Abstract 5517: PTC596-induced Bmi1 hyper-phosphorylation via Cdk1/2 activation resulting in tumor stem cell depletion

Abstract

The Polycomb group (PcG) transcription repressor BMI1 is highly expressed in human cancers and is required for the clonogenic self-renewal and tumorigenesis of human cancer cells including those in hematological cancer and neuroblastoma. PTC596 is efficacious in vivo across a range of xenograft tumor models, including models of glioblastoma, fibrosarcoma and leukemia as well as orthotopic models of GBM. With EC50 values of 30-200 nM in a variety of tumor cell lines, PTC596 selectively reduces the level of functional BMI1 protein resulting in the depletion of the tumor stem cell fraction. PTC596 induces the hyper-phosphorylation of BMI1 leading to its degradation and the reduction of polycomb repressive complex 1 (PRC1) activity. Mechanistic studies suggest that PTC596 inhibits APC/CCDC20 activity resulting in the persistent activation of CDK1 and CDK2 which mediate the hyperphosphorylation of BMI1. Studies are ongoing to elucidate the mechanism of PTC596 inhibition of APC/CCDC20 and its preferential depletion of the tumor stem cell fraction. Citation Format: Min Jung Kim, Liangxian Cao, Josephine Sheedy, Nicole Risher, Melissa Dumble, Chang-Sun Lee, Nadiya Sydorenko, Ramil Baiazitov, Wu Du, Young-Choon Moon, Marla L. Weetall, Joseph Colacino, Thomas W. Davis. PTC596-induced Bmi1 hyper-phosphorylation via Cdk1/2 activation resulting in tumor stem cell depletion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5517. doi:10.1158/1538-7445.AM2014-5517

Preclinical activity of the novel B‐cell‐specific Moloney murine leukemia virus integration site 1 inhibitor PTC‐209 in acute myeloid leukemia: Implications for leukemia therapy

“…PTC‐209 rapidly (as early as 2 h) reduced the BMI‐1 cellular levels, arguing against the idea that reduced BMI‐1 levels occur as a result of cell death in PTC‐treated cells. Recently, a more potent, orally active BMI‐1 inhibitor, PTC596, has been developed . Taken together, BMI‐1 inhibition may be a novel therapeutic strategy to kill leukemia stem cells.…”

“…Recently, a more potent, orally active BMI-1 inhibitor, PTC596, has been developed. (36) Taken together, BMI-1 inhibition may be a novel therapeutic strategy to kill leukemia stem cells.…”

Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications

“…Oral administration of PTC596 inhibits the tumor growth, depletes the tumor stem cell fraction, and significantly extends the lifespan . Mechanisticaly, PTC596 inhibits anaphase‐promoting complex/cyclosome (APC)/CCDC20 activity and increases the CDK1 and CDK2 that mediate BMI1 hyperphosphorylation . The candidate now has entered into clinical trials (ClinicalTrials.gov Identifier: NCT02404480) for advanced solid tumor treatment.…”

Polycomb repressive complexes in hematological malignancies

“…PTC596, a small compound that induces the degradation of the BMI1 protein, has entered a phase 1 clinical trial for patients with advanced solid tumors (www.clinicaltrials.gov #NCT02404480). 95 Finally, recent analyses have linked PRC2 insufficiency to drug resistance in leukemia. Low levels of EZH2 protein induce resistance to multiple drugs in AML partly because of the derepression of HOX genes, representative EZH2 targets.…”