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      Reproducibility of academic preclinical translational research: lessons from the development of Hedgehog pathway inhibitors to treat cancer

      Open Biology

      The Royal Society

      translational research, cancer, Hedgehog pathway, reproducibility, unconscious bias

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          Abstract

          Academic translational research is growing at a great pace at a time in which questions have been raised about the reproducibility of preclinical findings. The development of Hedgehog (HH) pathway inhibitors for the treatment of cancer over the past two decades offers a case study for understanding the root causes of failure to predict clinical outcomes arising from academic preclinical translational research. Although such inhibitors were once hoped to be efficacious in up to 25% of human cancer, clinical studies showed responses only in basal cell carcinoma and the HH subtype of medulloblastoma. Close examination of the published studies reveals limitations in the models used, lack of quantitative standards, utilization of high drug concentrations associated with non-specific toxicities and improper use of cell line and mouse models. In part, these issues arise from scientific complexity, for example, the failure of tumour cell lines to maintain HH pathway activity in vitro, but a greater contributing factor appears to be the influence of unconscious bias. There was a strong expectation that HH pathway inhibitors would make a profound impact on human cancer and experiments were designed with this assumption in mind.

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          Most cited references 131

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          Detection of circulating tumor DNA in early- and late-stage human malignancies.

          The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
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            Drug development: Raise standards for preclinical cancer research.

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              Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.

              Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.
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                Author and article information

                Journal
                Open Biol
                Open Biol
                RSOB
                royopenbio
                Open Biology
                The Royal Society
                2046-2441
                August 2018
                1 August 2018
                1 August 2018
                : 8
                : 8
                Affiliations
                Children's Research Institute , Children's Mercy Kansas City, 2401 Gillham Road, Kansas City, MI 64108, USA
                Author notes
                rsob180098
                10.1098/rsob.180098
                6119869
                30068568
                © 2018 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

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                August 2018

                Life sciences

                unconscious bias, reproducibility, hedgehog pathway, cancer, translational research

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