Advances in Cancer Research最新文献

The microtubule-targeting paclitaxel (PTX) and docetaxel (DTX) are widely used chemotherapeutic agents. However, the dysregulation of apoptotic processes, microtubule-binding proteins, and multi-drug resistance efflux and influx proteins can alter the efficacy of taxane drugs. In this review, we have created multi-CpG linear regression models to predict the activities of PTX and DTX drugs through the integration of publicly available pharmacological and genome-wide molecular profiling datasets generated using hundreds of cancer cell lines of diverse tissue of origin. Our findings indicate that linear regression models based on CpG methylation levels can predict PTX and DTX activities (log-fold change in viability relative to DMSO) with high precision. For example, a 287-CpG model predicts PTX activity at R² of 0.985 among 399 cell lines. Just as precise (R²=0.996) is a 342-CpG model for predicting DTX activity in 390 cell lines. However, our predictive models, which employ a combination of mRNA expression and mutation as input variables, are less accurate compared to the CpG-based models. While a 290 mRNA/mutation model was able to predict PTX activity with R² of 0.830 (for 546 cell lines), a 236 mRNA/mutation model could calculate DTX activity at R² of 0.751 (for 531 cell lines). The CpG-based models restricted to lung cancer cell lines were also highly predictive (R²≥0.980) for PTX (74 CpGs, 88 cell lines) and DTX (58 CpGs, 83 cell lines). The underlying molecular biology behind taxane activity/resistance is evident in these models. Indeed, many of the genes represented in PTX or DTX CpG-based models have functionalities related to apoptosis (e.g., ACIN1, TP73, TNFRSF10B, DNASE1, DFFB, CREB1, BNIP3), and mitosis/microtubules (e.g., MAD1L1, ANAPC2, EML4, PARP3, CCT6A, JAKMIP1). Also represented are genes involved in epigenetic regulation (HDAC4, DNMT3B, and histone demethylases KDM4B, KDM4C, KDM2B, and KDM7A), and those that have never been previously linked to taxane activity (DIP2C, PTPRN2, TTC23, SHANK2). In summary, it is possible to accurately predict taxane activity in cell lines based entirely on methylation at multiple CpG sites.

Protein disulfide isomerase (PDI) and its superfamilies are mainly endoplasmic reticulum (ER) resident proteins with essential roles in maintaining cellular homeostasis, via thiol oxidation/reduction cycles, chaperoning, and isomerization of client proteins. Since PDIs play an important role in ER homeostasis, their upregulation supports cell survival and they are found in a variety of cancer types. Despite the fact that the importance of PDI to tumorigenesis remains to be understood, it is emerging as a new therapeutic target in cancer. During the past decade, several PDI inhibitors has been developed and commercialized, but none has been approved for clinical use. In this review, we discuss the properties and redox regulation of PDIs within the ER and provide an overview of the last 5 years of advances regarding PDI inhibitors.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is currently the third leading cause of cancer death. The aggressiveness of PDAC stems from late diagnosis, early metastasis, and poor efficacy of current chemotherapies. Thus, there is an urgent need for effective biomarkers for early detection of PDAC and development of new therapeutic strategies. It has long been known that cellular glycosylation is dysregulated in pancreatic cancer cells, however, tumor-associated glycans and their cognate glycosylating enzymes have received insufficient attention as potential clinical targets. Aberrant glycosylation affects a broad range of pathways that underpin tumor initiation, metastatic progression, and resistance to cancer treatment. One of the prevalent alterations in the cancer glycome is an enrichment in a select group of sialylated glycans including sialylated, branched N-glycans, sialyl Lewis antigens, and sialylated forms of truncated O-glycans such as the sialyl Tn antigen. These modifications affect the activity of numerous cell surface receptors, which collectively impart malignant characteristics typified by enhanced cell proliferation, migration, invasion and apoptosis-resistance. Additionally, sialic acids on tumor cells engage inhibitory Siglec receptors on immune cells to dampen anti-tumor immunity, further promoting cancer progression. The goal of this review is to summarize the predominant changes in sialylation occurring in pancreatic cancer, the biological functions of sialylated glycoproteins in cancer pathogenesis, and the emerging strategies for targeting sialoglycans and Siglec receptors in cancer therapeutics.

Head and neck cancers are a heterogeneous group of highly aggressive tumors and collectively represent the sixth most common cancer worldwide. Most head and neck cancers are squamous cell carcinomas (HNSCCs). Current multimodal treatment concepts combine surgery, chemotherapy, irradiation, immunotherapy, and targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of HNSCC and revealed novel therapeutic targets and prognostic/predictive biomarkers. Notably, HNSCC is characterized by complex relations between stromal, epithelial, and immune cells within the tumor microenvironment (TME). The TME consists of different subsets of immune cells that infiltrate the tumors and interact with the tumor cells or with each other. Understanding multiple pivotal factors in HNSCC tumorigenesis and tumor progression may help define novel targets and develop more effective therapies for patients. This review provides a comprehensive overview of the latest advances in the molecular biology of HNSCC and their effects on clinical oncology; it is meant for a broad readership in the head and neck cancers field.

Pancreatic ductal adenocarcinoma (PDAC), a prominent cause of cancer deaths worldwide, is a highly aggressive cancer most frequently detected at an advanced stage that limits treatment options to systemic chemotherapy, which has provided only marginal positive clinical outcomes. More than 90% of patients with PDAC die within a year of being diagnosed. PDAC is increasing at a rate of 0.5-1.0% per year, and it is expected to be the second leading cause of cancer-related mortality by 2030. The resistance of tumor cells to chemotherapeutic drugs, which can be innate or acquired, is the primary factor contributing to the ineffectiveness of cancer treatments. Although many PDAC patients initially responds to standard of care (SOC) drugs they soon develop resistance caused partly by the substantial cellular heterogeneity seen in PDAC tissue and the tumor microenvironment (TME), which are considered key factors contributing to resistance to therapy. A deeper understanding of molecular mechanisms involved in PDAC progression and metastasis development, and the interplay of the TME in all these processes is essential to better comprehend the etiology and pathobiology of chemoresistance observed in PDAC. Recent research has recognized new therapeutic targets ushering in the development of innovative combinatorial therapies as well as enhancing our comprehension of several different cell death pathways. These approaches facilitate the lowering of the therapeutic threshold; however, the possibility of subsequent resistance development still remains a key issue and concern. Discoveries, that can target PDAC resistance, either alone or in combination, have the potential to serve as the foundation for future treatments that are effective without posing undue health risks. In this chapter, we discuss potential causes of PDAC chemoresistance and approaches for combating chemoresistance by targeting different pathways and different cellular functions associated with and mediating resistance.

Traditional chemotherapy against cancer is often severely hampered by acquired resistance to the drug. Epigenetic alterations and other mechanisms like drug efflux, drug metabolism, and engagement of survival pathways are crucial in evading drug pressure. Herein, growing evidence suggests that a subpopulation of tumor cells can often tolerate drug onslaught by entering a "persister" state with minimal proliferation. The molecular features of these persister cells are gradually unraveling. Notably, the "persisters" act as a cache of cells that can eventually re-populate the tumor post-withdrawal drug pressure and contribute to acquiring stable drug-resistant features. This underlines the clinical significance of the tolerant cells. Accumulating evidence highlights the importance of modulation of the epigenome as a critical adaptive strategy for evading drug pressure. Chromatin remodeling, altered DNA methylation, and de-regulation of non-coding RNA expression and function contribute significantly to this persister state. No wonder targeting adaptive epigenetic modifications is increasingly recognized as an appropriate therapeutic strategy to sensitize them and restore drug sensitivity. Furthermore, manipulating the tumor microenvironment and "drug holiday" is also explored to maneuver the epigenome. However, heterogeneity in adaptive strategies and lack of targeted therapies have significantly hindered the translation of epigenetic therapy to the clinics. In this review, we comprehensively analyze the epigenetic alterations adapted by the drug-tolerant cells, the therapeutic strategies employed to date, and their limitations and future prospects.

Microsomal glutathione transferase 1 (MGST1) is a member of the MAPEG family (membrane associated proteins in eicosanoid and glutathione metabolism), defined according to enzymatic activities, sequence motifs, and structural properties. MGST1 is a homotrimer which can bind three molecules of glutathione (GSH), with one modified to a thiolate anion displaying one-third-of-sites-reactivity. MGST1 has both glutathione transferase and peroxidase activities. Each is based on stabilizing the GSH thiolate in the same active site. MGST1 is abundant in the liver and displays a broad subcellular distribution with high levels in endoplasmic reticulum and mitochondrial membranes, consistent with a physiological role in protection from reactive electrophilic intermediates and oxidative stress. In this review paper, we particularly focus on recent advances made in understanding MGST1 activation, induction, broad subcellular distribution, and the role of MGST1 in apoptosis, ferroptosis, cancer progression, and therapeutic responses.