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Epithelial to Mesenchymal Transition: A Mechanism that Fuels Cancer Radio/Chemoresistance.
Dudas, J, Ladanyi, A, Ingruber, J, Steinbichler, TB, Riechelmann, H
Cells. 2020;(2)
Abstract
Epithelial to mesenchymal transition (EMT) contributes to tumor progression, cancer cell invasion, and therapy resistance. EMT is regulated by transcription factors such as the protein products of the SNAI gene family, which inhibits the expression of epithelial genes. Several signaling pathways, such as TGF-beta1, IL-6, Akt, and Erk1/2, trigger EMT responses. Besides regulatory transcription factors, RNA molecules without protein translation, micro RNAs, and long non-coding RNAs also assist in the initialization of the EMT gene cluster. A challenging novel aspect of EMT research is the investigation of the interplay between tumor microenvironments and EMT. Several microenvironmental factors, including fibroblasts and myofibroblasts, as well as inflammatory, immune, and endothelial cells, induce EMT in tumor cells. EMT tumor cells change their adverse microenvironment into a tumor friendly neighborhood, loaded with stromal regulatory T cells, exhausted CD8+ T cells, and M2 (protumor) macrophages. Several EMT inhibitory mechanisms are instrumental in reversing EMT or targeting EMT cells. Currently, these mechanisms are also significant for clinical use.
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Tumor hypermetabolism confers resistance to immunotherapy.
Liu, A, Curran, MA
Seminars in cancer biology. 2020;:155-163
Abstract
Advances in our understanding of tumor immune biology and development of cancer immunotherapies have led to improved outcomes for patients that suffer from aggressive cancers such as metastatic melanoma. Despite these advances, a significant proportion of patients still fail to benefit, and as a result, attention has shifted to understanding how cancer cells escape immune destruction. Of particular interest is the metabolic landscape of the tumor microenvironment, as recent studies have demonstrated how both competition for essential nutrients and depletion of specific amino acids can promote T cell dysfunction. Here, we will discuss the major energetic pathways engaged by both T cells and cancer cells, metabolic substrates present in the tumor microenvironment, and emerging therapeutic strategies that seek to improve T cell metabolic fitness and bolster the antitumor immune response.
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Targeted therapy for hepatocellular carcinoma.
Huang, A, Yang, XR, Chung, WY, Dennison, AR, Zhou, J
Signal transduction and targeted therapy. 2020;(1):146
Abstract
The last 3 years have seen the emergence of promising targeted therapies for the treatment of hepatocellular carcinoma (HCC). Sorafenib has been the mainstay of treatment for a decade and newer modalities were ineffective and did not confer any increased therapeutic benefit until the introduction of lenvatinib which was approved based on its non-inferiority to sorafenib. The subsequent success of regorafenib in HCC patients who progress on sorafenib treatment heralded a new era of second-line treatment and was quickly followed by ramucirumab, cabozantinib, and the most influential, immune checkpoint inhibitors (ICIs). Over the same period combination therapies, including anti-angiogenesis agents with ICIs, dual ICIs and targeted agents in conjunction with surgery or other loco-regional therapies, have been extensively investigated and have shown promise and provided the basis for exciting clinical trials. Work continues to develop additional novel therapeutic agents which could potentially augment the presently available options and understand the underlying mechanisms responsible for drug resistance, with the goal of improving the survival of patients with HCC.
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Therapy after cyclin-dependent kinase inhibition in metastatic hormone receptor-positive breast cancer: Resistance mechanisms and novel treatment strategies.
Sharifi, MN, Anandan, A, Grogan, P, O'Regan, RM
Cancer. 2020;(15):3400-3416
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Abstract
Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR-positive tumors ultimately develop resistance to endocrine therapy. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progression and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical challenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector retinoblastoma proteinĀ (pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways, in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6 inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.
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Challenges in the Treatment of Glioblastoma: Multisystem Mechanisms of Therapeutic Resistance.
Noch, EK, Ramakrishna, R, Magge, R
World neurosurgery. 2018;:505-517
Abstract
Glioblastoma is one of the most lethal human cancers, with poor survival despite surgery, radiation treatment, and chemotherapy. Advances in the treatment of this type of brain tumor are limited because of several resistance mechanisms. Such mechanisms involve limited drug entry into the central nervous system compartment by the blood-brain barrier and by actions of the normal brain to counteract tumor-targeting medications. In addition, the vast heterogeneity in glioblastoma contributes to significant therapeutic resistance by preventing adequate control of the entire tumor mass by a single drug and by facilitating escape mechanisms from targeted agents. The stem cell-like characteristics of glioblastoma promote resistance to chemotherapy, radiation, and immunotherapy through upregulation of efflux transporters, promotion of glioblastoma stem cell proliferation in neurogenic zones, and immune suppression, respectively. Metabolic cascades in glioblastoma prevent effective treatments through the optimization of glucose use, the use of alternative nutrient precursors for energy production, and the induction of hypoxia to enhance tumor growth. In the era of precision medicine, an assortment of molecular techniques is being developed to target an individual's unique tumor, with the hope that this personalized strategy will bypass therapeutic resistance. Although each resistance mechanism presents an array of challenges to effective treatment of glioblastoma, as the field recognizes and addresses these difficulties, future treatments may have more efficacy and promise for patients with glioblastoma.
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5'-Triphosphate siRNA targeting MDR1 reverses multi-drug resistance and activates RIG-I-induced immune-stimulatory and apoptotic effects against human myeloid leukaemia cells.
Li, D, Gale, RP, Liu, Y, Lei, B, Wang, Y, Diao, D, Zhang, M
Leukemia research. 2017;:23-30
Abstract
Multi-drug resistance (MDR), immune suppression and decreased apoptosis are important causes of therapy-failure in leukaemia. Short interfering RNAs (siRNAs) down-regulate gene transcription, have sequence-independent immune-stimulatory effects and synergize with other anti-cancer therapies in some experimental models. We designed a siRNA targeting MDR1 with 5'-triphosphate ends (3p-siRNA-MDR1). Treatment of leukaemia cells with 3p-siRNA-MDR1 down-regulated MDR1 expression, reduced-drug resistance and induced immune and pro-apoptotic effects in drug-resistant HL-60/Adr and K562/Adr human leukaemia cell lines. We show mechanisms-of-action of these effects involve alterations in the anti-viral cytosolic retinoic acid-inducible protein-I (RIG-I; encoded by RIG-I or DDX58) mediated type-I interferon signal induction, interferon-gamma-inducible protein 10 (IP-10; encoded by IP10 or CXCL10) secretion, major histocompatibility complex-I expression (MHC-I) and caspase-mediated cell apoptosis. 3p-siRNA-MDR1 transfection also enhanced the anti-leukaemia efficacy of doxorubicin. These data suggest a possible synergistic role for 3p-siRNA-MDR1 in anti-leukaemia therapy.