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EunJi Gang

Bio: EunJi Gang is an academic researcher from University of Southern California. The author has contributed to research in topics: Leukemia & Cancer stem cell. The author has an hindex of 2, co-authored 3 publications receiving 22 citations.

Papers
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Book ChapterDOI
TL;DR: The Wnt pathway, the role of Wnt signaling in different components of the TME, and therapeutic strategies for targeting Wnt signaled cells are reviewed.
Abstract: Dysregulated Wnt signaling plays a central role in initiation, progression, and metastasis in many types of human cancers. Cancer development and resistance to conventional cancer therapies are highly associated with the tumor microenvironment (TME), which is composed of numerous stable non-cancer cells, including immune cells, extracellular matrix (ECM), fibroblasts, endothelial cells (ECs), and stromal cells. Recently, increasing evidence suggests that the relationship between Wnt signaling and the TME promotes the proliferation and maintenance of tumor cells, including leukemia. Here, we review the Wnt pathway, the role of Wnt signaling in different components of the TME, and therapeutic strategies for targeting Wnt signaling.

17 citations

Journal ArticleDOI
TL;DR: The focus of this review/perspective is on identifying and validating a safe and efficacious mechanism to target an evolutionarily conserved signaling nexus, which constitutes a common "Achilles heel" for LSCs/CSCs, using small molecule-specific CBP/catenin antagonists.

13 citations

Journal ArticleDOI
03 Dec 2015-Blood
TL;DR: Primary ALL cells showed decreased viability after monotreatment with P5G10 in a short-term assay of 2 days with laminin-1 and were sensitized when P5 G10 was combined with VDL or TKI, compared to TKI monot treatment, indicating that other adhesion molecules also contribute to leukemia cell adhesion.

3 citations


Cited by
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24 Apr 2014
TL;DR: It is reported that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity.
Abstract: Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small-molecule modulator of Wnt/catenin signaling, which specifically binds to the N-terminus of CBP and not p300, within amino acids 1–110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/β- and γ-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C-terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug-resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL.

128 citations

Journal ArticleDOI
TL;DR: This review is focused on the several challenges and adjustments that the field of oncology research is facing to translate these advanced tumor cells models to drug discovery, taking advantage of the progress on culture technologies, imaging platforms, high throughput and automated systems.
Abstract: There is cumulating evidence that in vitro 3D tumor models with increased physiological relevance can improve the predictive value of pre-clinical research and ultimately contribute to achieve decisions earlier during the development of cancer-targeted therapies. Due to the role of tumor microenvironment in the response of tumor cells to therapeutics, the incorporation of different elements of the tumor niche on cell model design is expected to contribute to the establishment of more predictive in vitro tumor models. This review is focused on the several challenges and adjustments that the field of oncology research is facing to translate these advanced tumor cells models to drug discovery, taking advantage of the progress on culture technologies, imaging platforms, high throughput and automated systems. The choice of 3D cell model, the experimental design, choice of read-outs and interpretation of data obtained from 3D cell models are critical aspects when considering their implementation in drug discovery. In this review, we foresee some of these aspects and depict the potential directions of pre-clinical oncology drug discovery towards improved prediction of drug efficacy.

79 citations

Book ChapterDOI
TL;DR: The dichotomous behavior of this signaling pathway in determining stem cell fate decisions is explained, placing special emphasis on the interaction of β-catenin with either of the two highly homologous Kat3 coactivator proteins, CBP and p300.
Abstract: Wnt signaling in stem cells plays critical roles in development, normal adult physiology, and disease. In this chapter, we focus on the role of the Wnt signaling pathway in somatic stem cell biology and its critical role in normal tissue homeostasis and cancer. Wnt signaling can both maintain potency and initiate differentiation in somatic stem cells, depending on the cellular and environmental context. Based principally on studies from our lab, we will explain the dichotomous behavior of this signaling pathway in determining stem cell fate decisions, placing special emphasis on the interaction of β-catenin with either of the two highly homologous Kat3 coactivator proteins, CBP and p300. We will also discuss our results, both preclinical and clinical, demonstrating that small molecule modulators of the β-catenin/Kat3 coactivator interaction can be safely utilized to shift the balance between maintenance of potency and initiation of differentiation.

43 citations

Journal ArticleDOI
TL;DR: The tumor microenvironment plays a pivotal role in tumor initiation and progression by creating a dynamic interaction with cancer cells as mentioned in this paper, as it influences the growth and expansion of malignant cells in various ways.

37 citations

Journal ArticleDOI
TL;DR: Together, the findings highlight potentially promising treatment consisting of cotargeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐ALL settings.
Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological disorder that results from the clonal transformation of T-cell precursors. Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells. Notably, β-catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T-ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β-catenin pathway through ICG-001, a CBP/β-catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK-474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T-ALL cells. ICG-001 and ZSTK-474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β-catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-ALL settings.

37 citations