) amplification; half of these tumors carry the EGFRvIII deletion variant characterized by an in-frame deletion of exons 2-7, resulting in constitutive EGFR activation. Although EGFR tyrosine kinase inhibitors had only modest effects in glioblastoma, novel therapeutic agents targeting amplified EGFR or EGFRvIII continue to be developed. Depatuxizumab mafodotin (ABT-414) is an EGFR-targeting antibody drug conjugate consisting...
Tue May 05, 2020 17:57
Esophageal squamous cell carcinoma (ESCC) is a disease characterized by a high mutation rate of the TP53 gene, which plays pivotal roles in the DNA damage response (DDR) and is regulated by checkpoint kinase (CHK) 2. CHK1 is another key DDR-related protein, and its selective inhibition is suggested to be particularly sensitive to TP53-mutated cancers, because a loss of both pathways (CHK1 and/or CHK2-p53) is lethal due to the serious impairment of DDR. Such a therapeutic strategy is termed synthetic...
Tue May 05, 2020 17:57
Therapeutic advances for osteosarcoma (OS) have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for OS by reformulating and validating niclosamide, an established anthelminthic agent, as a Niclosamide Stearate Prodrug Therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anti-cancer drugs. Nanoparticles...
Tue May 05, 2020 17:57
KRAS-mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergise with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination...
Tue May 05, 2020 17:57
Platinum-based chemoradiotherapy is a mainstay of organ-preserving therapy for head and neck squamous cell carcinoma cancer (HNSCC) patients. However, the disease eventually becomes resistant to treatment necessitating new therapies. Checkpoint kinase 1 and 2 (CHK1/2) are serine/threonine kinases that activate cell cycle checkpoints and serve a critical role in the DNA-damage response (DDR). As resistance to cisplatin and radiation may involve a heightened DDR, we hypothesized that prexasertib, an...
Tue May 05, 2020 17:57
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