Michael Soth

Targeting p300 Reverses Acidic Microenvironment–Induced PARP Inhibitor Resistance

K. S. Cheng, Hao Nie, Wei Zhou, Dajiang Guo et autres

Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) are a first-line treatment for patients with epithelial ovarian cancer (EOC), but the development of resistance limits long-term therapeutic efficacy. Tumor acidosis is a hallmark of the tumor microenvironment (TME) that has been shown to promote …

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Abstract 370: Low physiological pH drives P300 mediated acetylation of PARP1 and promotes PARP inhibitor resistance.

Hao Nie, Wei Zhou, K. S. Cheng, Dajiang Guo et autres

Abstract Resistance to PARP inhibitors (PARPi) is a major clinical obstacle in epithelial ovarian carcinoma (EOC). Intrinsic and acquired PARPi resistance ultimately limit therapeutic efficacy and contribute to patient mortality. Despite multiple reported mechanisms of PARPi resistance, few studies have defined the …

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Structure-Guided Development of NRAS G12D Inhibitors Based on a 5-Azaindole Core

Joshua B. Cox, Vinay V. Nair, Pijus Kumar Mandal, Naphtali J. Reyna et autres

NRAS G12D mutations are predominantly found in melanoma and hematologic malignancies, and there is an unmet need for developing targeted therapies against this oncogene. Herein, we describe the structure-guided development of IACS-56676, a selective and potent NRAS G12D inhibitor useful as a …

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Nivolumab plus ipilimumab induce hyper-progression in renal medullary carcinoma: results of a phase II trial and preclinical evidence

Melinda Soeung, Xinmiao Yan, Ciro Zanca, Jing Qian et autres

Therapeutic options for patients with renal medullary carcinoma (RMC) are limited. Here we report the results of a phase II clinical trial (NCT03274258) of anti-PD1 nivolumab plus anti-CTLA4 ipilimumab in patients with RMC, with objective response rate as primary outcome. Enrollment was …

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NSD2 inhibitors rewire chromatin to treat lung and pancreatic cancers

Jinho Jeong, Simone Hausmann, Hanyang Dong, Kacper Szczepski et autres

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Abstract P2-06-01: CBP/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in TNBC

Xueying Yuan, Xiaoxin Hao, Hilda Wai-Han CHAN, Na Zhao et autres

Abstract Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain …

Correction: Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Warren C. Fiskus, Christopher Peter Mill, Christine E. Birdwell, John A. Davis et autres

Following the publication of this article an error was noted in Fig. 1. In the original publication, in panel A of Fig. 1, an incorrect Western blot for PBX3 was inadvertently used during the preparation of the figure.

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The pathogenicity of the glutamate metabolic cycle in schizophrenia determined by hippocampal spectroscopic profiling

Scott A. Small, Jia Guo, Ragy R. Girgis, Sunil Goodwani et autres

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Abstract 447: Preclinical development and characterization of IACS-16559, a dual bromodomain inhibitor of CBP/EP300, and its potential in AML subtypes

Ciro Zanca, Michael Soth, Ajay Kumar Saw, Uttara Saran et autres

Abstract Paralogs CBP and EP300 are transcriptional co-regulators, with a mechanism of action involving regulation of chromatin accessibility, direct acetylation of master transcriptional factors and bridging enhancers to activated promoters. They possess both reader and writer of the histone code due to …

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CREB-binding protein/P300 bromodomain inhibition reduces neutrophil accumulation and activates antitumor immunity in triple-negative breast cancer

Xueying Yuan, Xiaoxin Hao, Hilda L. Chan, Na Zhao et autres

Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB-binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of …

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CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

Xueying Yuan, Xiaoxin Hao, Hilda L. Chan, Na Zhao et autres

Abstract Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain …

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Abstract 3229: IACS-16559, a CBP/P300 bromodomain inhibitor for the treatment of specific AML subsets

Ciro Zanca, Michael Soth, Guang xun Gao, Jason P. Gay et autres

Abstract Block in differentiation and accumulation of undifferentiated blasts are hallmarks of Acute Myeloid Leukemia (AML) and epigenetic processes have been shown to play a critical role in hematological malignancies. Paralogs CREBBP and EP300, in association with co-factors, are hijacked during leukemogenesis …

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