Traditional therapeutic approaches such as chemotherapy and radiation therapy have burdened cancer patients with onerous physical and psychological challenges. Encouragingly, the landscape of tumor treatment has undergone a comprehensive and remarkable transformation. Emerging as fervently pursued modalities are small molecule targeted agents, antibody-drug conjugates (ADCs), cell-based therapies, and gene therapy. These cutting-edge treatment modalities not only afford personalized and precise tumor targeting, but also provide patients with enhanced therapeutic comfort and the potential to impede disease progression. Nonetheless, it is acknowledged that these therapeutic strategies still harbour untapped potential for further advancement. Gaining a comprehensive understanding of the merits and limitations of these treatment modalities holds the promise of offering novel perspectives for clinical practice and foundational research endeavours. In this review, we discussed the different treatment modalities, including small molecule targeted drugs, peptide drugs, antibody drugs, cell therapy, and gene therapy. It will provide a detailed explanation of each method, addressing their status of development, clinical challenges, and potential solutions. The aim is to assist clinicians and researchers in gaining a deeper understanding of these diverse treatment options, enabling them to carry out effective treatment and advance their research more efficiently. 

Exploring treatment options in cancer: Tumor treatment strategies

Innate immunity is the first response to protect against pathogens and cellular insults. Pattern recognition receptors sense pathogen- and damage-associated molecular patterns and induce an innate immune response characterized by inflammation and programmed cell death (PCD). In-depth characterization of innate immune PCD pathways has highlighted significant cross-talk. Recent advances led to the identification of a unique inflammatory PCD modality called PANoptosis, which is regulated by multifaceted PANoptosome complexes that are assembled by integrating components from other PCD pathways. The totality of biological effects observed in PANoptosis cannot be accounted for by any other PCD pathway alone. In this review, we briefly describe mechanisms of innate immune cell death, including molecular mechanisms of PANoptosis activation and regulation. We also highlight the PANoptosomes identified to date and provide an overview of the implications of PANoptosis in disease and therapeutic targeting. Improved understanding of innate immune-mediated cell death, PANoptosis, is critical to inform the next generation of treatment strategies.

PANoptosis: A Unique Innate Immune Inflammatory Cell Death Modality

Prostate cancer is the second most common malignancy in men and androgen deprivation therapy is the first-line therapy. However, most cases will eventually develop castration-resistant prostate cancer after androgen deprivation therapy treatment. Enzalutamide is a second-generation androgen receptor antagonist approved by the Food and Drug Administration to treat patients with castration-resistant prostate cancer. Unfortunately, patients receiving enzalutamide treatment will ultimately develop resistance via various complicated mechanisms. This review examines the emerging information on these resistance mechanisms, including androgen receptor-related signalling pathways, glucocorticoid receptor-related pathways and metabolic effects. Notably, lineage plasticity and phenotype switching, gene polymorphisms and the relationship between microRNAs and drug resistance are addressed. Furthermore, potential therapeutic strategies for enzalutamide-resistant castration-resistant prostate cancer treatment are suggested, which can help discover more effective and specific regimens to overcome enzalutamide resistance.

Mechanisms of enzalutamide resistance in castration-resistant prostate cancer and therapeutic strategies to overcome it.

PANoptosis is a new cell death proposed by Malireddi et al in 2019, which is characterized by pyroptosis, apoptosis and necroptosis, but cannot be explained by any of them alone. The interaction between pyroptosis, apoptosis and necroptosis is involved in PANoptosis. In this review, from the perspective of PANoptosis, we focus on the relationship between pyroptosis, apoptosis and necroptosis, the key molecules in the process of PANoptosis and the formation of PANoptosome, as well as the role of PANoptosis in diseases. We aim to understand the mechanism of PANoptosis and provide a basis for targeted intervention of PANoptosis-related molecules to treat human diseases. 

PANoptosis: A Cell Death Characterized by Pyroptosis, Apoptosis, and Necroptosis

Abstract Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population ( N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P &lt; 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 . 

First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial.

Abstract Prostate cancer harboring BRCA1/2 mutations are often exceptionally sensitive to PARP inhibitors. However, genomic alterations in other DNA damage response genes have not been consistently predictive of clinical response to PARP inhibition. Here, we perform genome-wide CRISPR-Cas9 knockout screens in BRCA1/2-proficient prostate cancer cells and identify previously unknown genes whose loss has a profound impact on PARP inhibitor response. Specifically, MMS22L deletion, frequently observed (up to 14%) in prostate cancer, renders cells hypersensitive to PARP inhibitors by disrupting RAD51 loading required for homologous recombination repair, although this response is TP53 -dependent. Unexpectedly, loss of CHEK2 confers resistance rather than sensitivity to PARP inhibition through increased expression of BRCA2, a target of CHEK2-TP53-E2F7-mediated transcriptional repression. Combined PARP and ATR inhibition overcomes PARP inhibitor resistance caused by CHEK2 loss. Our findings may inform the use of PARP inhibitors beyond BRCA1/2-deficient tumors and support reevaluation of current biomarkers for PARP inhibition in prostate cancer. 

/pdf/crispr-screens-reveal-genetic-determinants-of-parp-inhibitor-1qc7ra8r.pdf

CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer

Dickkopf-1 exerts protective effects by inhibiting PANoptosis and retinal neovascularization in diabetic retinopathy.

ABSTRACT Drug resistance is a significant challenge in the present treatment regimens of renal cell carcinoma (RCC). Our previous study confirmed that nc886 functions as an oncogene in RCC. Nevertheless, the role and underlying mechanism of nc886 in RCC drug resistance are unclear. In the present study, Sunitinib and Everolimus treatment, respectively, downregulated nc886 expression in a dose-dependent manner in all four renal cancer cell lines. Nc886 overexpression in 786-O cells and ACHN cells significantly reduced the sensitivity of cancer cells to both Sunitinib and Everolimus treatment, respectively, by promoting cell viability and inhibiting cell apoptosis, whereas nc886 silencing increased cancer cell sensitivity. In renal cancer cell line with the highest drug-resistance, 786-O cells, Sunitinib, or Everolimus treatment enhanced the cellular EMT and was further enhanced by nc886 overexpression while attenuated by nc886 silencing. In 786-O cells, nc886 overexpression significantly promoted EMT, ROCK2 phosphorylation, and β-catenin nucleus translocation under Sunitinib or Everolimus treatment. Moreover, ROCK2 silencing significantly reversed the effects of nc886 overexpression on EMT, ROCK2 phosphorylation, and β-catenin nucleus translocation, as well as drug-resistant renal cancer cell viability and apoptosis. In conclusion, it was demonstrated that nc886 promotes renal cancer cell proliferation, migration, and invasion, as demonstrated previously. nc886 also promotes renal cancer cell drug-resistance to Sunitinib or Everolimus by promoting EMT through Rock2 phosphorylation-mediated nuclear translocation of β-catenin.

Nc886 promotes renal cancer cell drug-resistance by enhancing EMT through Rock2 phosphorylation-mediated β-catenin nuclear translocation

The present study aimed to clarify the role of microRNA (miR)-5590-3p in the progression of renal cell carcinoma (RCC) and investigate the underlying mechanisms. The expression levels of miR-5590-3p, Rho-associated protein kinase (ROCK)2 and β-catenin in RCC cells were measured by reverse transcription-quantitative PCR and western blot analysis. Following overexpression of miR-5590-3p and ROCK2 by transfection of miR-5590-3p mimics and GV367-ROCK2, respectively, changes in the proliferation, migration and invasion of RCC cells were determined through colony-formation, wound-healing and Transwell assays, respectively. The direct binding interaction between miR-5590-3p and ROCK2, initially predicted using Targetscan, was validated by a dual-luciferase reporter assay. The results indicated that miR-5590-3p was downregulated in RCC. Overexpression of miR-5590-3p led to downregulation of ROCK2 and β-catenin and inhibited the proliferation, migration and invasion of RCC cells. The dual-luciferase reporter assay confirmed the binding relationship between miR-5590-3p and ROCK2. Of note, overexpression of ROCK2 effectively reversed the regulatory effects of miR-5590-3p on RCC cells. In conclusion, miR-5590-3p inhibits the proliferation, migration and invasion of RCC cells by targeting ROCK2, which is a potential molecular biomarker and therapeutic target for RCC.

miR-5590-3p inhibits the proliferation and metastasis of renal cancer cells by targeting ROCK2 to inhibit proliferation, migration and invasion

Objective To explore the role of LncHOTAIR in apoptosis and autophagy in lymphoma. Methods The interaction between LncHOTAIR and miR-6511b-5p, as well as between miR-6511b-5p and ATG7, was verified by a dual luciferase assay. LncHOTAIR overexpression lentivirus was transducted and siATG7s were transfected into Raji and BJAB lymphoma cells, and the efficiency was verified by qPCR. Lymphocyte proliferation was detected by the cell counting kit-8 (CCK8) test, and autophagy was detected by transmission electron microscopy. The protein expressions of ULK1, Beclin1, ATG7, LC3, Bax, cleaved-caspase 3, and Bcl-2 were detected using Western blots. Results There was a targeting relationship between LncHOTAIR and miR-6511b-5p and between miR-6511b-5p and ATG7. LncHOTAIR overexpression promoted the proliferation and autophagy of Raji and BJAB cells, significantly upregulated ATG7, Beclin1, ULK1, Bcl-2, and LC3-II/LC3-I levels, and downregulated Bax and cleaved-caspase3 levels. siATG7 significantly inhibited the proliferation and autophagy of Raji and BJAB cells and promoted their apoptosis. Conclusion LncHOTAIR/hsa-miR-6511b-5p/ATG7 could regulate the proliferation, apoptosis, and autophagy of Raji and BJAB lymphoma cells.

https://downloads.hindawi.com/journals/ecam/2022/2166605.pdf

Mechanism of LncHOTAIR Regulating Proliferation, Apoptosis, and Autophagy of Lymphoma Cells through hsa-miR-6511b-5p/ATG7 Axis

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