Wnt Pathway Targeted Therapy in GI Cancers: Integrating Benchside Insights with Bedside Applications

The Wnt signaling pathway is critical in the onset and progression of gastrointestinal (GI) cancers. Anomalies in this pathway, often stemming from mutations in critical components such as adenomatous polyposis coli (APC) or β-catenin, lead to uncontrolled cell proliferation and survival. In the case of colorectal cancer, dysregulation of the Wnt pathway drives tumor initiation and growth. Similarly, aberrant Wnt signaling contributes to tumor development, metastasis, and resistance to therapy in other GI cancers, such as gastric, pancreatic, and hepatocellular carcinomas. Targeting the Wnt pathway or its downstream effectors has emerged as a promising therapeutic strategy for combating these highly aggressive GI malignancies. Here, we review the dysregulation of the Wnt signaling pathway in the pathogenesis of GI cancers and further explore the therapeutic potential of targeting the various components of the Wnt pathway. Furthermore, we summarize and integrate the preclinical evidence supporting the therapeutic efficacy of potent Wnt pathway inhibitors with completed and ongoing clinical trials in GI cancers. Additionally, we discuss the challenges of Wnt pathway-targeted therapies in GI cancers to overcome these concerns for effective clinical translation.

In the Modern era, immune checkpoint inhibitors (ICIs) have been the cornerstone of success in the treatment of several malignancies. Despite remarkable therapeutic advances, complex matrix together with significant molecular and immunological differences have led to conflicting outcomes of ICI therapy in gastrointestinal (GI) cancers. As far we are aware, to date, there has been no study to confirm the robustness of existing data, and this study is the first umbrella review to provide a more comprehensive picture about ICIs’ efficacy and safety in GI malignancies. Systematic search on PubMed, Scopus, Web of Science, EMBASE, and Cochrane library identified 14 meta-analyses. The pooled analysis revealed that ICIs application, especially programmed death-1 (PD-1) inhibitors such as Camrelizumab and Sintilimab, could partially improve response rates in patients with GI cancers compared to conventional therapies. However, different GI cancer types did not experience the same efficacy; it seems that hepatocellular carcinoma (HCC) and esophageal cancer (EC) patients are likely better candidates for ICI therapy than GC and CRC patients. Furthermore, application of ICIs in a combined-modal strategy are perceived opportunity in GI cancers. We also assessed the correlation of PD-L1 expression as well as microsatellite status with the extent of the response to ICIs; overall, high expression of PD-L1 in GI cancers is associated with better response to ICIs, however, additional studies are required to precisely elaborate ICI responses with respect to microsatellite status in different GI tumors. Despite encouraging ICI efficacy in some GI cancers, a greater number of serious and fatal adverse events have been observed; further highlighting the fact that ICI therapy in GI cancers is not without cost, and further studies are required to utmost optimization of this approach in GI cancers.

Harnessing the potential of CAR-NK cell therapy in gastrointestinal cancers: From bench to bedside.

Background: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aim to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported recent studies.Scope: A literature search was made from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: “nivolumab”, “pembrolizumab”, “avelumab”, “GI cancers” “anti-PD1 therapy” and “anti-PD-L1 therapy”. The last search was on 2 November 2016. The most important limitation of our review is that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relies on phase 1 and 2 trials.Findings: Currently, there are two anti-PD-1 (nivolumab and pembrolizumab) and one anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastroesophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appears to be associated with tumor PD-L1 levels. According to two recently published phase 2 trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase 2/3 trials are still ongoing.Conclusion: Both pembrolizumab and nivolumab show promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.

Gastrointestinal (GI) cancers, including malignancies in the gastrointestinal tract and accessory organs of digestion, represent the leading cause of death worldwide due to the poor prognosis of most GI cancers. An investigation into the potential molecular targets of prediction, diagnosis, prognosis, and therapy in GI cancers is urgently required. Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), which plays an essential role in cell proliferation, apoptosis, and cell cycle regulation by binding to PCNA, is a potential molecular target of GI cancers as it contributes to a series of malignant properties, including tumorigenesis, epithelial-mesenchymal transition, migration, and invasion. Furthermore, PCLAF is an underlying plasma prediction target in colorectal cancer and liver cancer. In addition to GI cancers, PCLAF is also involved in other types of cancers and autoimmune diseases. Several pivotal pathways, including the Rb/E2F pathway, NF-κB pathway, and p53-p21 cascade, are implicated in PCLAF-mediated diseases. PCLAF also contributes to some diseases through dysregulation of the p53 pathway, WNT signal pathway, MEK/ERK pathway, and PI3K/AKT/mTOR signal cascade. This review mainly describes in detail the role of PCLAF in physiological status and GI cancers. The signaling pathways involved in PCLAF are also summarized. Suppression of the interaction of PCLAF/PCNA or the expression of PCLAF might be potential biological therapeutic strategies for GI cancers.

DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer. A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts. The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein-Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer. The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

e16101 Background: To date, although a number of biomarker-related investigations have focused on the intrinsic properties of tumor cells and immune microenvironment, how germline genetics influences efficacy of immune checkpoint inhibitors (ICIs) immunotherapy in gastrointestinal (GI) cancer is scarcely understood. Methods: Our investigation enrolled 94 metastatic GI cancer patients treated with ICIs recruited from Peking University Cancer Hospital (PUCH) between August 1, 2015, and May 24, 2019. A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was used for validation. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood mononuclear cell (PBMC) from all 94 patients. Tumor tissues from 86 patients were subjected to WES analysis and immune oncology-related RNA profiling. Results: We assessed the clinic relevance of germline HLA heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) to immunotherapy in patients with advanced GI cancers from the PUCH cohort. Our data showed that neither HLA heterozygosity nor mean HED correlated with the overall survival (OS) in the PUCH cohort. However, patients with high HLA-B HED showed a better OS and durable clinic benefit (DCB) rate compared with the lower subgroup (p &lt; 0.05 for all comparison). The prognostic value of HLA-B HED was consistently validated in the MSK GI cohort (N = 84). Notably, a combinatorial biomarker based on HLA-B HED and tumor mutation burden (TMB) could better stratify potential responders (86 patients with tumor samples). Survival analysis performed on the PUCH and MSK GI cancer datasets further demonstrated the potential joint utility of HLA-B HED and TMB for prognosis stratification. Moreover, HLA-B HED high subgroup was characterized with a lower prevalence of TP53 mutation and enrichment of multiple immune related pathways, indicating an immune-inflamed phenotype of this subgroup. Conclusions: Taken together, our data create an intriguing argument for the germline HLA-B sequence divergence and TMB as complementary biomarkers in guiding patient selection for GI cancer immunotherapy. Further investigation revealed a potential HLA-B restricted mutational pattern of TP53, and can be indicative of tumor immune microenvironment in GI cancer.

Advances in nanotechnology have opened new frontiers in the diagnosis and treatment of cancer. Nanoparticle-based technology improves the precision of tumor diagnosis when combined with imaging, as well as the accuracy of drug target delivery, with fewer side effects. Optimized nanosystems have demonstrated advantages in many fields, including enhanced specificity of detection, reduced toxicity of drugs, enhanced effect of contrast agents, and advanced diagnosis and therapy of gastrointestinal (GI) cancers. In this review, we summarize the current nanotechnologies in diagnosis and treatment of GI cancers. The development of nanotechnology will lead to personalized approaches for early diagnosis and treatment of GI cancers.

Background Many studies have shown the link between the pretreatment serum transthyretin and prognosis in gastrointestinal (GI) cancers. However, based on the conclusion, the initial findings were inconsistent. Hence, this meta-analysis was performed to identify the prognostic values of the pretreatment serum transthyretin in GI cancers. Methods Previous studies published before November 2018 were collected from a comprehensive literature search of several databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were applied in the assessment of the intensity of associations. Also, the publication bias and the robustness of merged data were assessed. All statistical analyses were undertaken using STATA/SE 14.1. Results The combined data indicated that the pretreatment serum transthyretin level was related to the prognosis in GI cancers. The group with reduced pretreatment transthyretin had a significantly worse overall survival (OS) (HR = 1.71, 95% CI: 1.37-2.05). The subgroup analysis for OS further showed the predictive value of transthyretin. In addition, the low serum transthyretin level could be an unfavorable factor for recurrence-free survival (RFS) or progression-free survival (PFS) (HR = 1.66, 95% CI: 1.14-2.18) in GI cancers. Conclusion The low pretreatment serum transthyretin level implies an unfavorable prognosis for patients with GI cancers. The monitoring of pretreatment transthyretin level could contribute to the risk stratification and individualized therapy in GI cancers.

Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.

The high incidence and mortality rates associated with gastrointestinal cancers represent a significant global health challenge. In recent years, CAR T cell therapy has emerged as a promising immunotherapeutic approach, demonstrating favorable clinical outcomes. However, the application of traditional CAR T cell therapy in gastrointestinal cancers faces numerous challenges, including the suppressive tumor microenvironment and limitations in anti-tumor efficacy. The application of engineered bacteria offers a novel strategy to enhance CAR T cell therapy by modulating the tumor microenvironment and boosting immune responses, potentially leading to improved therapeutic outcomes. This review synthesizes the current research advancements related to engineered bacteria-assisted CAR T cell therapy in gastrointestinal cancers, exploring its underlying mechanisms, clinical applications, and future developmental directions.

150 Background: Somatostatin receptors (sstr) are expressed in various normal and malignant tissues, including non-neuroendocrine GI solid tumors. Gastric cancer (GC) cells mainly express sstr2 and sstr5, colorectal cancer (CRC) cells predominantly express sstr1 followed by sstr5 and sstr2, and hepatocellular carcinoma (HCC) cells express mainly sstr5 as well as sstr1,2,3. Somatostatin analogues (SAs) may have direct and indirect antitumor activity. Octreotide and lanreotide primarily target sstr2, whereas the new agent pasireotide has high affinity for sstr1,2,3 and sstr5. Methods: Published data evaluating the antitumor properties of SAs in GI tumors were reviewed. Results: The table lists the results of clinical studies in which SAs were evaluated as antitumor therapies in GI cancers. Conclusions: Although octreotide and lanreotide are efficacious in the treatment of symptoms of neuroendocrine tumors, these agents have demonstrated mixed results in the antitumor treatment of non-neuroendocrine GI tumors. Data suggesting potential favorable outcomes with SAs alone or in combination with other agents have been seen in solid tumors with predominant sstr2 expression such as GC. Novel SAs such as pasireotide may have improved antitumor effects in non-neuroendocrine solid tumors expressing multiple sstr compared with octreotide and lanreotide. [Table: see text] [Table: see text]

ABSTRACTIntroduction: Gastrointestinal (GI) cancers altogether represent the most common cancer type. HER2 is found to be present in nearly all histologic types of GI cancers in variable degrees of expression. Over the last decade, substantial advances have been made in targeting HER2-positive cancers.Areas covered: The present review summarizes the current progress and future directions for HER2 targeted therapies in GI cancers, including esophagogastric, pancreaticobiliary, and colon cancers. To date trastuzumab is the only anti-HER2 therapy approved for metastatic esophagogastric adenocarcinoma. Efforts are ongoing to expand the therapeutic role of HER2 to other GI cancers and overcome mechanisms of drug resistance. Novel agents and combinations are being tested in most HER2 positive GI cancers including early stage disease. These are of recent interest in colorectal cancer with studies indicating that HER2 overexpression might increase resistance to anti-EGFR therapy and may be potentially targeted.Expert commentary: With the current ability to sequence tumors and detect genetic alterations, emphasis should be put on genomically-selected pan-tumor targeted therapies. HER2 is a perfect example of a promising drug target in GI cancers.

5-Methylcytosine (m5C) is a kind of methylation modification that occurs in both DNA and RNA and is present in the highly abundant tRNA and rRNA. It has an important impact on various human diseases including cancer. The function of m5C is modulated by regulatory proteins, including methyltransferases (writers) and special binding proteins (readers). This study aims at comprehensive study of the m5C RNA methylation-related genes and the main pathways under m5C RNA methylation in gastrointestinal (GI) cancer. Our result showed that the expression of m5C writers and reader was mostly up-regulated in GI cancer. The NSUN2 gene has the highest proportion of mutations found in GI cancer. Importantly, in liver cancer, higher expression of almost all m5C regulators was significantly associated with lower patient survival rate. In addition, the expression level of m5C-related genes is significantly different at various pathological stages. Finally, we have found through bioinformatics analysis that m5C regulatory proteins are closely related to the ErbB/PI3K–Akt signaling pathway and GSK3B was an important target for m5C regulators. Besides, the compound termed streptozotocin may be a key candidate drug targeting on GSK3B for molecular targeted therapy in GI cancer.

Mesenchymal stem (or stromal) cells (MSCs) are nonhematopoietic progenitor cells that can be obtained from bone marrow aspirates or adipose tissue, expanded and genetically modified in vitro, and then used for cancer therapeutic strategies in vivo. Here, we review available data regarding the application of MSC-based tumor-targeted therapy in gastrointestinal cancer, provide an overview of the general history of MSC-based gene therapy in cancer research, and discuss potential problems associated with the utility of MSC-based therapy such as biosafety, immunoprivilege, transfection methods, and distribution in the host.