Search Results (1,046)

Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated remarkable efficacy in tumors carrying BRCA1/2 pathogenic variants (PVs) through the mechanism of synthetic lethality. PVs in other homologous recombination (HR) genes may also impair homologous recombination repair and confer sensitivity to PARPis; however, their predictive value remains uncertain and appears to vary according to the affected gene and tumor type. We review and critically discuss the current evidence regarding the predictive value of non-BRCA HR gene pathogenic variants as biomarkers of PARPi sensitivity across ovarian, breast, prostate, and pancreatic cancers. A narrative review was conducted between October 2023 and December 2025, first identifying pivotal clinical trials of PARP inhibitors across ovarian, breast, prostate, and pancreatic cancers, followed by a targeted search of PubMed, Embase, Web of Science, and Google Scholar for relevant preclinical and clinical studies. Seventeen clinical studies and multiple preclinical reports were analyzed regarding genomic frequency, HRD association, and treatment response. Preclinical studies consistently demonstrated increased PARPi sensitivity in models with alterations in several non-BRCA HR genes. Clinical evidence, however, was heterogeneous. PALB2 demonstrated the strongest and most consistent association with PARPi benefit across tumor types, while RAD51C and RAD51D also showed clinically meaningful activity, particularly in ovarian cancer. In contrast, evidence supporting PARPi sensitivity in tumors harboring ATM, CHEK2, CDK12, and several other HR gene alterations remained limited or inconsistent. Differences in gene function, biallelic inactivation, variant type, and current limitations of HRD companion diagnostic assays likely contribute to the observed variability in clinical response. Non-BRCA HR gene alterations represent promising predictive biomarkers for PARPi therapy but should not be considered a homogeneous group. Future biomarker-driven studies integrating comprehensive genomic profiling and functional assessment of homologous recombination deficiency are needed to refine patient selection and optimize the clinical application of PARPis beyond BRCA1/2-associated cancers. Full article

BRCA1/2 alterations have emerged as clinically relevant biomarkers in prostate cancer because of their prognostic significance and predictive value for response to poly(ADP-ribose) polymerase inhibitors. As indications for molecular testing expand, histopathologists play a pivotal role in ensuring the quality and reliability of somatic BRCA testing. This narrative review provides a histopathologist-oriented overview of the principal pre-analytical, technical, and morphological issues influencing BRCA testing in PC, with emphasis on tissue selection, specimen processing, nucleic acid preservation, and genotype–phenotype correlations. The success of somatic BRCA testing depends on several pre-analytical variables, including fixation, storage time, tumor cellularity (generally ≥10–20% neoplastic cells for reliable NGS analysis), specimen type, and DNA quality. Bone metastasis specimens require special attention because decalcification procedures may compromise nucleic acid integrity and molecular testing performance. From a morphological perspective, BRCA-associated PCs, especially those harboring BRCA2 alterations, are characterized by adverse clinicopathological features, including a higher grade and stage at diagnosis. Although intraductal carcinoma of the prostate and cribriform architecture are associated with genomic instability and poor prognosis, their value as surrogate markers of BRCA1/2 alterations remains uncertain. Histopathologists play a central role in optimizing BRCA testing through appropriate specimen selection, tissue handling, and multidisciplinary collaboration, thereby supporting precision medicine in prostate cancer. Full article

Being the basic building blocks of chromatin, nucleosomes and their stability determine the genome accessibility for different DNA-dependent proteins. This characteristic is labile under cell-life processes. One of the abundant DNA-binding proteins, which is important for genome compaction, is poly(ADP-ribose) polymerase1 (PARP1). Despite the extensive experimental data on the chromatin compaction regulation under ADP-ribosylation, the details of the interplay of nucleosome with PARP1 in the absence of protein activation remain unclear. In this study, we discovered unusual changes of the nucleosome wrapping strength upon PARP1 interaction using a single-molecule approach—optical tweezers. We demonstrated that PARP1 binding leads to weakening of the contacts of inner DNA turn in nucleosome. Full article

Background/Objectives: Though PARP inhibition has improved the management of advanced prostate cancer, patient outcomes may be modest and disease progression on treatment is common. We sought to improve understanding of tumor cell response to PARP inhibition to support development of novel strategies to enhance and/or prolong PARP inhibitor (PARPi) efficacy. Methods: Cell viability assays and microscopy were used for initial characterization of PARPi response in models of advanced prostate cancer. RNA sequencing was performed to investigate time-dependent transcriptomic changes induced by PARP inhibition. Western blots, flow cytometry, and both additional viability assays and microscopy were used to validate RNA sequencing results and test potential therapeutic strategies. Results: Characterization of responses to PARP inhibition reveals time-dependent changes which may be targeted to improve treatment efficacy. In line with the expected PARPi mechanism of action, short-term treatment is largely associated with activation of ATM and the DNA damage response and cell cycle checkpoint signaling. Targeting ATM with clinical stage inhibitors significantly enhances reduction of tumor cell viability by PARP inhibition. Tumor cells exposed to longer-term treatment exhibit SLUG-dependent epithelial–mesenchymal transition (EMT) and evidence for altered fatty acid metabolism, both of which may be targeted to enhance PARPi anti-tumor cell effects. Conclusions: This study provides insight into both short and longer-term cellular response to PARPi treatment and provides a foundation for additional efforts to explore effective strategies to maximize the utility of PARP inhibition for managing prostate cancer. Full article

Breast cancer remains one of the most prevalent malignancies affecting women worldwide and continues to be a leading cause of cancer-related morbidity and mortality. Patients may present with either localized or advanced disease, with clinical outcomes increasingly influenced by molecular subtype and genetic profile. This review highlights the key genetic factors involved in breast cancer, current diagnostic and therapeutic strategies, and promising emerging approaches that may shape future clinical management. Breast cancer diagnosis typically involves clinical breast examination, imaging techniques such as mammography and ultrasound, and confirmatory biopsies. Genetic mutations in specific genes are strongly linked to the development, progression, and metastasis of the disease. Treatment options for localized breast cancer continue to include surgery (lumpectomy or mastectomy) and radiotherapy, combined with systemic therapies tailored to tumor biology, such as endocrine therapy, human epidermal growth factor receptor 2 (HER2)-targeted therapy, and cyclin-dependent kinase (CDK)4/6 inhibitors. For advanced or metastatic breast cancer, recent therapeutic advances include the use of immunotherapy (e.g., immune checkpoint inhibitors), Poly (ADP-ribose) polymerase (PARP) inhibitors for Breast Cancer gene (BRCA)-mutated cancers, antibody–drug conjugates, and novel targeted agents, which have significantly improved patient outcomes in selected populations. Recent findings in breast cancer genetics have highlighted the critical role of germline and somatic mutations, particularly in genes such as BRCA1, BRCA2, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and TP53, in driving tumor initiation, progression, and therapeutic response. Molecular profiling and next-generation sequencing technologies have enabled more precise tumor classification and facilitated the development of personalized treatment strategies. Despite these advances, treatment resistance and disease recurrence remain major challenges, particularly in aggressive subtypes such as triple-negative breast cancer. Consequently, ongoing research is exploring alternative and complementary approaches, including nanotechnology-based drug delivery systems, gene editing techniques such as clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9) (CRISPR-Cas9), cancer vaccines, and the integration of traditional and plant-derived compounds. These strategies aim to enhance therapeutic efficacy, reduce systemic toxicity, and overcome resistance mechanisms. Full article

Natural products represent a valuable source of anticancer agents, although their mechanisms of action are often incompletely understood. In this study, we evaluated the cytotoxic effects of the ethyl acetate (EA) fraction derived from Schima superba bark. The EA fraction exhibited selective cytotoxicity against HepG2 and MCF-7 cancer cells, with minimal effects on normal HEK293 cells, and induced apoptosis as evidenced by time- and dose-dependent activation of caspase-3. Phytochemical profiling by UPLC-QTOF-MS/MS identified 18 major constituents, predominantly phenylethanoid glycosides and triterpenoids. To gain insight into the underlying mechanism, molecular docking, 200 ns molecular dynamics simulations, and MM-PBSA analyses were performed targeting poly (ADP-ribose) polymerase 1 (PARP1) and caspase-3. Among the identified compounds, cistanoside D displayed favorable binding affinity toward both targets, but formed a more stable and energetically favorable complex with PARP1 during molecular dynamics simulations, whereas its interaction with caspase-3 was comparatively weak. These findings suggest that cistanoside D may preferentially interact with PARP1, while the observed activation of caspase-3 is likely associated with downstream apoptotic processes rather than direct enzymatic modulation. This study provides an integrated evaluation of the phytochemical composition and anticancer potential of Schima superba bark extract, and identifies cistanoside D as a promising candidate for further investigation. These results contribute to a better understanding of the molecular basis underlying the bioactivity of this medicinal plant and support its potential as a source of anticancer agents. Full article

Inflammatory bowel disease (IBD) is characterized by chronic intestinal inflammation in which excessive cell death and the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) amplify mucosal injury. Although necrosis—particularly regulated forms including necroptosis and ferroptosis—has emerged as a contributor to IBD pathogenesis, the therapeutic potential of targeting necrotic cell death remains incompletely explored. We investigated whether MIT-001 (previously known as NecroX-7), a mitochondria-targeted reactive oxygen species (ROS) scavenger with anti-necrotic activity, ameliorates intestinal inflammation in an acute dextran sulfate sodium (DSS)-induced colitis model. In vitro, MIT-001 reduced hydrogen peroxide-induced necrotic cell death in IEC-18 intestinal epithelial cells and was associated with a qualitative reduction in the 55-kDa cleaved poly(ADP-ribose) polymerase-1 (PARP-1) fragment (a marker of necrosis), with no apparent change in the apoptosis-related 89-kDa fragment. In vivo, oral administration of MIT-001 to C57BL/6 mice with DSS-induced colitis was associated with preservation of colon length, reduced histological injury, and a marked decrease in HMGB1-positive cells in colonic tissue. Among pro-inflammatory cytokines, IL-1β expression was significantly reduced, while IL-12, monocyte chemoattractant protein-1 (MCP-1), and TNF-α showed non-significant downward trends. These findings indicate that MIT-001 ameliorates DSS-induced colitis in association with reduced HMGB1 and IL-1β expression, supporting further investigation of mitochondria-targeted anti-necrotic strategies as a potential adjunctive approach in IBD. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) remains a highly aggressive malignancy with poor clinical outcomes. Although poly(ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in tumors with homologous recombination deficiency, their efficacy in BRCA wild-type HNSCC remains limited. Reactive oxygen species (ROS)-induced DNA damage may increase cellular dependence on DNA repair pathways and thereby enhance sensitivity to PARP inhibition. This study investigated whether ROS-mediated DNA damage could sensitize BRCA wild-type HNSCC cells to the PARP inhibitor olaparib. Methods: BRCA wild-type HSC-3 and SCC-25 HNSCC cell lines were exposed to H₂O₂ to induce oxidative stress. Intracellular ROS levels were quantified using DCFDA assays, DNA double-strand breaks were evaluated by γ-H2AX ELISA, PARP activity was assessed by ELISA, and cell viability was determined using MTT assays. Expression levels of DNA repair genes (PARP1, PARP2, BRCA1, BRCA2, RAD51, and MLH1), checkpoint kinases (ATM, ATR, and CHK1), the homologous recombination regulator FANCD2, and redox defense genes (NQO1, GPX4, and SLC7A11) were analyzed by qRT-PCR. Therapeutic selectivity was assessed using HGF-1 normal human gingival fibroblasts as a normal cell control. Apoptosis was measured through caspase-3/7 activity assays, and drug interactions were evaluated using the Chou–Talalay method. Results: H₂O₂ treatment increased intracellular ROS levels in both cell lines, accompanied by significant induction of DNA damage as demonstrated by elevated γ-H2AX levels. ROS induction markedly enhanced olaparib sensitivity, significantly reducing IC₅₀ values in both HSC-3 and SCC-25 cells. Combined H₂O₂ and olaparib treatment produced strong synergistic cytotoxicity, suppressed DNA repair, checkpoint kinase, and redox defense gene expression, and increased caspase-3/7 activity compared with control cells. Importantly, the combination demonstrated selective cytotoxicity toward cancer cells, with normal HGF-1 cells retaining significantly higher viability. Conclusions: ROS-induced DNA damage significantly enhances the anti-tumor activity of olaparib in BRCA wild-type HNSCC cells through a functional synthetic lethal-like interaction involving the simultaneous collapse of DNA repair capacity, checkpoint activation, and oxidative stress buffering, culminating in apoptosis induction. These findings support the rationale for combining ROS-generating therapies with PARP inhibitors in HNSCC treatment. Full article

Triple-negative breast cancer (TNBC), particularly when associated with breast cancer susceptibility gene 1/2 (BRCA1/2) alterations or homologous recombination deficiency (HRD), remains therapeutically challenging because DNA repair vulnerabilities coexist with molecular heterogeneity, resistance, and toxicity constraints. This narrative review synthesizes mechanistic, preclinical, clinical, and translational evidence on DNA damage response (DDR)-targeted and synthetic lethality-based strategies in TNBC. We summarize TNBC biological heterogeneity, current biomarker-guided treatment options, mechanisms of poly(ADP-ribose) polymerase (PARP) inhibition and resistance, and emerging DDR targets, including ataxia telangiectasia and Rad3-related/checkpoint kinase 1 (ATR/CHK1), WEE1, DNA-dependent protein kinase (DNA-PK), RAD51, DNA polymerase theta (POLQ), neddylation-related pathways, and targeted protein degradation. The review highlights that PARP inhibitors and platinum agents provide clinically validated examples of exploiting HRD in selected populations, whereas most next-generation DDR inhibitors remain preclinical, investigational, or in early clinical trials. Resistance mechanisms, including BRCA reversion, homologous recombination restoration, replication fork stabilization, and checkpoint adaptation, limit durable benefit. Safety, target selectivity, overlapping toxicities, and the lack of standardized functional biomarkers further constrain translation. Future progress will require prospective biomarker validation, dynamic HRD assessment, rational scheduling of combinations, and medicinal chemistry approaches that improve therapeutic index rather than a broad application of DDR inhibition across all TNBC. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP), particularly PARP-1, is overexpressed in prostate cancer and linked to poor prognosis. PARP inhibitors show efficacy in homologous recombination deficiency (HRD)-positive tumors, but 30–70% of patients develop resistance, often due to low PARP expression. Tissue biopsies have limitations in assessing PARP levels, highlighting the need for noninvasive imaging tools. This study aimed to develop a novel [⁶⁸Ga]Ga-PARP-targeted radiotracer for prostate cancer visualization and therapy monitoring, with potential implications for targeted radionuclide therapy. Methods: PET/CT imaging was conducted in 22RV1 prostate cancer xenograft-bearing mice using the [⁶⁸Ga]Ga-FL9-7 probe. Imaging was performed at 1, 2, and 3 h post-injection. Standardized uptake values (SUV) were quantified to evaluate tumor and organ uptake, and tumor-to-normal tissue (T/NT) contrast ratios were calculated. Results: [⁶⁸Ga]Ga-FL9-7 rapidly accumulated in tumors, with optimal imaging contrast achieved at 3 h post-injection. Normal organ uptake (e.g., kidneys) peaked at 1 h and subsequently declined, while tumor uptake increased over time. This differential clearance and retention resulted in the highest T/NT ratio at the 3 h time point. Conclusions: The [⁶⁸Ga]Ga-FL9-7 probe enables effective noninvasive visualization of PARP-1 expression in prostate cancer, demonstrating clinical potential for tumor localization and monitoring of PARP-targeted therapies. This work also lays the groundwork for further development of PARP-targeted radionuclide therapy strategies. Full article

Cisplatin (cis-diamminedichloroplatinum(II) [DDP]) is a key chemotherapeutic agent for advanced endometrial cancer; however, chemoresistance substantially limits its clinical benefit. Extracellular vesicles (EVs) mediate intercellular communication and influence tumour cell behaviour and therapeutic response. We investigated whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) and natural killer cell-derived extracellular vesicles (NK-EVs) modulate cisplatin responsiveness in endometrial cancer cells (RL95-2 and HEC-1A). MSC-EVs and NK-EVs were isolated and characterised using nanoparticle tracking analysis, scanning electron microscopy, and EV marker profiling. MSC-EVs and NK-EVs reduced RL95-2 and HEC-1A cell viability in a dose-dependent manner, with MSC-EVs exhibiting substantial effects at lower particle concentrations. In a cisplatin-resistant HEC-1A (HEC-1A DDP-R) model, MSC-EVs were associated with greater reductions in cell viability under cisplatin treatment conditions, whereas NK-EVs showed comparatively modest effects. Mechanistic analyses demonstrated altered expression of apoptosis- and cell cycle–related proteins, including increased cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 levels and reduced cyclin A and cyclin D1 expression following MSC-EV treatment. Annexin V-fluorescein isothiocyanate/propidium iodide flow cytometry demonstrated increased apoptotic cell populations after MSC-EV treatment, with MSC-EV + DDP co-treatment resulting in the highest apoptotic fraction in chemoresistant HEC-1A cells. Collectively, these findings indicate that MSC-EVs are associated with altered cellular responses to cisplatin in chemoresistant endometrial cancer cells, accompanied by changes in apoptosis-related protein expression, apoptotic cell populations, and cell-cycle regulators. Further investigation is required to determine their mechanistic role and therapeutic potential in overcoming chemoresistance. Full article

Ischemic stroke triggers a severe redox disequilibrium that critically shapes cell survival within the penumbra. Although oxidative DNA damage arises from excessive ROS production, the capacity to repair such lesions is tightly constrained by cellular metabolic status. Growing evidence indicates that astrocytes, key metabolic regulators of the neurovascular unit, modulate neuronal susceptibility to genomic injury through redox buffering, NAD⁺ maintenance, and metabolic support. In the metabolically impaired yet structurally preserved penumbra, astrocytic control of glutathione turnover, mitochondrial function, and lactate shuttling may determine whether oxidative DNA lesions are efficiently repaired or progress toward energetic collapse. Poly(ADP-ribose) polymerase 1 activation following DNA strand breaks couples genomic stress to NAD⁺ depletion and bioenergetic failure, forming a critical interface between redox biology and metabolism. This framework posits that astrocytes preserve genomic integrity not by directly altering DNA repair pathways but by sustaining the energetic capacity required for an effective DNA damage response. Elucidating this astrocyte-centered redox–metabolic axis may reveal therapeutic strategies to stabilize penumbral tissue and improve stroke outcomes. Full article

Background: The therapeutic landscape of metastatic prostate cancer has rapidly evolved with the integration of biomarker-driven strategies, particularly targeting homologous recombination repair (HRR) alterations. Poly(ADP-ribose) polymerase inhibitors (PARPi) have demonstrated clinically meaningful benefit, especially in Breast Cancer genes 1/2-altered tumors, through synthetic lethality. However, the expansion of PARPi across multiple Treatment settings has introduced substantial complexity in patient selection, Treatment sequencing, and biomarker interpretation. This review aims to move beyond a descriptive synthesis of clinical trials and provide a clinically applicable, decision-oriented framework for the use of PARP inhibitors in metastatic prostate cancer. Methods: We conducted a narrative review of pivotal phase II and III trials published between 2020 and 2026 evaluating PARPi as monotherapy or in combination strategies. Evidence was critically analyzed with a focus on biomarker relevance, Treatment positioning, and real-world applicability. Evidence Synthesis: PARPi consistently improve radiographic progression-free survival, with the most robust and clinically meaningful benefit observed in BRCA-altered disease. In contrast, non-BRCA HRR alterations demonstrate heterogeneous and often limited predictive value, highlighting the limitations of a binary biomarker approach. Combination strategies in first-line metastatic castration-resistant prostate cancer (mCRPC) have expanded therapeutic options but raise important concerns regarding toxicity, overTreatment, and unclear benefit in biomarker-unselected populations. In parallel, variability in molecular testing strategies and access continues to limit real-world implementation. Conclusions: PARP inhibitors represent a cornerstone of precision oncology in metastatic prostate cancer, but their optimal use requires a refined, biomarker-informed approach. In this context, we propose a pragmatic 2026 clinical decision framework integrating molecular characteristics, prior Treatment exposure, and clinical factors. This approach aims to bridge the gap between clinical trial evidence, guideline recommendations, and real-world practice. Full article

Background/Objectives: Poly (ADP-ribose) polymerase (PARP1) has emerged as a promising therapeutic target in human breast cancer particularly in BRCA1/2 mutation carriers where a synthetic lethal interaction leads to massive tumor cell death upon specific inhibitors’ administration. Current clinically approved PARP inhibitors (Talazoparib and Olaparib) show outstanding therapeutic capabilities but suffer from severe side effects. Most importantly, some of them can cause life-threatening cardiotoxicity through hERG off-target effects. Here, we performed an extensive study to identify lead compounds with improved binding modes and favorable predicted pharmacokinetics using an integrated computational strategy. Methods: An artificial intelligence-driven drug design (AIDDISON™ v2023) workflow was employed to search ultra-large chemical space libraries for active compounds, which were then optimized via computer-aided methods to form a PARP-Tailored Database (PTD). This database was then analyzed through a virtual screening workflow, molecular docking studies, molecular dynamics (MD) simulations, MM/GBSA binding free energy calculations, DFT analysis and ADME/Tox predictions using the Schrödinger suite (v2023-2), MobaXterm v25.2, Gaussian 16.0, ProTox-3 and Pred-hERG v5.0 respectively. Results: Three compounds (1a–1c) were identified as promising candidates. Among them 1a appeared to be the most active compound with a favorable docking score (−9.488 kcal/mol) that is not only higher than 1b and 1c but also higher than that of Talazoparib (−6.778 kcal/mol). MD simulations of 1a–1c in the active site revealed an average RMSD of ~2.5–3.6 Å which is better compared to the parent Talazoparib (5.6 Å). Interestingly, on the 250 ns extended MD study, 1a exhibited a slightly reduced RMSD between 2.4 and 3.2 Å, whereas Talazoparib retained higher fluctuations of ~5 Å to 6 Å. MM/GBSA binding energy analysis indicated 1a to have better predicted binding affinity (−67.820 kcal/mol), which is also better than Talazoparib (−63.734 kcal/mol). DFT calculations showed good electronic properties and in silico ADMET studies also indicated 1a to have good drug-likeness and lower predicted hepatotoxicity and cardiotoxicity risk. Conclusions: These findings identify compound 1a as a promising lead, while compounds 1b and 1c remain viable candidates for further optimization. However, experimental validation is critical to confirm the predicted biological activity and safety profiles. Full article

Background/Objectives: Ataxia telangiectasia-mutated kinase is encoded by the ATM gene. This gene is altered in many cancer types; however, it is most relevant for eligibility of poly-ADP-ribose polymerase inhibitor (PARPi) therapy in metastatic castrate-resistant prostate cancer in Canada. Non-benign ATM alterations are relatively uncommon, seen in less than 10% of prostate cancers; however, many of these are variants of uncertain significance with limited evidence of clinical significance or actionability. Methods: To aid in variant classification of next-generation sequencing results, ATM immunohistochemistry (IHC) is performed on patient tumour samples to serve as patient-specific functional evidence for ATM protein loss. Results: ATM IHC demonstrates strong concordance with known loss-of-function variants and copy number losses. Additionally, it can be used to clarify ATM protein loss in cases involving variants of uncertain significance (VUSs) or copy number deletions. Conclusions: Incorporation of ATM IHC into clinical testing for prostate cancer represents a relatively cost-effective orthogonal approach that can rescue poor-quality NGS results and clarify the functional impact of ATM VUSs on protein expression. Overall, this strategy may provide useful supportive evidence in prostate cancer biomarker testing and interpretation. Full article