Search Results (1,087)

Head and neck squamous cell carcinomas (HNSCCs) represent a heterogeneous group of tumors with a complex molecular profile. Despite therapeutic advances, patient prognosis remains poor, emphasizing the need for more effective treatment strategies. Traditional chemotherapy, with cisplatin and 5-fluorouracil (5-FU), remains the gold standard but is limited by toxicity and tumor resistance. Immunotherapy, particularly immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1), has improved overall survival, especially in patients with high PD-L1 expression. In parallel, targeted therapies such as poly (ADP-ribose) polymerase 1 (PARP1) inhibitors—which impair DNA repair and increase replication stress—have shown promising activity in HNSCC. Cyclin-dependent kinase (CDK) inhibitors are also under investigation due to their potential to correct dysregulated cell cycle control, a hallmark of HNSCC. This review aims to summarize current and emerging pharmacotherapies for HNSCC, focusing on chemotherapy, immunotherapy, and PARP and CDK inhibitors. It also discusses the evolving role of targeted therapies in improving clinical outcomes. Future research directions include combination therapies, nanotechnology-based delivery systems to enhance treatment specificity, and the development of diagnostic tools such as PARP1-targeted imaging to better guide personalized treatment approaches. Full article

The ataxia–telangiectasia-mutated (ATM) protein plays a crucial role in the DNA damage response, particularly in the homologous recombination (HR) pathway. This study aimed to assess the impact of deleterious ATM variants on homologous recombination deficiency (HRD) and response to PARP inhibitors (PARPi) in melanoma patients, using a cell line established from melanoma tissue of a patient carrying the c.5979_5983del germline ATM variant. Despite proven loss of heterozygosity, lack of ATM activation, and HRD, our model did not show sensitivity to PARPi. We assessed the potential contribution of the Schlafen family member 11 (SLFN11) helicase, whose expression is inversely correlated with PARPi sensitivity in other cancers, to the observed resistance. The ATM mutant cell line lacked SLFN11 expression and featured hypermethylation-mediated silencing of the SLFN11 promoter. While sensitive to the ATR inhibitor (ATRi), the addition of ATRi to PARPi was unable to overcome the resistance. Our findings suggest that ATM mutational status and HRD alone do not adequately account for variations in sensitivity to PARPi in our model. A comprehensive approach is essential for optimizing the exploitation of DNA repair defects and ultimately improving clinical outcomes for melanoma patients. Full article

Background: The identification of pathogenic variants in the Breast Cancer Genes 1 and 2 (BRCA1/2) is a critical predictive biomarker for poly (ADP-ribose) polymerase inhibitor (PARPi) therapy in epithelial ovarian cancer (EOC). The aim of this study is to define real-world rates and determinants of germline and somatic BRCA1/2 testing and subsequent PARPi utilisation in Australia using a national clinical quality registry. Methods: This multi-centre cohort study analysed data from 1503 women with non-mucinous EOC diagnosed between May 2017 and July 2022, captured by the Australian National Gynae-Oncology Registry (NGOR). We evaluated rates of germline and somatic testing and PARPi use, using multivariate logistic regression to identify associated clinical and demographic factors. Results: Overall germline and somatic testing rates were 68% and 32%, respectively. For the high-grade serous ovarian cancer (HGSOC) cohort, rates were higher, at 78% and 39%, respectively. Germline testing was significantly less likely for women aged >80 years (OR 0.49), those in regional areas (OR 0.61), and those receiving single-modality treatment. Somatic testing uptake increased significantly following public reimbursement for PARPi (p = 0.004). Among eligible women with a newly diagnosed BRCA pathogenic variant and advanced disease (n = 110), 52% commenced first-line maintenance PARPi. Conclusions: This national study offers valuable insights into Australian ovarian cancer care, highlighting opportunities to enhance testing equity for older women (aged >80) and regional patients. Furthermore, it identifies the translation of a positive test into PARPi therapy as a complex area that warrants further collaborative investigation to optimise patient outcomes. Full article

DNA damage repair is a hallmark of any cancer growth, eventually leading to drug resistance and death. The poly ADP-ribose polymerase (PARP) enzyme is vital in repairing damaged DNA in normal and cancer cells with mutated DNA damage response (DDR) genes. Inhibitors of the PARP enzyme aid in chemotherapy, as shown by drug combinations such as Olaparib and Irinotecan in breast cancer treatment. However, the effect of Olaparib in colon cancer has not been studied extensively. Synthetic drugs have a significant limitation in cancer treatment due to drug resistance, leading to colon cancer relapse. Bioavailability of Olaparib and other PARP inhibitors is limited due to their hydrophobicity, which poses a significant challenge. These limitations and challenges can be addressed by encapsulating Olaparib in nanoparticles that could possibly increase the bioavailability of the drug at the site of action. New age nanoparticles, such as hybrid nanoparticles, provide superior quality in terms of design and circulatory time of the drug in the plasma. The side effects of Olaparib as a chemotherapeutic pave the way for exploring phytochemicals that may have similar effects. The combined impact of Olaparib and phytochemicals such as genistein, resveratrol and others in nano-encapsulated form can be explored in the treatment of colon cancer. Full article

BRCA1 and BRCA2 are associated with advanced prostate cancer progression and poor prognosis. Copy number variants (CNVs) of these genes play a crucial role in guiding targeted treatments, particularly for patients receiving PARP inhibitors. However, CNV detection using multiplex ligation-dependent probe amplification (MLPA) is often limited by tumor heterogeneity, leading to ambiguous results. This study therefore aimed to evaluate BRCA1/2 CNVs in advanced prostate cancer patients using droplet digital PCR (ddPCR) and compare the results with MLPA. DNA from 11 advanced prostate cancer tissues was analyzed using both methods, in parallel with four cell lines and seven healthy volunteers. Our findings revealed that ddPCR effectively classified normal CNV groups—including normal control cell lines, healthy volunteers, and samples with normal MLPA final ratios—from deletion groups, which included deletion control cell lines, samples with deletion final ratios from MLPA, and cases with previously ambiguous results. Interestingly, two cases involving BRCA1 and one case involving BRCA2 exhibited ambiguous results using MLPA; however, ddPCR enabled more precise classification by applying the Youden Index from ROC analysis and identifying optimal cutoff values of 1.35 for BRCA1 and 1.55 for BRCA2. These optimal thresholds allowed ddPCR to effectively reclassify the ambiguous MLPA cases into the deletion group. Overall, ddPCR could offer a more sensitive and reliable approach for CNV detection in heterogeneous tissue samples and demonstrates strong potential as a biomarker tool for guiding targeted therapy in advanced prostate cancer patients. However, further validation in larger cohorts is necessary to optimize cutoff precision, confirm diagnostic performance, and evaluate the full clinical utility of ddPCR. Full article

Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk early-stage settings. However, acquired resistance to PARP inhibitors and their limited applicability in non-BRCA TNBCs are now two major growing clinical problems. Activation of the IL-6/STAT3 signaling cascade has been implicated in therapeutic resistance. In this study, we evaluated the combined effects of the PARP inhibitor olaparib and the STAT3 inhibitor LLL12B in human TNBC cell lines with both BRCA mutations and wild-type BRCA status. Our results demonstrate that the PARP inhibitor olaparib can induce increased interleukin-6 (IL-6) in TNBC cells, with ELISA showing a 2- to 39-fold increase across five cell lines. MTT assays revealed that knocking down or inhibiting STAT3, a key downstream effector of the IL-6/GP130 pathway, sensitizes TNBC cells to olaparib. Treatment with either olaparib or LLL12B alone reduced TNBC cell viability, migration, and invasion. Notably, their combined administration produced a markedly enhanced inhibitory effect compared to individual treatments, regardless of BRCA mutation status. These findings highlight the potential of dual PARP and STAT3 inhibition as a novel targeted therapeutic strategy for both BRCA-mutant and BRCA-proficient TNBC. Full article

Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer’s disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS. Full article

Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology—comprising cell-model selection, transcriptomic analysis, and a gentamicin–Texas Red (GTTR) uptake assay—to guide the development of otoprotective strategies. We first utilized two murine auditory cell lines—UB/OC-2 and HEI-OC1. We focused on TMC1 and OCT2 and further explored the underlying mechanisms of ototoxicity. UB/OC-2 exhibited a higher sensitivity to gentamicin, which correlated with elevated OCT2 expression confirmed via RT-PCR and Western blot. Transcriptomic analysis revealed upregulation of PI3K-Akt, calcium, and GPCR-related stress pathways in gentamicin-treated HEI-OC1 cells. Protein-level analysis further confirmed that gentamicin suppressed phosphorylated Akt while upregulating ER stress markers (GRP78, CHOP) and apoptotic proteins (cleaved caspase 3, PARP). Co-treatment with PI3K inhibitors (LY294002, wortmannin) further suppressed Akt phosphorylation, supporting the role of PI3K-Akt signaling in auditory cells. To visualize drug entry, we used GTTR to evaluate its applicability as a fluorescence-based uptake assay in these cell lines, which were previously employed mainly in cochlear explants. Sodium thiosulfate (STS) and N-acetylcysteine (NAC) significantly decreased GTTR uptake, suggesting a protective effect against gentamicin-induced hair cell damage. In conclusion, our findings showed a complex ototoxic cascade involving OCT2- and TMC1-mediated drug uptake, calcium imbalance, ER stress, and disruption of PI3K-Akt survival signaling. We believe that UB/OC-2 cells serve as a practical in vitro model for mechanistic investigations and screening of otoprotective compounds. Additionally, GTTR may be a simple, effective method for evaluating protective interventions in auditory cell lines. Overall, this study provides molecular-level insights into aminoglycoside-induced ototoxicity and introduces a platform for protective strategies. Full article

BGP-15, a poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor exerts cardioprotective effects; however, the underlying mechanisms remain unclear. Therefore, our study aimed to investigate the effects of BGP-15 on the imatinib (Imtb)-induced cardiac inflammation at the biochemical level. Male rats were divided to control, Imtb-treated (60 mg/kg/day for 14 days), and Imtb + BGP-15-treated animals. In this group Imtb was co-administered with BGP-15 at the dose of 10 mg/kg/day. At the end of the experiment, nuclear factor-kappa B/p65 (NF-κB/p65), nuclear transcription factor erythroid-2 related factor (Nrf2), heme oxygenase-1 (HO-1), high mobility group box 1 (HMGB1), and myeloperoxidase (MPO) were measured by Western blot. Chemokine and interleukins (ILs) were determined by Legendplex. Additionally, cardiac specific changes were visualized by immunohistochemistry. We demonstrated that Imtb increased NF-κB/p65, IL-6, IL-1β, IL-18, MCP-1, HMGB1, as well as the expression and activity of MPO. Conversely, the expressions of antioxidant Nrf2 and HO-1 were decreased. Administration of BGP-15 effectively mitigated these inflammatory alterations by significantly reducing pro-inflammatory cytokines and MPO activity, while simultaneously restoring and enhancing the levels of Nrf2 and HO-1, thereby promoting antioxidant defenses. The immunohistochemical staining further supported these biochemical changes. Our study provides new and comprehensive biochemical insight for managing Imtb-induced inflammatory responses via BGP-15-induced PARP1 inhibition. Full article

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

Current guidelines recommend either radical prostatectomy (RP) or radiation with androgen deprivation therapy (ADT) for unfavorable intermediate- or high-risk prostate cancer. There has been emerging interest in the potential benefits of neoadjuvant ADT prior to RP for this population. Past trials indicate neoadjuvant ADT may be associated with reduced surgical complexity, pathologic downstaging, decreased positive margins, and decreased rates of nodal positivity, although they have not shown benefits for cancer progression and survival. Accordingly, neoadjuvant ADT is currently not recommended for surgical patients. Conversely, ADT is a mainstay of treatment in metastatic disease, and interest remains in expanding its use towards patients with clinically localized disease. There are several ongoing trials of second-generation androgen blockers such as enzalutamide, darolutamide, radiopharmaceuticals, and poly (ADP-ribose) polymerase (PARP) inhibitors to explore long-term cancer-specific survival benefits with neoadjuvant use. In this narrative review, we provide a comprehensive overview of the recent literature and ongoing efforts to incorporate neoadjuvant therapy for clinically localized prostate cancer patients who are at high-risk of recurrence after prostatectomy. Full article

Background: Administration of PARP inhibitors against breast and ovarian cancers with BRCA1 and BRCA2 mutations has shown clinical benefits in patients. However, these agents are also toxic and have a narrow therapeutic index. Objectives: In this work, we aimed to identify membrane proteins that are specifically upregulated in these cancers. Methods: We interrogated public datasets to analyze genes upregulated or downregulated when these mutations were present, compared with wild-type cancers. Surface protein expression and functional annotation analyses were also performed. Results: In breast cancer, we identified 11 upregulated and 44 downregulated transcripts in BRCA1-mut, while 10 upregulated and 57 downregulated transcripts were identified in BRCA2-mut cancers. In ovarian cancer, 79 transcripts were upregulated and 123 were downregulated in BRCA1-mut cancers, while five were upregulated and seven were downregulated in BRCA2-mut tumors. Regarding the biological function related to these genes, in BRCA1-mutated ovarian cancers, the main functions of upregulated genes included MHC assembly or regulation of the interferon gamma pathway; in BRCA2-mut ovarian cancers, regulation of phosphorylation and signaling; in BRCA1-mut breast cancers, cell damage repair and angiogenesis; and finally, in BRCA2-mut breast cancers, cytokine production and T-cell migration. Genes expressed in the surface membrane or extracellular matrix and related to patient outcomes included B3GNT7 and CTSV in BRCA2-mut breast cancers, exhibiting detrimental prognoses. CD6, CXCL9, and CXCL13 were associated with favorable outcomes in BRCA1-mutant ovarian cancers. The last three genes were also correlated with the infiltration of effector T cells and dendritic cells in ovarian tumors. Conclusions: In summary, we identified deregulated candidate genes that could be used as therapeutic targets. Full article

Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In this study, we assessed the antiproliferative effects of clinically approved JAK2 inhibitors in TNBC cell lines (MDA-MB-231 and HS578T) using the MTT assay. Among the four JAK2 inhibitors evaluated (fedratinib, cerdulatinib, peficitinib, and filgotinib), fedratinib significantly inhibited the proliferation of TNBC cells with IC₅₀ values below 2 μM. Fedratinib also demonstrated superior efficacy in inhibiting long-term colony formation compared to other JAK2 inhibitors. Western blot analyses showed that fedratinib uniquely inhibits the phosphoinositide 3-kinase (PI3K)/AKT pathway and moderately affects the MAP kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, in addition to targeting JAK2/STAT3 signaling. Moreover, fedratinib distinctly decreased MYC and cyclin D1 protein levels while inducing poly (ADP-ribose) polymerase (PARP) cleavage and apoptotic cell death more effectively than other JAK2 inhibitors. We next investigated the effects of simultaneously inhibiting JAK2/STAT3 together with the MEK/ERK or PI3K/AKT pathways, as well as the impact of triple pathway inhibition. Notably, combining ceduratinib with either cobimetinib (MEK inhibitor) and ipatasertib (AKT inhibitor) or trametinib (MEK inhibitor) and alpelisib (PI3K inhibitor) mimicked the effects of fedratinib on the cell proliferation, MYC and cyclin D1 suppression, and pro-apoptotic protein induction. These finding suggest that JAK2 inhibition enhances the anticancer effects of concurrent MEK/ERK and PI3K/AKT pathway inhibition, while JAK2 inhibition alone shows minimal efficacy in TNBC cells. Full article

Poly(ADP-ribose) polymerases (PARP) are a family of enzymes that were proven to play an essential role in the initiation and activation of DNA repair processes in the case of DNA single-strand breaks. The inhibition of PARP enzymes might be a promising option for the treatment of several challenging types of cancers, including triple-negative breast cancer (TNBC) and non-small cell lung carcinoma (NSCLC). This study utilizes several techniques to screen the compound collection of the Leibniz Institute of Plant Biochemistry (IPB) to identify novel hPARP-1 inhibitors. First, an in silico pharmacophore-based docking study was conducted to virtually screen compounds with potential inhibitory effects. To evaluate these compounds in vitro, a cell-free enzyme assay was developed, optimized, and employed to identify hPARP-1 inhibitors, resulting in the discovery of two novel scaffolds represented by compounds 54 and 57, with the latter being the most active one from the compound library. Furthermore, fluorescence microscopy and synergism assays were performed to investigate the cellular and nuclear pathways of hPARP-1 inhibitor 57 and its potential synergistic effect with the DNA-damaging agent temozolomide. The findings suggest that the compound requires further lead optimization to enhance its ability to target the nuclear PARP enzyme effectively. Nonetheless, this new scaffold demonstrated a five-fold higher PARP inhibitory activity at the enzyme level compared to the core structure of olaparib (OLP), phthalazin-1(2H)-one. Full article

Ovarian cancer is the most lethal gynecologic malignancy, which causes 313,959 new cases and 207,252 deaths worldwide annually. The lack of specific symptoms, together with no effective screening tools, results in 75% of patients receiving their diagnosis at an advanced stage. The combination of cytoreductive surgery with platinum-based chemotherapy plays a pivotal role in the treatment of advanced epithelial ovarian cancer, but patients still experience poor long-term survival because of frequent relapses and chemotherapy resistance. The treatment landscape has evolved because bevacizumab and Poly-ADP Ribose Polymerase inhibitors now serve as frontline and maintenance therapies for homologous recombination-deficient tumors. Treatment decisions for recurrent disease depend on platinum sensitivity assessment, which determines the appropriate therapeutic approach, while targeted agents deliver significant benefits to specific patient groups. The development of antibody-drug conjugates such as mirvetuximab soravtansine and immunotherapy, including checkpoint inhibitors and cancer vaccines, demonstrates promising investigative potential. The precision of therapy improves through the use of emerging biomarkers and molecular profiling techniques. The future management of this disease may change because of innovative approaches that include adoptive cell therapy, cytokine therapy, and oncolytic viruses. The progress made in ovarian cancer treatment still faces challenges when it comes to drug resistance, survival improvement, and life quality preservation. The development of translational research alongside clinical trials remains essential to bridge treatment gaps while creating personalized therapies based on molecular and clinical tumor characteristics. Full article