Eukaryotes use autophagy as a mechanism for maintaining cellular homeostasis by degrading and recycling organelles and proteins. This process assists in the proliferation and survival of advanced ...cancers. There is mounting preclinical evidence that targeting autophagy can enhance the efficacy of many cancer therapies. Hydroxychloroquine (HCQ) is the only clinically-approved autophagy inhibitor, and this systematic review focuses on HCQ use in cancer clinical trials. Preclinical trials have shown that HCQ alone and in combination therapy leads to enhancement of tumor shrinkage. This has provided the base for multiple ongoing clinical trials involving HCQ alone and in combination with other treatments. However, due to its potency, there is still a need for more potent and specific autophagy inhibitors. There are multiple autophagy inhibitors in the pre-clinical stage at various stages of development. Additional studies on the mechanism of HCQ and other autophagy inhibitors are still required to answer questions surrounding how these agents will eventually be used in the clinic.
Targeting the lysosome in cancer Piao, Shengfu; Amaravadi, Ravi K.
Annals of the New York Academy of Sciences,
20/May , Letnik:
1371, Številka:
1
Journal Article
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Lysosomes are membrane‐bound intracellular organelles that receive macromolecules delivered by endocytosis, phagocytosis, and autophagy for degradation and recycling. Over the last decade, advances ...in lysosome research have established a broad role for the lysosome in the pathophysiology of disease. In this review, we highlight the recent discoveries in lysosome biology, with an emphasis on their implications for cancer therapy. We focus on targeting the lysosome in cancer by exploring lysosomal biogenesis and its role in the crosstalk between apoptosis and autophagy. We also discuss how lysosomal inhibition could emerge as a new therapeutic strategy to overcome drug resistance in cancer.
Cancer cells encounter numerous stresses that pose a threat to their survival. Tumor microenviroment stresses that perturb protein homeostasis can produce endoplasmic reticulum (ER) stress, which can ...be counterbalanced by triggering the unfolded protein response (UPR) which is considered the canonical ER stress response. The UPR is characterized by three major proteins that lead to specific changes in transcriptional and translational programs in stressed cells. Activation of the UPR can induce apoptosis, but also can induce cytoprotective programs such as autophagy. There is increasing appreciation for the role that UPR-induced autophagy plays in supporting tumorigenesis and cancer therapy resistance. More recently several new pathways that connect cell stresses, components of the UPR and autophagy have been reported, which together can be viewed as non-canonical ER stress responses. Here we review recent findings on the molecular mechanisms by which canonical and non-canonical ER stress responses can activate cytoprotective autophagy and contribute to tumor growth and therapy resistance. Autophagy has been identified as a druggable pathway, however the components of autophagy (ATG genes) have proven difficult to drug. It may be the case that targeting the UPR or non-canonical ER stress programs can more effectively block cytoprotective autophagy to enhance cancer therapy. A deeper understanding of these pathways could provide new therapeutic targets in cancer.
Macroautophagy/autophagy is a resistance mechanism to targeted therapy in BRAF mutant cancers. Preclinical evidence and clinical trial data demonstrate that hydroxychloroquine (HCQ) is an effective ...autophagy inhibitor at clinically achievable concentrations. Here we highlight the results of a recently published single-arm phase I/II multi-institution trial of dabrafenib, trametinib, and the autophagy inhibitor HCQ (the BAMM trial) that established the safety and activity of this regimen in BRAF V600-mutant melanoma patients. Compared to the pivotal trials that led to FDA approval of dabrafenib and trametinib, the BAMM trial enrolled a high percentage of patients with elevated LDH and prior immunotherapy, reflecting the trend that poorer-prognosis patients are treated with targeted therapy in the modern era where multiple immunotherapy regimens are available for melanoma. Dabrafenib, trametinib, and hydroxychloroquine are safe and produce a high response rate (85%). Progression-free survival does not meet the pre-specified threshold for the entire cohort but looks especially promising in patients with elevated LDH and prior treatment. A national randomized study has been launched to study this regimen further in poor-prognosis BRAF V600-mutant melanoma patients.
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Cancer cells are exposed to various intrinsic and extrinsic factors that disrupt protein homeostasis, producing endoplasmic reticulum (ER) stress. To cope with these situations, ...cancer cells evoke a highly conserved adaptive mechanism called the unfolded protein response (UPR) to restore the ER homeostasis. Recently, several pharmacological agents have been found to exhibit anti-tumor activity by targeting the UPR components. The development of potent and specific compounds that target the UPR components has not only shed light on the regulation of the UPR in cancer cells, but also brought the field closer to clinical drug candidates. Here we present an overview of the milestones in the field of UPR biology in cancer with a focus on new strategies for pharmacological inhibition.
Lysosomal Biology in Cancer Fennelly, Colin; Amaravadi, Ravi K
Methods in molecular biology,
2017, Letnik:
1594
Journal Article
Odprti dostop
Cells depend on the lysosome for sequestration and degradation of macromolecules in order to maintain metabolic homeostasis. These membrane-enclosed organelles can receive intracellular and ...extracellular cargo through endocytosis, phagocytosis, and autophagy. Lysosomes establish acidic environments to activate enzymes that are able to break down biomolecules engulfed through these various pathways. Recent advances in methods to study the lysosome have allowed the discovery of extended roles for the lysosome in various diseases, including cancer, making it an attractive and targetable node for therapeutic intervention. This review focuses on key aspects of lysosomal biology in the context of cancer and how these properties can be exploited for the development of new therapeutic strategies. This will provide a contextual framework for how advances in methodology could be applied in future translational research.
Metabolic and therapeutic stresses activate several signal transduction pathways that regulate cell death and cell survival in cancer cells. Although decades of research unraveled the pathways that ...regulate apoptosis and allowed the development of novel diagnostic and therapeutic modalities in cancer treatment, only recently has the regulation and significance of tumor cell autophagy and necrosis become the focus of investigations. Necrosis is an irreversible inflammatory form of cell death. In contrast, autophagy is a reversible process that can contribute both to tumor cell death and survival. This review describes recent advances in understanding the regulation of autophagy and necrosis and their implications for cancer therapy. Currently available methods to measure autophagy and necrosis are highlighted. The effect of tumor cell autophagy and necrosis on host immunity is explored. Finally, therapeutic approaches that target autophagy and necrosis in cancer are described.
Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. We demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and ...PDL1-independent resistance to immune checkpoint blockade (ICB) and to combinations such as radiation plus anti-CTLA4. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways and expands distinct T cell populations with improved function despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.
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•Chronic IFNG promotes epigenomic and transcriptomic features of resistant tumors•IFN-driven PDL1-independent resistance comprises multiple inhibitory pathways•Targeting IFN-driven resistance improves function of distinct exhausted T cell subsets•Blocking tumor IFN signaling can bypass need for combination checkpoint blockade
Prolonged interferon signaling in tumor cells increases resistance to immune checkpoint blockade through multiple inhibitory pathways, and inhibiting this response can bypass the need for multi-agent blockade.
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