MedComm – Oncology最新文献

Treatment with immune checkpoint inhibitors (ICIs) has recently achieved unprecedented clinical benefits, becoming a critical treatment for patients with cancer. However, a set of patients are resistant to immune checkpoint inhibitor therapy, likely due to the limited presence or lack of tumor-infiltrating lymphocytes in their tumors. Increasing data indicate that antiangiogenic therapy substantially reduces cancer-induced immunosuppression and is an effective way to enhance the efficacy of cancer immunotherapies by combination with ICIs. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and programmed cell death-1 (PD-1) blockade dramatically abrogated tumor growth, inhibited microvessel density, and promoted tumor apoptosis, compared to treatment with the single agents. Further investigation using flow cytometry showed that combined therapy significantly increased CD8⁺ T-cell infiltration into tumors and promoted the level of CD8⁺ IFN-γ⁺ T cells. Moreover, combined therapy effectively reduced the frequencies of CD11b⁺ F4/80⁺ tumor-associated macrophages (TAMs) and slightly increased M1/M2 ratio in the tumors. RNA-seq analysis of tumor tissue following combined therapy also demonstrated upregulated expression of genes associated with the antitumor immune response. These data support the rationale for combining antiangiogenic and ICIs for cancer therapy.

Human epidermal growth factor receptor 3 (HER3) is a member of the transmembrane receptor tyrosine kinase family. Upregulation of HER3 pathway has been implicated as a mechanism of resistance in solid tumors, particularly in estrogen receptor positive, HER2 positive breast cancer and epidermal growth factor (EGFR) mutant nonsmall cell lung cancer. Several studies suggest that HER3 overexpression represents a negative prognostic biomarker associated with poor survival. Preclinical and clinical studies of anti-HER3 investigational therapies suggest that expression of the HER3 ligand, neuregulin, may predict response to treatment. Despite its emergence as a key cancer therapeutic target, HER3 cannot be targeted with traditional tyrosine kinase inhibitors therapy due to its weak kinase activity. Monoclonal and bispecific antibodies targeting HER3 have been developed and tested in early phase trials. Objective responses were limited when first-generation HER3-specific monoclonal antibodies were investigated as monotherapies in phase 1 and 2 clinical trials for nonsmall cell lung cancer (NSCLC) and metastatic breast cancer (MBC). MBC and NSCLC HER3 specific antibody-drug conjugates have shown encouraging results in resistance in cancer cells, particularly in those that overexpress HER3. These agents have shown some promise in early phase trials in both NSCLC and MBC setting in heavily pretreated patients with varying degrees of response. It is unclear which subgroup of patients will truly benefit from targeting HER3 as these therapies are under investigation.

Distant metastasis is one of the main reasons for the failure of nasopharyngeal carcinoma (NPC) treatment, and descending type of nasopharyngeal carcinoma (type D NPC) is more prone to distant metastasis. Few people have explored the relationship between the radiomics characteristics of lymph nodes and the distant metastasis of type D NPC. Therefore, we establish a nomogram based on radiomics risk factors to predict distant metastasis in patients with type D NPC. This study retrospectively included 144 type D NPC (T1-2N2-3MO, AJCC 8th). 2600 features were extracted each from CT and MRI examinations conducted before treatment, respectively. Feature selection was performed by least absolute shrinkage and selection operator regression. A binary logistic regression model was used to construct a nomogram, and the C-index and calibration curve were used to evaluate the discrimination and accuracy of the nomogram. Combining CT and MRI radiomics features with a multimodal radiomics model, the average area under curve of the synthetic minority oversampling technique (SMOTE) data set was 0.873 (95% confidence interval [CI]: 0.797–0.949). The C-index in the training and validation sets of the original data set were 0.91 (95% CI: 0.848–0.972) and 0.815 (95% CI: 0.664–0.967); the sensitivity were 0.75 and 0.545, the specificity were 0.932 and 0.903, and the accuracy were 0.882 and 0.81. Therefore, we concluded that the multimodal radiomics model in predicting distant metastasis in descending type of NPC patients was good. The proposed model can provide a reference for precise treatment and prognosis prediction.

Immune checkpoint blockade has dramatically altered the concept of cancer therapeutics over the past few years. Beyond the existing classical pathways, novel immune checkpoints, such as T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) structural domain (TIGIT), have also emerged in recent years and have promising therapeutic potential. Recent researches have provided ample evidence that TIGIT is extensively involved in various cancerous and noncancerous diseases such as chronic inflammation, autoimmune diseases, abnormal pregnancy status, and most recently coronavirus disease 2019. In contrast to the programmed cell death receptor 1 pathway which primarily affects T-cell function, targeting TIGIT pathway regulates multiple types of immunocytes but has fewer immune-related adverse events. Owing to its unique advantages and extensive involvement in diseases, extensive clinical trials blockade TIGIT or combine it with other targets are ongoing, and numerous phase II clinical trials have already seen promising results. In this review, we summarized the existing research on TIGIT in various diseases and discussed the perspective and challenges related to targeting this molecular for therapy, with an attempt to provide directions for subsequent studies.

Recently, a study published in Cell by Venkataramani et al.¹ demonstrated that neuronal (NEU), neural progenitor (NPC)-like, and nonmesenchymal (non-MES)-like glioblastoma cells (GBCs) could drive brain tumor cell invasion. Those astrocyte (AS)-unconnected, invasive GBCs (“unconnected^TUM/AC”) transitioned over time and infiltrated into other regions, largely consisting of tumor cell and AS-connected, stable GBCs (“connected^TUM/AC”). This work elegantly indicated that GBCs are not only connected with each other via gap junctions but are also connected with neurons. In addition, NEU activity drives glioma progression via glutamatergic neuron-to-brain tumor synaptic communication and nonsynaptic paracrine stimulation.^{2, 3} However, how these tumors integrate into complex NEU circuits remains unclear.

Glioblastomas are the most frequently occurring malignant type of primary brain tumor, comprising 12%–15% of all intracranial tumors. However, even with current standard therapies, the majority of patients succumb to the disease within 2 years of diagnosis.⁴ Due to the high heterogeneity and invasion of glioblastoma, gross total resection, radiotherapy, and chemotherapy with DNA-alkylaing agent (temozolomide) are largely ineffective.⁵ Suvà and co-workers⁶ demonstrated that GBCs exist in four cellular states: NPC-like, oligodendrocyte progenitor (OPC)-like, AS-like, and MES-like states. Despite different subtypes, no specific treatment works more effectively. Thus, research into malignant gliomas is complex and challenging.

Increasing evidence has been found to illustrate the functional and synaptic integration of glioma into the brain network, facilitating brain tumor progression. The NEU activities function through gap junctions, neurotransmitters, ion channels, synapses, tumor microtubes (TMs), and NEU molecules to establish communication with glioma. As reported, there have been several recent discoveries that have described how neurons may form synaptic connections with brain tumor cells. Among cell–cell communication, gap junctions consisted of connexin proteins, which form conductive pores in the plasma membranes among adjacent NEU cells, increasing glioma cell invasiveness and migration.^{7, 8} γ-Aminobutyric acid and glutamate are the predominant neurotransmitters that impair glioma cell growth.^{3, 9} We aimed to provide a simplified explanation of crosstalk on neuron-glioma, found by Venkataramani.

To understand the rapid spread of malignant glioma, patient-derived human GBC cells were injected into mice via intracranial stereolocalization and the GBCs were separated into two subtypes: unconnected^TUM/AC GBCs and connected^TUM/AC GBCs. Connected^TUM/AC GBCs were found to be anatomically connected with other

Pancreatic cancer cell-derived homotrimer type 1 collagen plays an important role in the pathogenesis of pancreatic cancer. Homotrimer type 1 collagen produced by pancreatic cancer cells upregulated proliferation-related pathways through the integrin α3β1 axis. Deletion of homotrimer type 1 collagen in genetically engineered mouse models altered the intratumoral microbiome, increased T-cell infiltration, enhanced anti-PD-1 therapy, and ultimately inhibited tumor growth.

It has been clear that mitochondria are not just nucleus-relying entities; instead, they also modulate nuclear events reversely. Long noncoding RNAs (lncRNAs) are classified into nuclear-encoded and mitochondrial-derived lncRNAs (nulncRNAs and mtlncRNAs, respectively). Relative to nulncRNAs, the mtlncRNAs are far from being well characterized. Here we report a mtlncRNA, MDL1, that interacts with both p53 and Tid1 proteins and acts as retrograde signaling. MDL1 can regulate a network of nuclear genes, including p53 targets, and functions in cells in a p53-dependent manner. Mechanistically, MDL1 is necessary for maintenance of the reciprocal interaction between p53 and Tid1, thereby facilitating formation of a ternary MDL1/p53/Tid1 complex that inhibits the nuclear translocation of p53. Since p53 is a canonical transcription factor, the observed inhibition of p53 nuclear translocation would contribute to the MDL1-mediated mitochondrial retrograde regulation on nuclear genes expression. This study advances our understanding of lncRNA biology, and also sheds new light on the role of mtlncRNAs in mitochondrial-nuclear functional network and in diverse biological processes.

Ovarian cancer (OC) is currently one of the most life-threatening types of gynecological malignancy with limited treatment options and poor clinical outcomes. Human caseinolytic protease P (HsClpP) is located in the mitochondria and plays an important role in several tumors. Moreover, HsClpP is overexpressed in OC and several other tumor cells. Thus, HsClpP modulation is regarded as a potential approach for OC treatment. In this study, we identified and validated a novel boron peptide Compound 43-8F as a potent HsClpP inhibitor. Upon 43-8F treatment, mitochondrial damage was observed to be closely correlated with upregulated intracellular reactive oxygen species production, decreasement of membrane potential, and ATP content suppression. Meanwhile, the expression level of SDHB and the ATF4 was increased after 43-8F treatment, suggesting that 43-8F treatment induces mitochondrial respiratory disorders and activates the integrated stress response pathway to inhibit tumor cell growth. Further, 43-8F exhibited a good therapeutic and safety profile in OC xenograft model in nude mice. Together, these results suggest that 43-8F exerts an anti-ovarian cancer effect by inhibiting HsClpP pathway.

Dihydroorotate dehydrogenase (DHODH) is a quite attractive target in cancer therapy. Nevertheless, the antitumor effects of DHODH inhibitors against colorectal cancer (CRC) and the underlying mechanism have seldom been studied. Here, we explored the anti-CRC efficacy of M62, a novel and potent DHODH inhibitor. In the study, M62 significantly inhibited the proliferation of CRC cells and induced S phase arrest. The antiproliferative effects caused by M62 were rescued by uridine supplementation. Mechanistically, messenger RNA sequencing results showed that M62-triggered gene changes related to mitochondrial dysfunction, DNA damage, and DNA damage repair. Further validation showed that M62 treatment induced the generation of reactive oxygen species and decreased ΔΨm and ATP production. Meanwhile, M62 induced the accumulation of γ-H2AX and longer comet tail moment, which were both markers of DNA damage. The downregulated DNA repair proteins and PI3K/ATK pathway were observed after M62 treatment. Furthermore, M62 significantly inhibited CRC xenograft tumor growth without detectable toxicity. Therefore, we conclude that M62 inhibits CRC growth both in vitro and in vivo by causing mitochondrial dysfunction and DNA damage, suggesting that DHODH inhibitors are potential therapeutic strategies for treating CRC.

Immunotherapy, which aims to enhance the functions of the host's immune system to eliminate invading pathogens and mutant cells, has been widely used for cancer treatment. Despite the enormous progress in immunotherapy, the efficiency of immunotherapy is urgent to be improved. The tumor microenvironment is composed of multiple types of infiltrating immune cells and stromal cells (such as endothelial cells, fibroblasts, and tumor cells), extracellular matrix, various cytokines, chemokines, growth factors, and metabolites, all of which play crucial roles in tumor progress, metastasis, relapse and the outcome of immunotherapy. Emerging evidence indicates a better understanding of the characteristics of the tumor microenvironment and its associated factors, which could lead to uncovering novel promising immunotherapy approaches. This review will summarize the current knowledge of heterogeneity and function of the immune cells in the tumor microenvironment, the current progress of immunotherapy focusing on immune checkpoint blockade and chimeric antigen T cell therapy, as well as the challenge and limitations of the current immunotherapy strategy. Overall, we aim to provide the conceptions of tumor immune microenvironment and application of immunotherapy, highlighting the potential strategies to improve tumor immunotherapy.