ORCID Profile
0000-0002-6482-3474
Current Organisation
University of Sydney
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Publisher: American Physiological Society
Date: 12-2022
DOI: 10.1152/AJPENDO.00401.2021
Abstract: This is the first study to describe a model in which the preptin-coding portion of the Igf2 gene has been genetically ablated in mice. The mice do not show reduced size at birth associated with Igf2 knockout suggesting that IGF2 functionality is maintained, yet we demonstrate a change in the processing of mature Igf2. Female knockout mice have diminished glucose-stimulated insulin secretion, whereas the insulin response in males is not different to wild type.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523467
Abstract: Supplementary Data from Response to BRAF-targeted Therapy Is Enhanced by Cotargeting VEGFRs or WNT/β-Catenin Signaling in BRAF-mutant Colorectal Cancer Models
Publisher: MDPI AG
Date: 22-08-2019
DOI: 10.3390/BIOM9090402
Abstract: The hyper-activation of the phosphoinositide (PI) 3-kinase signaling pathway is a hallmark of many cancers and overgrowth syndromes, and as a result, there has been intense interest in the development of drugs that target the various isoforms of PI 3-kinase. Given the key role PI 3-kinases play in many normal cell functions, there is significant potential for the disruption of essential cellular functions by PI 3-kinase inhibitors in normal tissues so-called on-target drug toxicity. It is, therefore, no surprise that progress within the clinical development of PI 3-kinase inhibitors as single-agent anti-cancer therapies has been slowed by the difficulty of identifying a therapeutic window. The aim of this review is to place the cellular, tissue and whole-body effects of PI 3-kinase inhibition in the context of understanding the potential for dose limiting on-target toxicities and to introduce possible strategies to overcome these.
Publisher: American Association for Cancer Research (AACR)
Date: 05-10-2022
DOI: 10.1158/1535-7163.MCT-21-0941
Abstract: The fact that 10% of colorectal cancer tumors harbor BRAF V600E mutations suggested targeting BRAF as a potential therapy. However, BRAF inhibitors have only limited single-agent efficacy in this context. The potential for combination therapy has been shown by the BEACON trial where targeting the EGF receptor with cetuximab greatly increased efficacy of BRAF inhibitors in BRAF-mutant colorectal cancer. Therefore, we explored whether efficacy of the mutant BRAF inhibitor vemurafenib could be enhanced by cotargeting of either oncogenic WNT/β-catenin signaling or VEGFR signaling. We find the WNT/β-catenin inhibitors pyrvinium, ICG-001 and PKF118-310 attenuate growth of colorectal cancer cell lines in vitro with BRAF-mutant lines being relatively more sensitive. Pyrvinium combined with vemurafenib additively or synergistically attenuated growth of colorectal cancer cell lines in vitro. The selective and potent VEGFR inhibitor axitinib was most effective against BRAF-mutant colorectal cancer cell lines in vitro, but the addition of vemurafenib did not significantly increase these effects. When tested in vivo in animal tumor models, both pyrvinium and axitinib were able to significantly increase the ability of vemurafenib to attenuate tumor growth in xenografts of BRAF-mutant colorectal cancer cells. The magnitude of these effects was comparable with that induced by a combination of vemurafenib and cetuximab. This was associated with additive effects on release from tumor cells and tumor microenvironment cell types of substances that would normally aid tumor progression. Taken together, these preclinical data indicate that the efficacy of BRAF inhibitor therapy in colorectal cancer could be increased by cotargeting either WNT/β-catenin or VEGFRs with small-molecule inhibitors.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.BMC.2019.02.050
Abstract: Replacing one of the morpholine groups of the phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 with a variety of sulfonamide-linked solubilizing substituents produced a new class of active and potent PI3Kα inhibitors, with several derivatives demonstrating high PI3Kα enzyme potency and good cellular potency in two human derived cell lines. The overall results suggest a preference for linear and somewhat flexible solubilizing functions. From this series, compound 16, also known as SN32976, was selected for advanced preclinical evaluation.
Publisher: Wiley
Date: 22-06-2021
DOI: 10.1002/MDS.28665
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523467.V1
Abstract: Supplementary Data from Response to BRAF-targeted Therapy Is Enhanced by Cotargeting VEGFRs or WNT/β-Catenin Signaling in BRAF-mutant Colorectal Cancer Models
No related grants have been discovered for Christina Buchanan.