Differentiation antagonizing non-protein coding RNA (DANCR) is a newly identified oncogenic long noncoding RNA found in various cancers. However, the functional role of DANCR in tumor angiogenesis and the underlying mechanisms are still unclear. The expression of DANCR was determined in ovarian malignant tissues and cell lines. The functional role of DANCR in tumor angiogenesis was revealed by the following methods: CD31 staining of ovarian tumor tissues, matrigel-plug assay tissues, HUVEC-related tube formation assay, and invasion assay. Enzyme-linked immunosorbent assay, Western blotting, luciferase assay, and rescue experiments were used to investigate the underlying mechanisms of DANCR-regulating angiogenesis. DANCR was upregulated in ovarian malignant tissues and ovarian cancer cells. Knockdown of DANCR efficiently impaired ovarian tumor growth through inhibition of tumor angiogenesis. Furthermore, the conditional culture medium from DANCR-knockdown ovarian cells significantly inhibited tube formation and invasion of HUVEC in vitro. Mechanistic investigation indicated that vascular endothelial growth factor A (VEGF-A, VEGF) plays a crucial role during DANCR inhibition of tumor angiogenesis in ovarian cancer. Further results demonstrated that miR-145 is the direct binding target of DANCR during regulation of VEGF expression and tumor angiogenesis in ovarian cancer cells. Collectively, DANCR plays a promotional role in tumor angiogenesis in ovarian cancer through regulation of miR-145/VEGF axis. Therefore, DANCR may be a novel therapy target for ovarian cancer.

LncRNA DANCR promotes tumor growth and angiogenesis in ovarian cancer through direct targeting of miR-145.

Purpose: Gastric cancer is a common tumor of the digestive system. Identification of potential molecules associated with gastric cancer progression and validation of potential biomarkers for gastric cancer diagnosis are very important. Thus, the aim of our study was to determine the serum metabolic characteristics of the serum of patients with chronic gastritis (CG) or gastric cancer (GC) and validate candidate biomarkers for disease diagnosis. Experimental design: A total of 123 human serum samples from patients with CG or GC were for untargeted metabolomics analysis via UHPLC-Q-TOF/MS to determine characteristics of the serum. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and heat map were used for multivariate analysis. In addition, commercial databases were used to identify the pathways of metabolites. Differential metabolites were identified based on a heat map with a t-test threshold (p 1.5 or FC 1). Then, differential metabolites were analyzed by receiver operating characteristic (ROC) curve to determined candidate biomarkers. All samples were analyzed for fasting lipid profiles. Results: Analysis of serum metabolomic profiles indicated that most of the altered metabolic pathways in the three groups were associated with lipid metabolism (p 1.5 or FC 1). Moreover, differential metabolites, including hexadecasphinganine, linoleamide and N-Hydroxy arachidonoyl amine had high diagnostic performance according to PLS-DA. In addition, fasting lipid profile analysis showed the serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein A1 (Apo-A1) were decreased concomitant to the progression of the progression of the disease compared with those in the control group (p < 0.05). Conclusions: Thus, this study demonstrated that lipid metabolism may influence the development of CG to GC. Hexadecasphinganine, linoleamide and N-Hydroxy arachidonoyl amine were selected as candidate diagnostic markers for CG and GC.

/pdf/serum-metabolic-profiling-analysis-of-chronic-gastritis-and-2h7f64bkss.pdf

Serum Metabolic Profiling Analysis of Chronic Gastritis and Gastric Cancer by Untargeted Metabolomics.

Hypermethylation in gastric cancer.

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide with a five-year survival rate of around 25%, and 4% when diagnosed at a metastatic stage. Cancer stem cells (CSC) have recently been characterized as being responsible for resistance to radio/chemotherapies and metastasis formation, opening up perspectives for new targeted therapies. Those CSCs express biomarkers such as cluster of differentiation 44 (CD44) and display high aldehyde dehydrogenase activity that converts vitamin A-derived retinal into retinoic acids. All-trans retinoic acid (ATRA), which has pro-differentiating properties, has revolutionized the prognosis of acute promyelotic leukemia by increasing its remission rate from 15% to 85%. Recent studies have started to show that ATRA also has an anti-tumoral role on solid cancers such as GC. The purpose of this review is therefore to summarize the work that evaluated the effects of ATRA in GC and to evaluate whether its anti-cancerous action involves gastric CSCs targeting. It has been demonstrated that ATRA can block the cell cycle, enhance apoptosis, and decrease gastric CSCs properties in GC cell lines, tumorspheres, and patient-derived xenograft mice models. Therefore, retinoids and new synthetic retinoids seem to be a promising step forward in targeted therapy of gastric CSC in combination with existing chemotherapies. Future studies should probably focus on these points.

https://www.mdpi.com/1422-0067/19/11/3388/pdf

Efficiency of All-Trans Retinoic Acid on Gastric Cancer: A Narrative Literature Review

Gastric cancer is the second leading cause of cancer-related mortality and the fourth most common cancer globally. High intratumor heterogeneity of advanced gastric cancer poses great challenges to targeted therapy due to simultaneous activation of many redundant cancer-driving pathways. A central common signaling mechanism in cancer is proline-directed phosphorylation, which is further regulated by the unique proline isomerase Pin1. Pin1 inhibition exerts anticancer activity by blocking multiple cancer-driving pathways in some cancers, but its role in gastric cancer is not fully understood. Here we detected Pin1 protein expression in 1065 gastric cancer patients and paired normal tissues using immunohistochemistry and Western blot, and then examined the effects of Pin1 overexpression, and genetic and chemical Pin1 inhibition using Pin1 short hairpin RNA or small molecule inhibitor all-trans retinoic acid (ATRA) on tumorigenesis of human gastric cancer in vitro and in vivo, followed by biochemical analyses to elucidate Pin1 regulated oncogenic pathways. We found that Pin1 was significantly overexpressed in primary and metastasized tumors, with Pin1 overexpression being correlated with advanced stage and poor prognosis. Furthermore, whereas Pin1 overexpression promoted the transformed phenotype in immortalized and nontransformed human gastric cells, either genetic or chemical Pin1 inhibition in multiple human gastric cancer cells potently suppressed cell growth, G1/S transition and colony formation in vitro, as well as tumor growth in xenograft tumor models in vivo, which were further supported by downregulation of multiple key oncoproteins in PI3K/AKT and Wnt/β-catenin signaling pathways. These results not only provide the first evidence for a critical role of Pin1 in the tumorigenesis of gastric cancer but also suggest that targeting Pin1 using ATRA or other inhibitors offers an effective new therapeutic approach for treating advanced gastric cancer.

Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β-catenin oncogenic pathways.

Background: Gastric cancer is frequently lethal despite aggressive multimodal therapies, and new treatment approaches are therefore needed. Retinoids are potential candidate drugs: they prevent cell differentiation, proliferation and malignant transformation in gastric cancer cell lines. They interact with nuclear retinoid receptors (the retinoic acid receptors [RARs] and retinoid X receptors [RXRs]), which function as transcription factors, each with three subclasses, α, β and γ. At present, little is known about retinoid expression and influence on prognosis in gastric cancers. Patients and Methods: We retrospectively analyzed the expression of the subtypes RARa, RARβ, RARγ, RXRa, RXRβ, RXRγ by immunohistochemistry in 147 gastric cancers and 51 normal gastric epithelium tissues for whom clinical follow-up data were available and correlated the results with clinical characteristics. In addition, we quantified the expression of retinoid receptor mRNA using realtime PCR (RT-PCR) in another 6 gastric adenocarcinoma and 3 normal gastric tissues. From 2008 to 2010, 80 patients with gastric cancers were enrolled onto therapy with all-trans-retinoic acid (ATRA). Results: RARa, RARβ, RARγand RXRγ positively correlated with each other (p < 0.001) and demonstrated significantly lower levels in the carcinoma tissue sections (p < 0.01), with lower RARβ, RARγ and RXRa expression significantly related to advanced stages (p < =0.01). Tumors with poor histopathologic grade had lower levels of RARa and RARβ in different histological types of gastric carcinoma (p < 0.01). Patients whose tumors exhibited low levels of RARa expression had significantly lower overall survival compared with patients who had higher expression levels of this receptor (p < 0.001, HR=0.42, 95.0% CI 0.24-0.73), and patients undergoing ATRA treatment had significantly longer median survival times (p = 0.007, HR=0.41, 95.0% CI 0.21-0.80). Conclusions: Retinoic acid receptors are frequently expressed in epithelial gastric cancer with a decreased tendency of expression and RARa may be an indicator of a positive prognosis. This study provides a molecular basis for the therapeutic use of retinoids against gastric cancer.

http://koreascience.or.kr:80/article/JAKO201226935182748.pdf

Retinoid receptors in gastric cancer: expression and influence on prognosis.


 Background: Novel drugs are needed to tackle forms of prostate cancer that demonstrate resistance to hormonal agents. Halda has invented an innovative cancer treatment approach that does not rely on oncogenic drivers. Regulated Induced Proximity Targeting Chimera (RIPTAC™) therapeutics are heterobifunctional small molecules that work via a hold and kill mechanism that has the potential to overcome drug resistance mechanisms. RIPTAC therapeutics function by holding together two proteins, a cancer-specific protein, and a protein with essential function (EP) in a ternary complex, resulting in abrogation of the essential function and subsequent cancer cell death. We exemplify this platform to treat metastatic castration resistant prostate cancer (mCRPC), where the RIPTAC therapeutic utilizes the Androgen Receptor (AR) as a tumor specific protein to selectively inhibit an essential protein involved in transcriptional regulation and provide in vivo efficacy coupled with a therapeutic index. Methods: RIPTACs therapeutics were assayed for their ability to form a ternary complex with AR and the EP using a novel TR-FRET based assay in VCaP prostate cancer cells that harbor AR amplification. Selective apoptosis in ARhigh cells was observed using a Caspase 3/7 Glo assay (Promega). EP pharmacodynamic modulation was ascertained using qRT-PCR and western blotting in both in vitro and in vivo samples. RIPTACs were optimized for oral bioavailability, and tumor ternary complex formation in prostate cancer cell line-derived xenograft models.Results: RIPTAC therapeutics display nanomolar in vitro potency in AR:RIPTAC:EP ternary complex formation, which results in abrogation of the EP function and antiproliferative activity in prostate cancer cell lines, but not in AR-knockout control cells. The prostate cancer RIPTAC therapeutics are active in vitro against clinically relevant AR mutants. Lead molecules utilizing AR as a tumor specific protein are orally bioavailable in multiple preclinical species and induce ternary complex formation in VCaP tumor xenografts grown in mice. We present in vivo data where lead RIPTACs demonstrate significant tumor growth inhibition in several prostate cancer models and induce tumor regressions in VCaP xenografts grown in castrated male mice. Conclusions: Taken together, our in vitro mechanistic data and in vivo PD/efficacy observations in multiple prostate cancer models support further investigation of prostate cancer RIPTAC therapeutics as a novel heterobifunctional therapeutic modality in mCRPC.
 Citation Format: Xinheng Yu, Kyle J. Eastman, Kanak Raina, Kelli M. Jones, Chris D. Forbes, Abigail Hundt, Marco Garcia, Rebecca Stronk, Katia Howard, Andrew McGovern, Rebekka Chenard, Allison Denny, Mia Forgione, Kyle Bassoli, Ethan Garvin, James J. Mousseau, Hao Li, Madeline P. King, Amit Bhardwaj, Katherine J. Kayser-Bricker, Craig M. Crews. Prostate cancer RIPTAC™ therapeutics demonstrate activity in preclinical models of Enzalutamide-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1629.

Abstract 1629: Prostate cancer RIPTAC™ therapeutics demonstrate activity in preclinical models of Enzalutamide-resistant prostate cancer

184 Background: Resistance to Androgen Receptor Signaling Inhibitors (ARSIs) in prostate cancer occurs in almost all patients and is driven primarily by genomic alterations in AR and increases in AR expression. In the metastatic castration-resistant setting, more than 80% of these patients harbor amplifications of the AR gene or the upstream enhancer region of DNA. Our RIPTAC technology leverages the high level of AR expression to selectively kill prostate cancer cells while sparing normal tissues. Methods: We describe here a novel orally bioavailable heterobifunctional small molecule AR RIPTAC that recruits an essential cellular protein (EP) into a stable ternary complex with AR, thereby inhibiting EP function and leading to cell death selectively in AR-positive cells. Molecules were designed to achieve cooperative binding between AR and EP, oral bioavailability and AR-selective cell killing. Results: AR RIPTACs form a ternary complex between AR and EP across PCa cell lines with an EC50 ~1nM, leading to concomitant inhibition of the EP and antiproliferative activity across PCa cell lines. The cell killing activity of AR RIPTACs is dependent on the presence of AR in the cell. AR RIPTACs induce apoptosis at low nM concentrations in cells overexpressing AR but not in control cells. In castrated mice bearing VCaP xenografts, AR RIPTACs accumulate in the tumor and induce AR:RIPTAC:EP ternary complex formation at a low oral dose, resulting in tumor specific inhibition of the EP and tumor growth inhibition. Leading AR RIPTACs possess pharmacokinetic properties suitable for a drug candidate, and readily achieve efficacious exposures following oral dosing in mouse, rat and dog. Conclusions: In summary, we report preclinical data on orally bioavailable heterobifunctional AR RIPTACs that are active in multiple prostate cancer models. The lead molecules are being evaluated in toxicology studies, with IND filing slated for 2024.

An oral androgen receptor RIPTAC for prostate cancer.

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Retinoid receptors in gastric cancer: expression and influence on prognosis.

Abstract 1629: Prostate cancer RIPTAC™ therapeutics demonstrate activity in preclinical models of Enzalutamide-resistant prostate cancer

An oral androgen receptor RIPTAC for prostate cancer.