icg-001 and Neoplasms

Throughout our life, long-lived somatic stem cells (SSC) regenerate adult tissues both during homeostatic processes and repair after injury. The role of aberrant regulation of SSC has also recently gained prominence in the field of cancer research. Following malignant transformation, so termed cancer stem cells (CSC), endowed with the same properties as SSC (i.e. the ability to both self-renew and generate differentiated progenitors), play a major part in tumor initiation, therapy resistance and ultimately relapse. The same signaling pathways involved in regulating SSC maintenance are involved in the regulation of CSC. CSC exist in a wide array of tumor types, including leukemias, and brain, breast, prostate and colon tumors. Consequently, one of the key goals in cancer research over the past decade has been to develop therapeutic strategies to safely eliminate the CSC population without damaging the endogenous SSC population. A major hurdle to this goal lies in the identification of the key mechanisms that distinguish CSC from the normal endogenous tissue stem cells. This review will discuss the discovery of the specific CBP/catenin antagonist ICG-001 and the ongoing clinical development of the second generation CBP/catenin antagonist PRI-724. Importantly, specific CBP/catenin antagonists appear to have the ability to safely eliminate CSC by taking advantage of an intrinsic differential preference in the way SSC and CSC divide.

Topics: Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Catenins; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplastic Stem Cells; Peptide Fragments; Pyrimidinones; Sialoglycoproteins; Wnt Signaling Pathway

In this issue of Cell Chemical Biology,Benoit et al. (2017) report the selective targeting of cancer stem cells (CSCs) by the ICG-001/CWP family of molecules. Their findings reveal that Sam68 is a transcriptional modulator uniquely required for the dysregulated Wnt/β-catenin signaling in CSCs over healthy stem cells.

Topics: Antineoplastic Agents; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Humans; Neoplasms; Neoplastic Stem Cells; Pyrimidinones; Signal Transduction; Wnt Proteins; Wnt Signaling Pathway

The inhibitor of apoptosis (IAP) protein survivin is highly expressed in cancers, but not in normal differentiated tissues. TCF/beta-catenin signaling has been reported to participate in the regulation of survivin transcription in colon cancer. We have recently characterized ICG-001, a small molecule specific inhibitor of the beta-catenin/Creb-binding protein (CBP) interaction. Inhibition of the beta-catenin/CBP interaction represses a subset of TCF/beta-catenin-mediated transcription. ICG-001 potently inhibits survivin gene transcription and expression. ICG-001-mediated downregulation of survivin expression enhanced caspase-3 activity and apoptosis, which was rescued by overexpression of wild type but not mutant (C84A) survivin. Small interfering RNA and genetic reduction of CBP also decreased survivin expression. Chromatin immunoprecipitation assay confirmed that CBP is the crucial coactivator for TCF/beta-catenin-mediated survivin transcription. Furthermore, ICG-001-induced recruitment of p300 to the survivin promoter led to concomitant recruitment of SUMO-1, HDAC6 and PML proteins, which have been associated with transcriptional repression. These findings demonstrate that CBP and p300 play very distinct roles in survivin gene transcription.

Topics: Animals; Apoptosis; beta Catenin; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Caspases; Cell Line, Tumor; Cytoskeletal Proteins; E1A-Associated p300 Protein; Female; Gene Expression; Humans; Immunoblotting; Immunohistochemistry; Inhibitor of Apoptosis Proteins; Male; Mice; Microtubule-Associated Proteins; Models, Biological; Neoplasm Proteins; Neoplasms; Nuclear Proteins; Pyrimidinones; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Signal Transduction; Survivin; Trans-Activators; Transcription, Genetic