iCare 1: A prospective clinical trial to predict treatment response based on genomics-informed computational biology in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

Drusbosky, Leylah; Hawkins, Kimberly E.; Turcotte, Madeleine; Anderson, Glenda G.; Vali, Shireen; Abbasi, Taher; Zou, Fei; Farhadfar, Nosha; Murthy, Hemant S.; Horn, Biljana; Leather, Helen; Castillo, Paul; Brown, Randy A.; Norkin, Maxim; Hiemenz, John W.; Wingard, John R.; Hsu, Jack W.; Cogle, Christopher R.

doi:10.1200/jco.2018.36.15_suppl.7024

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“…HDAC blockade unchains PPARγ-mediated anti-proliferative and anti-angiogenic signaling Because PPARγ has an extensive repertoire of downstream target genes while HDAC1/2 alters chromatin accessibility and gene expression on a genome-wide scale, pharmacological modulation of these pleiotropic regulators of gene transcription would invariably perturb a myriad of biological pathways simultaneously. To sieve out anticancer mechanisms efficiently, we began by conducting in silico simulations using a validated systems pharmacology model [28][29][30][31][32][33][34][35][36][37][38] (Supplementary Results: Part S3). We then validated these bioinformatics predictions through RT-qPCR and in vitro angiogenesis assays (Supplementary Results: Part S3).…”

Section: Hdac Inhibition Enhances Pparγ Expression Acetylation and Ppre Activitymentioning

confidence: 99%

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

et al. 2021

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Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)–positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.

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Section: Hdac Inhibition Enhances Pparγ Expression Acetylation and Ppre Activitymentioning

confidence: 99%

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

iCare 1: A prospective clinical trial to predict treatment response based on genomics-informed computational biology in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

Cited by 1 publication

References 0 publications

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers

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