Showing papers by "Luke Whitesell published in 2015"
TL;DR: This work functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays, suggesting that disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.
453 citations
TL;DR: In this article, the authors show that highly selective cytocidal action and evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.
Abstract: Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fungal sterol ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. To our surprise, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.
69 citations
01 Apr 2015
TL;DR: Surprisingly, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.
Abstract: Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. This benefit, however, often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report markedly less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and they bind their target (the fungal sterol ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. To our surprise, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies.
47 citations
TL;DR: A biomimetic approach for the synthesis of enantiomerically enriched aglains and rocaglamides via kinetic resolution of a bridged ketone utilizing enantioselective transfer hydrogenation is reported.
Abstract: We have previously reported asymmetric syntheses and absolute configuration assignments of the aglains (+)-ponapensin and (+)-elliptifoline and proposed a biosynthetic kinetic resolution process to produce enantiomeric rocaglamides and aglains. Herein, we report a biomimetic approach for the synthesis of enantiomerically enriched aglains and rocaglamides via kinetic resolution of a bridged ketone utilizing enantioselective transfer hydrogenation. The methodology has been employed to synthesize and confirm the absolute stereochemistries of the pyrimidone rocaglamides (+)-aglaiastatin and (−)-aglaroxin C. Additionally, the enantiomers and racemate of each metabolite were assayed for inhibition of the heat-shock response, cytotoxicity, and translation inhibition.
40 citations
TL;DR: In this article, the authors investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer.
Abstract: The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature-dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon re-exposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelial model and genetic tools to inhibit the heat-shock response (HSR), we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work therefore highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents.
31 citations
Patent•
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TL;DR: In this paper, the Heat Shock Protein-1 (HSF1) gene and HSF1 gene products in tumor stroma were used for tumor prognosis, treatment-specific prediction, or treatment selection.
Abstract: In some aspects, the invention relates to Heat Shock Protein- 1 (HSF1 ) gene and HSF1 gene products in tumor stroma. In some aspects, the invention provides methods of tumor prognosis, treatment-specific prediction, or treatment selection, the methods comprising measuring the level of HSF1 expression or HSF1 activation in a sample obtained from the tumor that comprises tumor-associated stromal cells. In some aspects, the invention relates to the discovery that increased HSF1 expression and increased HSF1 activation in tumor-associated stromal cells correlate with poor outcome in cancer. In some embodiments, the methods comprise measuring HSF1 expression or activation specifically in tumor-associated stromal cells. In some embodiments, the methods comprise measuring HSF1 expression or activation specifically in tumor-associated stromal cells and specifically in cancer cells. In some embodiments HSF1 expression or activation is measured using an antibody that specifically binds to HSF1. In some embodiments HSF1 expression or activation is measured by measuring expression of genes that are regulated by HSF1 in tumor-associated stromal cells. In some aspects, the invention relates to inhibiting HSF1 in tumor-associated stromal cells as an approach to cancer therapy.
5 citations
TL;DR: The data suggest that the HSR and UPR are recruited as cell survival mechanisms against the SLs treatments, giving rise to possible future chemotherapeutic combinatorial treatment options.
Abstract: Strigolactones (SLs) are a novel class of plant hormones that inhibit the self-renewal of undifferentiated meristem cells in shoots regulating above-ground plant architecture. Data from our lab have shown that SL analogues are able to inhibit the growth and survival of a wide array of cancer-derived cell lines including: prostate, colon, lung, breast and osteosarcoma (U2OS) while minimally affecting cultured normal cells. Treatment of cancer cells with SL analogues leads to the activation of stress-related signaling including p38MAPKs and JNK1/2, as well as the activation of the heat shock master regulator, heat shock transcription factor 1 (HSF1), and heat shock response (HSR) gene expression. We further show that SLs generate reactive oxygen species (ROS) and that SL treatments of cancer cells leads to the activation of GRP78, the master regulator of the unfolded protein response (UPR). To further characterize the relationship between SLs, HSR and UPR, several clones of HSF1 shRNA knockdown, in U2OS cells were generated and are currently being studied. Interestingly, while wild type mouse embryonic fibroblast (MEF) cells are refractory to SLs treatments, we demonstrate that HSF1 knockout in MEFs enhances the sensitivity of the cells to SLs treatments. Taken together, our data suggest that the HSR and UPR are recruited as cell survival mechanisms against the SLs treatments, giving rise to possible future chemotherapeutic combinatorial treatment options. Citation Format: Victor S. Wang, Nu Nu Kyin, Claire Pollock, Hyjoung Lee, Xin Li, Cristina Prandi, Yoram Kapulnik, Hinanit Koltai, Luke Whitesell, Ronit Yarden. The characterization of the effects of the strigolactones on the heat shock response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1777. doi:10.1158/1538-7445.AM2015-1777
2 citations
TL;DR: It is demonstrated that inactivation of HSF1 in acute myeloid leukemias (AMLs) by RHT exerts pronounced apoptogeniceffects with preferential activity against FLT3-ITD mutant cells in cell culture and in mice.
1 citations