There is an urgent need to develop novel therapies for malignant solid tumors. Tumor hypoxia, a reduction In partial oxygen pressure is a characteristic of solid tumor growth and develops following insufficient oxygen supply from preexisting vasculature. This phenomenon stimulates tumor progression by activating physiological responses that permit tumor-induced angiogenesis and metabolic adaptation to growth under a hypoxic environment. It is also a major factor in the resistance of cancer cells to radio- and chemo-therapies. Hypoxia triggers activation of Hypoxia-lnducible Factor 1 (HIF-1), a transcription factor that drives transcription of genes encoding pro-angiogenic factors and glycolytic enzymes that contribute to tumor growth. Strategies that inhibit HIF-1 function through HIF-?? knockdown or knockout approaches have reduced tumor growth in experimental models including glioblastoma, the most malignant brain tumor for which there is currently no effective therapy. Here we would like to test the hypothesis that small molecules that inhibit the HIF-1 pathway will inhibit the growth of glioblastoma, either singly or in combination with other agents. We have developed a novel pipeline of such potential therapeutic agents by screening a natural product-like library of small molecular compounds using a HIF-1-responsive cell-based reporter assay. We have generated extensive preliminary data showing that two structural classes of compounds identified have potent anti-HIF activity in vitro and in vivo. Furthermore, we have found that our lead HIF inhibitor acts via a unique mechanism and is able to strongly inhibit in vivo tumor growth upon systemic administration. Here we plan to further develop these lead molecules, test them further in animal models of glioblastoma as a model for an aggressive solid tumor relying on HIF-1 activation for its growth, and determine their precise mechanism of action. These studies are innovative in that these molecules have a novel unique chemical structure and mechanism of action, and there is a pressing need for small molecule HIF pathway inhibitors. These small molecules have great potential as candidate therapeutics for a large number of solid tumors that rely on the HIF pathway for their growth. These preclinical studies have the potential to directly benefit human health by increasing the survival of cancer patients, a main goal of the National Cancer Institute. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Developmental Therapeutics Study Section (DT)
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Forry, Suzanne L
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Emory University
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Dai, Xin; Kaluz, Stefan; Jiang, Ying et al. (2017) A novel small-molecule arylsulfonamide causes energetic stress and suppresses breast and lung tumor growth and metastasis. Oncotarget 8:99245-99260
Ferguson, Jalisa; De Los Santos, Zeus; Devi, Narra et al. (2017) Examining the structure-activity relationship of benzopyran-based inhibitors of the hypoxia inducible factor-1 pathway. Bioorg Med Chem Lett 27:1731-1736
Kim, Yong Joon; Kaluz, Stefan; Mehta, Anil et al. (2017) Purifying Properly Folded Cysteine-rich, Zinc Finger Containing Recombinant Proteins for Structural Drug Targeting Studies: the CH1 Domain of p300 as a Case Example. Bio Protoc 7:
Kalinina, Juliya; Ahn, Jun; Devi, Narra S et al. (2016) Selective Detection of the D-enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase. Clin Cancer Res 22:6256-6265
Luke, Jason J; Triozzi, Pierre L; McKenna, Kyle C et al. (2015) Biology of advanced uveal melanoma and next steps for clinical therapeutics. Pigment Cell Melanoma Res 28:135-47
Zerrouqi, Abdessamad; Pyrzynska, Beata; Brat, Daniel J et al. (2014) P14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway. Cancer Res 74:1371-8
Fan, Jun; Shan, Changliang; Kang, Hee-Bum et al. (2014) Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Mol Cell 53:534-48
Burroughs, Sarah K; Kaluz, Stefan; Wang, Danzhu et al. (2013) Hypoxia inducible factor pathway inhibitors as anticancer therapeutics. Future Med Chem 5:553-72
Zerrouqi, Abdessamad; Pyrzynska, Beata; Febbraio, Maria et al. (2012) P14ARF inhibits human glioblastoma-induced angiogenesis by upregulating the expression of TIMP3. J Clin Invest 122:1283-95
Kalinina, Juliya; Carroll, Anne; Wang, Liya et al. (2012) Detection of ""oncometabolite"" 2-hydroxyglutarate by magnetic resonance analysis as a biomarker of IDH1/2 mutations in glioma. J Mol Med (Berl) 90:1161-1171

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