MedComm – Oncology最新文献

In two recent publications in Science¹ and Cell Discovery,² researchers have discovered that iron–sulfur cluster assembly scaffold protein (ISCU) plays crucial roles on maintaining glutathione (GSH) homeostasis, α-KG catabolism, DNA methylation and so on. These groundbreaking findings not only establish crucial connections among iron–sulfur (Fe–S) metabolism, GSH homeostasis, alpha-ketoglutarate (α-KG) catabolism, DNA methylation, and tumor growth but also emphasize the significant and integrated regulation of mitochondrial function and gene expression by ISCU (Figure 1).

Liu et al.¹ unveiled the vital role of ISCU in maintaining optimal mitochondrial functions by restoring the balance between iron and GSH. In addition, a previous study³ has provided evidence that glutamine, a precursor of GSH, promotes tumor growth through a KRAS-regulated metabolic pathway in pancreatic ductal adenocarcinoma (PDAC), thereby suggesting that ISCU potentially influences tumor development by modulating GSH homeostasis. Ren et al.² uncovered a previously undisclosed association between Fe–S metabolism and tumor growth in kirsten rat sarcoma viral oncogene homolog (KRAS)-activated PDAC. Such findings offer a promising avenue for the treatment of KRAS-activated PDAC, as well as for interventions targeting ISCU-mediated cellular processes.

PDAC is a highly lethal disease with a mounting incidence and unfavorable prognostic outcomes, underscoring the urgent requirement for the development of efficacious therapeutic approaches. Thus, accurate biomarkers to help stratify risk would greatly improve current diagnostic and decision-making dilemmas. Fe–S clusters are ancient, ubiquitous metal cofactors that possess various physiological functions in antioxidant, iron regulation, the tricarboxylic acid (TCA) cycle, and many other metabolic reactions. Accumulated evidence suggests that abnormal Fe–S clusters assembly pathways lead to mitochondrial dysfunction and cause various diseases, particularly with an impact on tumor development.⁴ For instance, nitrogen fixation gene 1 (NFS1) cysteine desulfurase, as an indispensable protein in Fe–S cluster biogenesis, plays a vital role in mitochondrial metabolic reprogramming. In human colorectal cancer, NFS1 can suppress PANoptosis under oxaliplatin chemotherapy, and NFS1 high expression was linked to unfavorable survival outcomes and hyposensitivity to chemotherapy in patients.⁵ In addition, succinate dehydrogenase complex iron–sulfur subunit B (SDHB) is also an Fe–S cluster protein consisting of three Fe–S clusters. In SDHB-deficient cancer cells, succinate levels are elevated, resulting in hypermethylation of histones and DNA, and glutamine becomes the primary source of TCA cycle metabolites via reductive carboxylation.⁶

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Recently, the group of Prof. Carolyn Bertozzi, a laureate of the Nobel Prize in chemistry 2022, reported the detailed mechanism of lysosome-targeting chimera (LYTAC) in the journal of Science,¹ after the publication of their first LYTAC molecule in Nature in 2020.² The establishment of LYTAC, a subtype of targeted protein degradation technology, expands the scope of protein degradation to extracellular and membrane-associated targets, and Bertozzi group's new discovery is expected to accelerate the development of LYTAC in cancer therapy.

Cell membranes play a critical role in various cellular processes, including signaling transduction, cell adhesion, transport of biomolecules and immunity. Proteins embedded in or associated with the cell membrane are key executants of the function of cell membrane, and their dysregulation contributes to tumorigenesis and development of human cancers.³ For example, epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase for epithelial growth factor (EGF) and transforming growth factor α (TGF-α), belonging to the ErbB receptor family. Activation of EGFR signaling promotes cell proliferation, survival, angiogenesis and metastasis of diverse malignancies.³ Moreover, hepatocyte growth factor receptor (c-Met, HGFR) is another oncogenic receptor tyrosine kinase in diverse cancers. Upon the binding to hepatocyte growth factor (HGF), c-Met is activated via autophosphorylation, leading to the initiation of oncogenic downstream signaling cascades, such as PI3K/AKT and RAS/ERK pathways.³ Given their central role in cancer-promoting processes, EGFR and c-Met has become attractive targets for cancer therapies. Small-molecule tyrosine kinase inhibitors (EGFR: gefitinib, afatinib, osimertinib, etc.; c-Met: capmatinib, tepotinib, savolitinib, etc.) and monoclonal antibodies (EGFR: cetuximab, panitumumab; EGFR/c-Met: amivantamab; c-Met: emibetuzumab), have been developed and approved for the treatment of various cancers, including lung and colorectal cancers (Figure 1A). But severe acquired resistance (e.g., via EGFR mutations) and limited therapeutic efficacy (slightly prolonged overall survival) of these treatments restrict their clinical benefit for patients. Moreover, nonenzymatic function of membrane proteins, such as protein–protein interactions, could not be interfered with by kinase inhibitors or monoclonal antibodies, calling for new strategies to control these oncogenic membrane proteins.

Targeted protein degradation (TPD) is a therapeutic approach that aims to selectively remove disease-causing or undesirable proteins from cells by inducing their degradation, with multiple therapies entering clinical trials and targeting proteins that are previously considered “undruggable.”⁴ There are two main protein degradation mechanisms within cel

Epigenetic regulation refers to the alteration of gene expression independent of changes in DNA sequence. It involves chemical modifications such as DNA methylation, histone methylation, and histone acetylation, which are regulated by a coordinated interplay of various regulators to ensure precise spatial and temporal regulation of gene expression. Epigenetic aberrations are commonly observed in cancer and are considered as hallmarks of cancer. In recent years, small molecules targeting specific epigenetic regulators have been developed and are demonstrating promising therapeutic potential in preclinical and clinical trials for cancer treatment. In this review, we summarize the essential regulatory mechanisms and dysfunctions of epigenetic regulators involved in DNA methylation, histone methylation, and histone acetylation during tumor development and progression. Moreover, we discuss the current advances and challenges in cancer epigenetic therapy that target these mechanisms in both hematologic malignancies and solid tumors. Finally, we discuss the potential of combining epigenetic drugs with other therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, as a promising approach for cancer treatment. Overall, we aim to enhance the understanding of epigenetic regulation in cancer therapy and explore targeted therapeutic strategies based on these mechanisms, to ultimately advance cancer therapy and improve patient prognosis.

Cancer stem cells (CSCs) constitute a minority cell population characterized by unbounded proliferative potential in both solid and hematological cancers. Despite sharing key stem cell attributes, CSCs possess unique traits, including the initiation and propagation of tumors and resistance to conventional therapies. The purpose of this review is to delve into the origins and fundamental characteristics of CSCs, emphasizing their role in tumor growth and metastasis. The focus extends to unraveling cellular signaling pathways driving oncogenic processes and understanding aberrant cellular crosstalk crucial for targeted cancer therapies. Beginning with an exploration of CSC properties and behavior, we progress to dissecting the cellular signaling network that fuels oncogenic pathways. The discussion spans the inception of CSCs, their survival strategies, and adaptation to new environments. We then transit to recent therapeutic advancements targeting CSCs, culminating in an exploration for precise therapeutic targeting. This review henceforth, underscores the vital significance of comprehending CSCs in cancer progression and treatment resistance. By unraveling the complex signaling pathways and survival mechanisms unique to CSCs, it paves the way for targeted therapeutic strategies that hold immense promise in enhancing cancer treatment efficacy while minimizing collateral damage.

A recent study by Moon et al.¹ published in Nature Medicine highlights the role of OncoNPC, a machine learning tool, in diagnosing cancers of unknown primary (CUP). The study offers an insight into the efficacy and accessibility of OncoNPC over traditional diagnostic tools and highlights the wider implications of machine learning technologies in delivering precision medicine.

The emergence of targeted immunotherapy over the past decade has led to a paradigm shift in clinical oncology. The efficacy of therapeutic agents in treating cancers such as chronic myeloid leukemia and HER2-positive breast cancer, for example, are now well established.² However, CUPs, metastatic diseases where the primary tumor could not be identified present a significant challenge in this new era of precision medicine. CUPs account for 3%–5% of cancer diagnoses and present significant challenges in providing targeted therapy due to diagnostic uncertainty, and limited therapeutic targets.³ Indeed, the mortality rate in patients with CUPs is up to 80% at 12 months postdiagnosis.⁴

Several authors have hypothesized pathological mechanisms that might underlie CUPs. Lopez-Lazaro⁵ reconciled existing research on stem cells driving tumorigenesis by suggesting CUPs may occur as a result of stem cell migration followed by malignant transformation. This could, in theory, present as metastatic cancer in the absence of a clear primary tumor. Alternative studies have suggested CUPs occur from early dissemination of a primary tumor resulting in rapidly progressive metastatic disease.⁴ This would account for the significant mortality rate associated with CUPs as early dissemination could increase metastatic burden and limit therapeutic interventions.

Current approaches for investigating CUPs focus primarily on immunohistochemistry (IHC) techniques or molecular profiling of tumor samples. Interpretation of IHC results can be inherently subjective. Studies using IHC techniques to investigate CUPs were only able to suggest a primary tumor in 25% of patients.⁶ Molecular profiling compromises several techniques such as whole genome sequencing or gene expression analysis to determine the primary tumor based on the molecular characteristics of tumor cells. The efficacy of these methods remains unclear, however, as implementation into clinical practice is often limited by cost-effectiveness.

Moon et al utilized next-generation sequencing (NGS) data within this study to guide genomic profiling of CUPs.¹ NGS elicits a cellular genetic profile by simultaneously analyzing millions of fragments of DNA. This method is relatively cost-effective and significant tumor NGS data already exists.⁷ This study therefore uses NGS data in concordance with electronic health

Cellular senescence is a state characterized by permanent cell cycle stoppage, which has long been viewed as a protective mechanism against neoplasia. However, accumulating evidence reveal that cellular senescence variously stimulates tumorigenesis and malignant progression in certain contexts. Senescence-associated secretory phenotype (SASP) is a crucial feature of senescent cells and the main way they function. Prostate cancer (PCa) is apparently an age-related tumor with a high prevalence in the elderly. With the aggravation of population aging the morbidity of PCa continues to rise. And with the progress of the disease, most patients eventually develop castration-resistant PCa (CRPC) or drug resistance, which poses a challenge for the treatment of PCa and aggravates the burden on patients and society. Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs formed by back-splicing of pre-mRNAs. Characterized by special covalently closed circular structure, they play important regulatory roles in various tumors. Numerous studies have revealed that circRNAs can regulate PCa and cellular senescence in diverse ways. This review explores a potential mode that circRNAs regulate PCa, reveales a significant mechanism of tumorigenesis and progression for PCa, suggesting a new strategy for PCa research.

A significant proportion of hepatocellular carcinoma (HCC) is pathologically associated with hepatitis B virus (HBV) infection, followed by unsatisfied clinical outcomes. The increasing unmet need for HBV-associated hepatocellular carcinoma (HBV-HCC) treatment drives to deeper understand the role of the intricate immune microenvironment, tumor cell plasticity and dynamics of tumor evolution in HBV-associated hepatic carcinogenesis. Thus, a comprehensive understanding of cross-talk between HBV, host cells, and tumor microenvironment is of fundamental importance for identifying immune imbalance and heterogeneity in HBV-HCC. Over the past 5 years, the application of single-cell RNA sequencing (scRNA-seq) in the understanding of heterogeneity and dynamics of immune cells, clonal evolution, and cancer stem cell (CSC) subsets of tumor cells has established a landscape for HBV-HCC tumor ecosystem. Novel insights into anatomizing immune escape mechanisms and tumor drug resistance have remarkably facilitated the revolution of HBV-HCC clinical treatment. Here, we provided a summary of HCC at single-cell resolution and details on the basic workflow, limitations, and improvements of scRNA-seq. The review highlights novel insights derived from scRNA-seq on advances in the immune microenvironment and tumor heterogeneity of HBV-HCC.

The coronavirus disease 2019 (COVID-19) pandemic brought about unprecedented challenges to global healthcare systems. Among the most vulnerable populations are cancer patients, who face dilemmas due to their compromised immune systems and the intricate interplay with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. This comprehensive review delves into the multifaceted relationship between COVID-19 and cancer. Through an analysis of existing literature and clinical data, this review unravels the structural intricacies of the virus and examines its profound implications for cancer patients, thereby bridging the knowledge gap between virology and oncology. The review commences with an introduction regarding the COVID-19 pandemic and cancer. It then transitions into a detailed examination of the SARS-CoV-2 virus and its variants such as Alpha (PANGO lineage B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529 lineage). Subsequently, an insightful analysis of the impact of COVID-19 on major cancer types (viz., Lung, Colon, Brain, and gastrointestinal cancer) is elaborated. Finally, the therapeutic avenues, oncological care, and management are discussed. The nexus between COVID-19 and cancer adds a layer of complexity to patient care, emphasizing the importance of tailored approaches for those grappling with both conditions. Amid the landscape defined by the evolving viral strains, this review navigates through the multifaceted implications of COVID-19 on cancer patients and underscores the significance of integrating virology and oncology.

Colon cancer is the third most frequently diagnosed cancer worldwide. Considerable progress has been made in the therapeutic strategies and the accuracy of predicting the patients' prognosis. In the past decade, immunotherapy, represented by programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) signaling inhibitors have made remarkable advances in many solid tumors, but limited effect in colon cancer. In particular, colon cancer demonstrates a remarkably poor response to immunotherapy compared with other cancers, with a notable exception of tumors harboring high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR).¹ MSI-H or dMMR tumors are characterized by high mutational/neo-antigen burden, and an inflammatory tumor microenvironment with abundant tumor-infiltrating lymphocytes (TILs).² Although better efficacy could be achieved in a small group of patients with MSI-H or dMMR tumors, a proportion of other patients could benefit from immunotherapy. Thus, more appropriate biomarkers are needed to be discovered to predict the patients' prognosis and immunotherapeutic efficacy.

Different T-cell subsets in the tumor immune microenvironment (TIME) are closely related to the antitumor response and the prognosis of tumor patients. Tumor-specific CD8⁺ T cells are the core cellular components that exert antitumor effects in TIME, by recognizing specific receptors on the tumor surface and secreting cytokines or via the Fas/FsaL pathway. Multiple T-cell subsets are characterized by respective differentiation markers. Currently, with the deepening research of T-cell subsets, the detection of relevant immune indicators and the formulation of therapeutic schedules have attracted increasing clinical attention. By monitoring the expression of T-cell differentiation markers in patients with colon cancer, the benefit of patients receiving immunotherapy can be further evaluated, thus providing a theoretical basis for judging the clinical prognosis and designing more feasible treatment plans.

In this research, we systematically analyzed the prognostic values of multiple markers for different T-cell subsets³ using the Cancer Genome Atlas (TCGA) data set. Among all markers for different T cell subsets, we found that CD95 expression was correlated with better overall survival (OS) and progression-free survival (PFS), while BCL2 and CD122 were only correlated with PFS (Figure 1A,B). Therefore, CD95 was speculated to be associated with prognosis in colon cancer and was selected for further investigation and validation. The analysis of single-cell RNA-sequencing data set confirmed that CD95 was highly expressed in immune cells, especially in various T-cell subtypes (Figure S1A–C). CD95 is a member of the tumor necrosis factor receptor (TNF-R) superfamily and treated as characteristic marker of memeroy cells. It could also be used as the

Covalent inhibitors have been a rapidly growing field in drug discovery due to their therapeutic potential and unique advantages in cancer therapy. As opposed to noncovalent inhibitory drugs, covalent inhibitors reversibly or irreversibly modify proximal nucleophilic amino acid residues on proteins, aiming to selectively recognize and bind to protein targets and addressing some of the challenges faced by noncovalent drugs. Most successful targeted covalent inhibitors depend primarily on binding-site cysteine residues, but this has limitations for certain protein targets that lack targetable cysteine residues. Recently, the rational design of covalent inhibitors or covalent probes targeting other nucleophilic residues, such as lysine, tyrosine, serine, has turned out to be another promising strategy for cancer therapy. Thus, the development of novel strategies to extend the scope of covalent binding and improve the binding properties is required. This review gives a summary of the development of covalent inhibitors targeting noncysteine from different aspects, including target identification, structure–activity relationships, drug discovery strategies, and binding properties, in the hope of providing a scientific reference for future covalent drug discovery as a means of expanding research in cancer therapy.