Chlorhexidine Dihydrochloride Shows Anti-tumor Effects in Desmoid Tumors and Colorectal Cancer.

Background/aim: Desmoid tumors (DTs), or aggressive fibromatosis, are rare neoplasms arising from connective tissue, frequently exhibiting local invasiveness. The limited treatment options and high recurrence rates of DTs highlight the need for novel therapeutic strategies. This study investigated the efficacy of chlorhexidine dihydrochloride (CD) in inhibiting the growth of DTs and colorectal cancer (CRC).

Anti-tumor Effects of Idarubicin Hydrochloride in Desmoid Tumors.

Background/aim: Desmoid tumors (DTs), also referred to as aggressive fibromatosis, originate from connective tissues and typically manifest with a propensity for local invasion. Despite extensive research efforts aimed at exploring novel anti-tumor agents for DTs, the development of effective clinical management strategies remains an ongoing challenge due to the limited success of current treatments, which frequently lead to inconsistent outcomes and a high recurrence rate of DTs. To overcome these limitations, we focused our research aim on a drug repositioning approach to identify existing medications that could be effective against DTs.

The Significance of N6-Methyladenosine RNA Methylation in Regulating the Hepatitis B Virus Life Cycle.

N6-methyladenosine (m6A) RNA methylation has recently emerged as a significant co-transcriptional modification involved in regulating various RNA functions. It plays a vital function in numerous biological processes. Enzymes referred to as m6A methyltransferases, such as the methyltransferaselike (METTL) 3-METTL14-Wilms tumor 1 (WT1)-associated protein (WTAP) complex, are responsible for adding m6A modifications, while m6A demethylases, including fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5), can remove m6A methylation.

API-2-Induced Cell Migration Is Overcome by Small Molecular Approaches Inhibiting β-Catenin.

Frequent mutation of (90%) in advanced colorectal cancer (CRC) results in the simultaneous activation of Wnt/β-catenin and AKT signaling pathways, and the current therapeutic limitations of the AKT inhibitors for treating CRC patients are nuclear β-catenin-induced EMT and bypassing apoptosis. In this study, we discover that the combinatorial treatment of an AKT inhibitor and KY1022, a β-catenin destabilizer, effectively overcomes the current limitations of API-2, an AKT inhibitor, by reducing nuclear β-catenin. Taken together, we demonstrate that the simultaneous suppression of Wnt/β-catenin with the AKT signaling pathways is an ideal strategy for suppressing the AKT-inhibitor-mediated metastasis and for maximizing the therapeutic effects of AKT inhibitors.

Review on Advanced Cancer Modeling for a Cancer Study.

Intensive efforts to develop anti-cancer agents have been made for over 60 years. However, cancer is still considered a lethal disease. To study the best anti-cancer agents for improving the survival rates of cancer patients, many researchers have focused on establishing advanced experimental applications reflecting on the biomimetics of cancer patients involving the heterogeneity of cancer cells.

Discovery of a novel CDK7 inhibitor YPN-005 in small cell lung cancer.

In contrast to non-small cell lung cancer, there has been no significant progress in the development of therapies for the small cell lung cancer (SCLC) in recent decades. Although various targeted agents, including immunotherapies, have recently been developed for testing in clinical trials, novel therapeutic agents are still needed for SCLC. We developed a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated YPN-005, and sought to determine whether it showed any anticancer effects in SCLC cells, cisplatin or etoposide-resistant cells, or organoids derived from SCLC patients.

Establishment and Long-Term Expansion of Small Cell Lung Cancer Patient-Derived Tumor Organoids.

Differential chemo-sensitivity of cancer cells, which is attributed to the cellular heterogeneity and phenotypic variation of cancer cells, is considered to be the main reason for tumor recurrence after chemotherapy. Here, we generated small cell lung cancer patient-derived tumor organoids and subjected them to long-term expansion with the addition of WNT3A or R-spondin1. We confirmed that the organoids have similar genetic profiles, molecular characteristics, and morphological architectures to the corresponding patient tumor tissue during and after long-term expansion.

5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation.

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in Apc/Lgr5 mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs).

Destabilization of β-catenin and RAS by targeting the Wnt/β-catenin pathway as a potential treatment for triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a severe and heterogeneous disease that lacks an approved targeted therapy and has a poor clinical outcome to chemotherapy. Although the RAS-ERK signaling axis is rarely mutated in TNBC, ~50% of TNBCs show an increased copy number and overexpression of epidermal growth factor receptor (EGFR). However, EGFR-targeted therapies have offered no improvement in patient survival, underscoring the need to explore downstream targets, including RAS.

Natural Killer Cells as a Potential Biomarker for Predicting Immunotherapy Efficacy in Patients with Non-Small Cell Lung Cancer.

Background: Immunotherapy with immune checkpoint inhibitors for non-small cell lung cancer (NSCLC) has emerged as an important treatment option. Although immunotherapy may significantly improve survival and quality of life, response rates are as low as 20% in NSCLC patients.

Objective: The identification of reliable biomarkers predicting response to immunotherapy is required urgently to determine patient selection guidelines.

Small molecule-induced simultaneous destabilization of β-catenin and RAS is an effective molecular strategy to suppress stemness of colorectal cancer cells.

Background: Cancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood.

Methods: Gene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set.

A mutant KRAS-induced factor REG4 promotes cancer stem cell properties via Wnt/β-catenin signaling.

Mutant KRAS provides a driving force for enhancement of cancer stem cells (CSCs) characteristics contributing transformation of colorectal cancer (CRC) cells harboring adenomatous polyposis coli (APC) mutations. Here, we identified the factors mediating the promotion of CSCs properties induced by KRAS mutation through microarray analyses of genes specifically induced in CRC spheroids harboring both KRAS and APC mutations. Among them, REG4 was identified as a key factor since CRISPR/Cas9-mediated knockout of REG4 most significantly affected the stem cell characteristics in which CSCs markers were effectively suppressed.

WDR76 degrades RAS and suppresses cancer stem cell activation in colorectal cancer.

Background: Stabilization of RAS is a key event for the hyper-activation of Wnt/β-catenin signaling and activation of cancer stem cell (CSC) in colorectal cancer (CRC). WD Repeat protein 76 (WDR76) mediates the polyubiquitination-dependent degradation of RAS in hepatocellular carcinoma (HCC). We investigated whether WDR76 destabilizes RAS and acts as a tumor suppressor inhibiting CSC activation in CRC.

A Therapeutic Strategy for Chemotherapy-Resistant Gastric Cancer via Destabilization of Both β-Catenin and RAS.

Treatment of advanced gastric cancer patients with current standard chemotherapeutic agents frequently results in resistance, leading to poor overall survival. However, there has been no success in developing strategies to overcome it. We showed the expression levels of both β-catenin and were significantly increased and correlated in tissues of 756 gastric cancer (GC) patients and tissues of primary- and acquired-resistance patient-derived xenograft tumors treated with 5-fluorouracil and oxaliplatin modulated with leucovorin (FOLFOX).

A Ras destabilizer KYA1797K overcomes the resistance of EGFR tyrosine kinase inhibitor in KRAS-mutated non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) inhibitors such as erlotinib and gefitinib are widely used for treatment of non-small cell lung cancer (NSCLC), but they have shown limited efficacy in an unselected population of patients. The KRAS mutations, which are identified in approximately 20% of NSCLC patients, have shown to be associated with the resistance to the EGFR tyrosine kinase inhibitors (TKIs). Currently, there is no clinically available targeted therapy which can effectively inhibit NSCLC tumors harboring KRAS mutations.

A small molecule approach to degrade RAS with EGFR repression is a potential therapy for KRAS mutation-driven colorectal cancer resistance to cetuximab.

Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of β-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis.

β-Catenin-RAS interaction serves as a molecular switch for RAS degradation via GSK3β.

RAS proteins play critical roles in various cellular processes, including growth and transformation. RAS proteins are subjected to protein stability regulation via the Wnt/β-catenin pathway, and glycogen synthase kinase 3 beta (GSK3β) is a key player for the phosphorylation-dependent RAS degradation through proteasomes. GSK3β-mediated RAS degradation does not occur in cells that express a nondegradable mutant (MT) β-catenin.

Identification of Ras-degrading small molecules that inhibit the transformation of colorectal cancer cells independent of β-catenin signaling.

Although the development of drugs that control Ras is an emerging topic in cancer therapy, no clinically applicable drug is currently available. We have previously utilized knowledge of the Wnt/β-catenin signaling-dependent mechanism of Ras protein stability regulation to identify small molecules that inhibit the proliferation and transformation of various colorectal cancer (CRC) cells via degradation of both β-catenin and Ras. Due to the absence of Ras degradation in cells expressing a nondegradable mutant form of β-catenin and the need to determine an alternative mechanism of Ras degradation, we designed a cell-based system to screen compounds that degrade Ras independent of the Wnt/β-catenin signaling pathway.

Long-term functional outcomes after resection of tongue cancer: determining the optimal reconstruction method.

The appropriate tongue reconstruction method is critical for better functional outcomes. The aim of this study was to determine the optimal reconstructive method for restoring postoperative function based on the extent of resection. We retrospectively reviewed 43 patients with lateral oral tongue cancer who underwent glossectomy between January 2010 and October 2014.

KY1022, a small molecule destabilizing Ras via targeting the Wnt/β-catenin pathway, inhibits development of metastatic colorectal cancer.

APC (80-90%) and K-Ras (40-50%) mutations frequently occur in human colorectal cancer (CRC) and these mutations cooperatively accelerate tumorigenesis including metastasis. In addition, both β-catenin and Ras levels are highly increased in CRC, especially in metastatic CRC (mCRC). Therefore, targeting both the Wnt/β-catenin and Ras pathways could be an ideal therapeutic approach for treating mCRC patients.

Small-molecule binding of the axin RGS domain promotes β-catenin and Ras degradation.

Both the Wnt/β-catenin and Ras pathways are aberrantly activated in most human colorectal cancers (CRCs) and interact cooperatively in tumor promotion. Inhibition of these signaling may therefore be an ideal strategy for treating CRC. We identified KY1220, a compound that destabilizes both β-catenin and Ras, via targeting the Wnt/β-catenin pathway, and synthesized its derivative KYA1797K.

Metallic conduction induced by direct anion site doping in layered SnSe2.

The emergence of metallic conduction in layered dichalcogenide semiconductor materials by chemical doping is one of key issues for two-dimensional (2D) materials engineering. At present, doping methods for layered dichalcogenide materials have been limited to an ion intercalation between layer units or electrostatic carrier doping by electrical bias owing to the absence of appropriate substitutional dopant for increasing the carrier concentration. Here, we report the occurrence of metallic conduction in the layered dichalcogenide of SnSe2 by the direct Se-site doping with Cl as a shallow electron donor.

Targeting phospholipase D1 attenuates intestinal tumorigenesis by controlling β-catenin signaling in cancer-initiating cells.

Expression of the Wnt target gene phospholipase D1 (PLD1) is up-regulated in various carcinomas, including colorectal cancer (CRC). However, the mechanistic significance of its elevated expression in intestinal tumorigenesis remains unknown. In this study, we show that genetic and pharmacological targeting of PLD1 disrupts spontaneous and colitis-associated intestinal tumorigenesis in Apc(Min/+) and azoxymethane/dextran sodium sulfate mice models.