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New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 16901

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Special Issue Editors

Dr. Amir Avan

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Guest Editor

Metabolic Syndrome Research Center, Mashhad University of Medical Science, Mashhad 91886-17871, Iran
Interests: pancreatic cancer; colorectal cancer; gastrointestinal cancer

Dr. Elisa Giovannetti

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Guest Editor

Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
Interests: pharmacology; drug resistance; pharmacogenetics; predictive biomarkers; liquid biopsies; preclinical models; pancreatic cancer; NSCLC; mesothelioma
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Dear Colleagues,

Gastrointestinal cancers are one of most common chronic diseases and are among the top three causes of mortality in the world. Despite extensive improvements in surgery, chemotherapy, radiotherapy and target therapy over the last decades, the outlook for patients remains miserable, with short survival in advanced cancer stages and recurrence. MicroRNAs (miRNAs) are evolutionary conserved, short (~22 nucleotides in length), single-stranded RNA molecules that attributed to the big family of small non-coding RNAs. MiRNAs contribute in the tumorgenesis as either tumor suppressors (oncosuppressor) or oncogenes (oncomiR), therewith modulating the derepression of target miRNA. micro-RNAs can be circulated in body fluid, suggesting their values as noninvasive predictor marker of cancer diagnosis, classification, prognosis, and response to treatment. The thematic issue provide the readers working in basic biomedical sciences as well as clinicians a comprehensive overview on diagnostic, prognostic significance and targeting miRNAs and New therapeutic approaches including nanomedince in gastrointestinal cancers.

Dr. Amir Avan
Dr. Elisa Giovannetti
Guest Editors

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Published Papers (6 papers)

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Research

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20 pages, 6212 KiB

Open AccessArticle

Identification of Immunogenic Cell-Death-Related Subtypes and Development of a Prognostic Signature in Gastric Cancer

by Xuejun Gan, Xiaohuan Tang and Ziyu Li

Biomolecules 2023, 13(3), 528; https://doi.org/10.3390/biom13030528 - 14 Mar 2023

Cited by 2 | Viewed by 2019

Abstract

Background: Immunogenic cell death (ICD) is considered a promising type of regulated cell death and exerts effects by activating the adaptive immune response, reshaping the tumor environment (TME) and improving therapeutic efficacy. However, the potential roles and prognostic value of ICD-associated genes in gastric cancer (GC) remain unclear. Methods: The RNA expression data and clinical information of 1090 GC patients from six cohorts were collected. Consensus clustering was used to identify three distinct molecular subtypes. Then, a robust prognostic ICD_score for predicting prognosis was built via WGCNA and LASSO Cox regression according to the TCGA cohort, and the predictive capability of the ICD_score in GC patients was validated in the other cohorts. ICD-related immune features were analyzed using a CIBERSORT method and verified by immunofluorescence. Results: We found that ICD-related gene variations were correlated with clinical outcomes, tumor immune microenvironment (TIME) characteristics and treatment response. We then constructed an ICD signature that classifies cases as low- and high-ICD_score groups. The high-ICD_score group indicates unfavorable OS, a more advanced TNM stage, and presents an immune-suppressed phenotype, which has more infiltrations of pro-tumor immune cells, such as macrophages, which was verified by immunofluorescence. In addition, a nomogram containing the ICD_score showed a high predictive accuracy with AUCs of 0.715, 0.731 and 0.8 on Years 1, 3, and 5. Conclusion: We performed the first and synthesis ICD analysis in GC and built a clinical application tool based on the ICD signature, which paved a new path for assessing prognosis and guiding individual treatment. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

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17 pages, 5108 KiB

Open AccessArticle

Clinical Significance and Immune Infiltration Analyses of the Cuproptosis-Related Human Copper Proteome in Gastric Cancer

by Xiaohuan Tang, Ting Guo, Xiaolong Wu, Xuejun Gan, Yiding Wang, Fangzhou Jia, Yan Zhang, Xiaofang Xing, Xiangyu Gao and Ziyu Li

Biomolecules 2022, 12(10), 1459; https://doi.org/10.3390/biom12101459 - 12 Oct 2022

Cited by 9 | Viewed by 2405

Abstract

Background: The human copper Cu proteome, also termed Cu-binding proteins (CBP), is responsible for transporting “free” Cu to the cell that is related to cuproptosis. However, their role in gastric cancer (GC) has not been reported. Methods: RNA expression data of 946 GC patients were collected. A series of machine learning and bioinformatic approaches were combined to build a CBP signature to predict survival and immune microenvironment and guide the priority treatment. Immunohistochemistry and multicolor immunofluorescence (mIF) in 1076 resection slides were used to verify immune features. Results: A CBP signature was constructed using the machine learning method from TCGA that classifies cases as CBP_low and CBP_high groups. Multivariable Cox analysis confirmed that the CBP signature was an independent prognostic factor in the training and validation cohorts. Additionally, GC patients with low CBPscores showed an increase in anti-tumor immune microenvironment, which was further verified by mIF in pathological resections following immunotherapy. Importantly, patients with low CBPscores had higher levels of TMB/MSI and responded well to immunotherapy. Conclusions: We conducted the first and comprehensive CBP analysis of GC patients and established a clinically feasible CBP signature for predicting survival and response to treatment, which will be helpful for guiding personalized medicine. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

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12 pages, 842 KiB

Open AccessArticle

The Association of Metformin, Other Antidiabetic Medications and Statins on the Prognosis of Rectal Cancer in Patients with Type 2 Diabetes: A Retrospective Cohort Study

by Sami Erkinantti, Ari Hautakoski, Reijo Sund, Martti Arffman, Elina Urpilainen, Ulla Puistola, Esa Läärä, Arja Jukkola and Peeter Karihtala

Biomolecules 2022, 12(9), 1301; https://doi.org/10.3390/biom12091301 - 15 Sep 2022

Cited by 1 | Viewed by 1730

Abstract

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We identified 1271 eligible patients with T2D and incident RC between 1998 and 2011 from the Diabetes in Finland (FinDM) database. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of antidiabetic medication (ADM) and statins before the RC diagnosis and for post-diagnostic use in a time-dependent exposure manner. No sufficient evidence was found for either pre- or post-diagnostic metformin use and RC mortality (HR 0.96, 95% CI 0.67–1.38, and 0.70, 95% CI 0.45–1.10, respectively) when compared to other oral ADMs. Both pre- and post-diagnostic statin use appeared to be inversely associated with mortality from RC (HR 0.77 95% CI 0.63–0.94, and 0.57, 95% CI 0.42–0.78, respectively). Our study was inconclusive as to the association of metformin use with the prognosis of RC, but statin use was found to predict reduced mortality, both from RC and from other causes of death in persons with T2D. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

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16 pages, 3114 KiB

Open AccessArticle

Hyperthermia Enhances Efficacy of Chemotherapeutic Agents in Pancreatic Cancer Cell Lines

by Costanza E. Maurici, Robin Colenbier, Britta Wylleman, Luigi Brancato, Eke van Zwol, Johan Van den Bossche, Jean-Pierre Timmermans, Elisa Giovannetti, Marina G. M. C. Mori da Cunha and Johannes Bogers

Biomolecules 2022, 12(5), 651; https://doi.org/10.3390/biom12050651 - 29 Apr 2022

Cited by 9 | Viewed by 2420

Abstract

Chemotherapy (CT) is the standard care for advanced pancreatic ductal adenocarcinoma (PDAC); however, with limited efficacy. Hyperthermia (HT) treatment has been suggested as a sensitizer to improve outcomes. However, the direct effect of the HT and CT combination is not fully understood. Therefore, we aim to assess the direct cytotoxic effect of HT in PDAC cells as monotherapy or in combination with chemotherapeutics. Different temperatures (37-, 40.5-, 41-, and 41.5 °C) and durations (6-, 12-, and 24 h) were tested in PDAC cell lines (BxPC-3, Capan-1, Capan-2, PANC-1, and MIA-PaCa-2). Different concentrations of gemcitabine, 5-fluorouracil, and cisplatin were also tested in these conditions. The impact on cell metabolic activity was determined by an MTS assay. Enhancement of chemosensitivity was assessed by a reduction in half-maximal inhibitory concentration (

I C_{50}

). HT and chemotherapeutics interactions were classified as antagonistic, additive, or synergistic using the combination index. HT inhibited cell proliferation in a cell type, temperature, and duration-dependent manner. The induction of apoptosis was seen after 6 h of HT treatment, eventually followed by secondary necrosis. The HT and CT combination led to an

I C_{50}

reduction of the tested CT. At 12 h of HT, this effect was between 25 to 90% and reached a 95% reduction at 24 h. The additive or synergistic effect was demonstrated in all cell lines and chemotherapeutics, although, again, this depended on cell type, duration, and temperature. HT is cytotoxic and enhances the therapeutic effectiveness of gemcitabine, 5-fluorouracil, and cisplatin on PDAC cells. This result was further confirmed by the decrease in the expression of RRM2, TS, and ERCC1 in BxPC-3 and Capan-2 cells. These observations warrant further study in specific subsets of PDAC patients to improve their clinical outcomes. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

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Review

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16 pages, 307 KiB

Open AccessReview

Therapeutic Advances in the Treatment of Gastroesophageal Cancers

by Jenny J. Li, Jane E. Rogers, Kohei Yamashita, Rebecca E. Waters, Mariela Blum Murphy and Jaffer A. Ajani

Biomolecules 2023, 13(5), 796; https://doi.org/10.3390/biom13050796 - 6 May 2023

Cited by 2 | Viewed by 2625

Abstract

Gastroesophageal cancers are a group of aggressive malignancies that are inherently heterogeneous with poor prognosis. Esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, and gastric adenocarcinoma all have distinct underlying molecular biology, which can impact available targets and treatment response. Multimodality therapy is needed in the localized setting and treatment decisions require multidisciplinary discussions. Systemic therapies for treatment of advanced/metastatic disease should be biomarker-driven, when appropriate. Current FDA approved treatments include HER2-targeted therapy, immunotherapy, and chemotherapy. However, novel therapeutic targets are under development and future treatments will be personalized based on molecular profiling. Herein, we review the current treatment approaches and discuss promising advances in targeted therapies for gastroesophageal cancers. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

18 pages, 1714 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Radiobiological Aspects of FLASH Radiotherapy

by Eline Hageman, Pei-Pei Che, Max Dahele, Ben J. Slotman and Peter Sminia

Biomolecules 2022, 12(10), 1376; https://doi.org/10.3390/biom12101376 - 26 Sep 2022

Cited by 13 | Viewed by 4877

Abstract

Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

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