Cancer stem cells (CSCs) are thought to be a distinct population of cells within a tumor mass that are capable of asymmetric division and known to have chemoresistant characteristics. The description and identification of CSC models in cancer growth and recurrence has inspired the design of novel treatment strategies to overcome treatment resistance by targeting both CSCs and non-CSC tumor cells. Several cellular signaling pathways have been described as playing a role in the induction and maintenance of stemness in CSCs, such as the Wnt/β-catenin, Notch, STAT3, and Hedgehog pathways. In this review, we aim to review some of the ongoing CSC therapeutic targeting strategies in gastrointestinal malignancies.

Colorectal cancer (CRC) represents a heterogeneous group of diseases that imposes a considerable global and national health burden. Although most CRC patients are diagnosed at an early stage and undergo potentially curative treatment, a significant proportion experience recurrence. Currently, adjuvant chemotherapy decisions are primarily based on clinicopathological characteristics, which have well-recognized limitations in accurately identifying patients harboring minimal residual disease (MRD), often resulting in unnecessary chemotherapy exposure. Circulating tumor DNA (ctDNA) has emerged as a promising surrogate marker for MRD, offering a more precise approach to identifying patients at risk of recurrence after curative-intent surgery and refining adjuvant chemotherapy decisions. Growing evidence from multiple studies has demonstrated that ctDNA outperforms traditional clinicopathological factors as a marker for MRD. This review synthesizes key studies supporting the role of ctDNA in MRD detection for CRC patients and evaluates clinical trials investigating the application of ctDNA in guiding adjuvant therapy decisions. This emerging strategy holds the potential to transform the adjuvant treatment paradigm in colorectal cancer by optimizing therapeutic precision and minimizing unnecessary treatment.

Pancreatic adenocarcinoma is typically refractory to conventional treatments and associated with poor prognosis. While therapeutic advances over the past several years have improved patient outcomes, the observed benefits have been modest at best, highlighting the need for continued development of alternate treatment strategies. The tumor microenvironment has been identified as being integral to oncogenesis through its direct effect on cellular pathway communication, immune inhibition, and promoting chemo-resistance. A more in depth understanding of the biology of the disease, in addition with our ability to develop more effective novel therapies have led to ongoing studies that are investigating several promising treatment options in this disease. Herein, we highlight and review the therapeutic landscape in pancreatic adenocarcinoma.

(1) Background: Cabozantinib, a multikinase inhibitor, is approved by the Food and Drug Administration (FDA) for the treatment of advanced hepatocellular carcinoma (HCC) following progression on sorafenib. Recently, atezolizumab plus bevacizumab has been approved in the first line setting for advanced HCC and has become the new standard of care. Whether cabozantinib improves outcomes following progression on immunotherapy remains unknown. We describe the clinical outcomes following treatment with immunotherapy in patients with advanced HCC who received cabozantinib. (2) Methods: We conducted a multicentric, retrospective analysis of patients with advanced HCC diagnosed between 2010–2021 at Mayo Clinic in Minnesota, Arizona, and Florida who received cabozantinib. Median overall survival and progression free survival analyses were performed using the Kaplan–Meier method. Adverse events were determined using Common Terminology Criteria for Adverse Events (CTCAE). (3). Results: We identified 26 patients with advanced HCC who received cabozantinib following progression on immunotherapy. Median progression free survival on cabozantinib therapy was 2.1 months (95% CI: 1.3–3.9) and median overall survival from time of cabozantinib initiation was 7.7 months (95% CI: 5.3–14.9). (4) Conclusion: The optimal sequencing of therapy for patients with advanced HCC following progression on immunotherapy remains unknown. Our study demonstrates that patients may benefit from treatment with cabozantinib following progression on immunotherapy.

Oncolytic virotherapy represents a novel therapeutic strategy in the treatment of gastrointestinal malignancies. Oncolytic viruses, including genetically engineered and naturally occurring viruses, can selectively replicate in and induce tumor cell apoptosis without harming normal tissues, thus offering a promising tool in the armamentarium for cancer therapy. While this approach has garnered much interest over the past several decades, there has not been significant headway across various tumor types. The recent approval of talimogene laherparepvec, a second-generation oncolytic herpes simplex virus type-1, for the treatment of metastatic melanoma, confirms the therapeutic potential of oncolytic viral therapy. Herein, we will highlight and review the role of oncolytic viral therapy in gastrointestinal malignancies while discussing its limitations and potential alternative mechanisms to improve its treatment efficacy.

Background: Fluoropyrimidine with platinum-based chemotherapy has become the standard of care for advanced gastric and gastroesophageal (GEJ) cancer. Trials in colon cancer show that induction chemotherapy followed by maintenance chemotherapy is an efficacious strategy to maximize clinical response while minimizing toxicity. The current retrospective study aims to evaluate the efficacy and tolerability of maintenance versus continuous treatment in advanced GEJ malignancy.Methods: A retrospective analysis of patients with metastatic gastric/GEJ adenocarcinoma treated with fluoropyrimidine and platinum chemotherapy between 2007-2017 was performed. Patients who achieved at least stable disease after initial induction treatment were included. After 16 weeks of induction chemotherapy, patients were categorized into the continuous group if induction chemotherapy was continued and the maintenance group if chemotherapy was switched to maintenance fluoropyrimidine monotherapy or observed off treatment. Endpoints were progression-free survival (PFS), overall survival (OS), and toxicities.Results: In total, 90 patients met the criteria, 48 received continuous therapy, and 42 received maintenance. Baseline characteristics were comparable. No difference in PFS (9.9 vs 8.4 months p = .28) or in OS (16.1 vs 21.3 months p = .75) was observed, including after controlling for the best response on induction therapy and other variables. In patients on continuous induction therapy, there was a higher prevalence of grade three neuropathy (42.6% vs 9.8% p = .001) and neutropenic fever (13% vs 0% p =.03).Conclusions: Maintenance therapy following induction fluoropyrimidine and platinum-based therapy is associated with an improved toxicity profile and appears to have comparable efficacy to continuous treatment in metastatic gastric/GEJ cancer.