Search Results (35,227)

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Lutetium-177-PSMA-617 (Lu-PSMA) radioligand therapy (RLT) is established in metastatic castration-resistant prostate cancer (mCRPC), with regulatory approvals based on the VISION and TheraP trials. Subsequent trials have extended the evidence to taxane-naive mCRPC (PSMAfore) and demonstrated that combining Lu-PSMA with enzalutamide yields a significant overall survival benefit over enzalutamide alone (ENZA-p). However, higher and more homogeneous PSMA expression in treatment-naive disease, combined with lower tumor burden and preserved bone marrow reserve, provides a biological rationale for deploying RLT earlier in the disease course. In metastatic hormone-sensitive prostate cancer (mHSPC), the Phase III PSMAddition trial reported improved radiographic progression-free survival when Lu-PSMA was added to standard androgen deprivation therapy (ADT) plus androgen receptor pathway inhibitor (ARPI), and the Phase II UpFrontPSMA trial demonstrated enhanced biochemical responses with Lu-PSMA induction before docetaxel. In oligometastatic and oligorecurrent disease, the BULLSEYE and LUNAR trials have shown progression-free survival benefits, raising the possibility of deferring androgen deprivation therapy and its associated morbidity. Meanwhile, next-generation radionuclides, including actinium-225 (WARMTH) and the dual beta-Auger emitter terbium-161 (VIOLET), are entering clinical development to address the radiobiological limitations of Lutetium-177. This review synthesizes the evidence for PSMA-targeted radioligand therapy across the prostate cancer disease continuum and discusses patient selection, treatment sequencing, and the access and cost-effectiveness considerations that will shape adoption in earlier disease settings. 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

Background/Objectives: Curcumin shows broad anticancer activity but limited clinical success as a standalone agent because of poor bioavailability and inconsistent tumor exposure. This review introduces the concept of curcumin as a molecular synergy amplifier and proposes that successful combinations depend on three interdependent determinants: mechanistic complementarity, suppression of adaptive resistance networks, and pharmacokinetic synchronization. Methods: Evidence on combinations with chemotherapeutics, natural bioactives, and nanotechnology-enabled delivery systems was critically evaluated, with emphasis on mechanism, resistance reversal, drug ratio, administration sequence, and tumor exposure. Results: Curcumin enhances therapeutic efficacy by sensitizing cancer cells, suppressing adaptive resistance pathways, targeting cancer stemness, and promoting multiple forms of programmed cell death. Importantly, analysis of current evidence indicates that therapeutic success depends not only on molecular synergy but also on pharmacokinetic synchronization between curcumin and partner agents. Many combinations demonstrating strong in vitro synergy fail to translate in vivo because optimal drug ratios, timing, and tumor exposure cannot be maintained. Nanotechnology-based co-delivery systems partially overcome these limitations through synchronized delivery and controlled release. Conclusions: Curcumin should be viewed as a molecular synergy amplifier whose clinical utility depends on mechanistic complementarity and pharmacokinetic synchronization with co-administered therapies. This framework provides a rationale for the design of next-generation curcumin-based combination therapies and identifies key priorities for clinical translation. Full article

Treatment of non-small cell lung cancer (NSCLC) has been transformed by immunotherapy and targeted therapies. We aimed to characterize clinical features, treatment patterns, and healthcare resource use in patients with early and locally advanced NSCLC before incorporation of these therapies. This retrospective observational study included adults diagnosed with stage I–III NSCLC at four Spanish hospitals between 2014 and 2018, with follow-up until 2021, using artificial intelligence to extract data from electronic health records. A total of 951 patients were included (34.7% stage I, 16.7% stage II, 48.6% stage III), with a median age of 66 years and 31.9% female. Surgery was performed in 78.5% of stage I, 74.8% of stage II, and 35.5% of stage III patients. Among surgical patients, 62.5% received adjuvant chemo- and/or radiotherapy, 20.8% neoadjuvant therapy, and 15.7% both; among non-surgical patients, chemoradiotherapy was the most common treatment (50.4%). Beyond hospitalization, outpatient visits were the most frequently used healthcare resource. These findings provide a historical benchmark of NSCLC care before introduction of immunotherapy and targeted therapies in these settings, highlighting treatment variability and the need for earlier diagnosis, structured treatment pathways, and multidisciplinary management. Full article

Cytoreductive surgery remains one of the key treatment modalities in advanced ovarian cancer. Complete cytoreduction is the main surgical goal. PARP inhibitors are currently established mainly as maintenance therapy after response to platinum-based chemotherapy, particularly in patients with BRCA-mutated or homologous recombination-deficient tumors. Their use before cytoreductive surgery remains investigational. This review evaluates preoperative PARP inhibition from a surgical perspective. This narrative review summarizes current evidence, ongoing clinical trials, and perioperative considerations related to preoperative or neoadjuvant PARP inhibitor strategies in advanced ovarian cancer. Particular attention was given to the review of current clinical trials’ strategies, resectability, complete cytoreduction, patient selection, perioperative safety, treatment timing, and surgery-specific endpoints. Current studies explore several preoperative approaches, including short window-of-opportunity treatment before primary debulking surgery, PARP inhibitor monotherapy as potential conversion therapy in homologous recombination-deficient disease, PARP inhibitor-based strategies before interval debulking surgery, combination regimens with immunotherapy or antiangiogenic therapy, and preoperative PARP inhibitor use before secondary cytoreduction in recurrent disease. These studies suggest that preoperative PARP inhibition may provide biological and surgical insights, but available evidence remains preliminary. Key concerns include hematologic toxicity, surgical postponement, perioperative complications, wound healing, postoperative recovery, and the risk of delaying standard chemotherapy or surgery. Preoperative PARP inhibitor therapy is theoretically promising but an unproven strategy in ovarian cancer. Its future value will depend on prospective trials showing that it can safely improve resectability and complete cytoreduction without compromising treatment timing. Future studies should include surgery-specific endpoints in addition to conventional oncologic outcomes. Full article

Background: Immune checkpoint inhibitors (ICIs), particularly programmed death-ligand 1 (PD-L1) inhibitors such as atezolizumab, have significantly improved outcomes in cancer therapy. However, these agents may cause immune-related adverse effects, including nephrotoxicity associated with oxidative stress and cellular stress responses. This study aimed to investigate and comparatively evaluate the protective effects of adenosine triphosphate (ATP) and taxifolin against atezolizumab-induced renal tissue injury in rats. Methods: Animals were divided into four groups: healthy (HG), atezolizumab (ATZ), ATP + atezolizumab (ATAZ), and taxifolin + atezolizumab (TXAZ). ATP (4 mg/kg, i.p.) and taxifolin (50 mg/kg, oral) were administered for six days, while atezolizumab (10 mg/kg, i.p.) was given on days 1 and 4. On day 7, renal tissues were collected for biochemical, histopathological, and double immunofluorescence analyses. Results: Atezolizumab significantly increased malondialdehyde (MDA) levels and decreased total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) levels, indicating enhanced oxidative stress and impaired antioxidant defense. These changes were accompanied by tubular degeneration and increased expression of apoptotic markers. Both ATP and taxifolin significantly ameliorated these alterations; however, ATP demonstrated a more pronounced protective effect. Conclusions: In conclusion, ATP and taxifolin attenuated the biochemical, histopathological, and immunofluorescence alterations associated with atezolizumab administration. ATP exhibited a more pronounced protective effect than taxifolin under the conditions of this experimental model. Nevertheless, further experimental studies are required to elucidate the mechanisms underlying these effects. Full article

Malignant gliomas are highly aggressive primary brain tumors for which the therapeutic efficacy of cisplatin is frequently limited by intrinsic or acquired drug resistance. Despite advances in adjuvant therapies, overcoming chemoresistance remains a major challenge in the treatment of these malignancies. Emerging evidence indicates that long non-coding RNAs (lncRNAs), a class of non-protein-coding transcripts involved in gene regulation, play important roles in modulating treatment responses. Several lncRNAs, including differentiation antagonizing non-protein-coding RNA (DANCR), HOXD antisense growth-associated long non-coding RNA (HOXD-AS1), MEG3, MALAT1, and HOTAIR, have been implicated in pathways associated with glioma progression and therapeutic resistance. In particular, DANCR has been reported to promote cisplatin resistance in glioma cells through suppression of apoptosis and activation of pro-survival signaling pathways. This review summarizes current evidence regarding the roles of lncRNAs in cisplatin resistance, highlighting mechanisms such as regulation of drug transport, DNA damage repair, apoptosis, cancer stem-cell maintenance, and signaling pathways associated with treatment adaptation. We also discuss current limitations, challenges for clinical translation, and gaps in the existing evidence. A better understanding of lncRNA-mediated resistance mechanisms may facilitate the identification of novel therapeutic targets and inform future studies aimed at overcoming cisplatin resistance in malignant gliomas. Full article

Testicular receptor 4 (TR4, NR2C2) is an orphan nuclear receptor involved in the regulation of metabolism, inflammation, cardiovascular disease, and cancer. Accumulating evidence indicates that TR4 exhibits functional plasticity, exerting protective or pathogenic effects depending on tissue and disease context, and sometimes displaying opposing roles within the same disease. However, the mechanisms underlying this functional duality remain poorly understood. Recent studies indicate that TR4 activity is determined not only by the receptor itself but also by dynamic coregulatory networks. Through interactions with coactivators, corepressors, epigenetic regulators, and environmental signaling pathways, TR4 integrates metabolic cues to generate context-dependent transcriptional programs. Coactivator networks centered on PGC-1α, steroid receptor coactivator (SRC) family members, and CBP/p300 support oxidative metabolism and anti-inflammatory responses, whereas RIP140-, NCoR/SMRT-, and HDAC-associated networks promote lipid accumulation, chronic inflammation, fibrosis, and tumor progression. Regulators such as JAZF1 further influence TR4 activity by reshaping coregulator recruitment and target-gene selection. In this review, we summarize the structural basis of TR4 regulation and discuss how coregulatory network remodeling governs its functions in metabolic, cardiovascular, inflammatory, and malignant diseases. We propose that TR4 functions as a context-dependent transcriptional platform whose activities are defined by its coregulatory landscape, providing a framework for precision therapies. Full article

A 64-year-old Asian woman diagnosed with synchronous breast ductal carcinoma in situ (DCIS) and stage IV EGFR-mutated non-small cell carcinoma of the lung (NSCLC). A decision was made to defer management of the DCIS and initiate Osimertinib for lung cancer treatment, since this was a life-limiting diagnosis. At 9 months, restaging FDG-PET CT showed an interval response in the NSCLC and complete loss of FDG avidity at the biopsy-proven DCIS site. Breast MRI confirmed complete imaging resolution of the DCIS. The clinical resolution of breast DCIS during third-generation EGFR inhibitor therapy has not been previously reported in humans and highlights a potential role for the EGFR/HER2 (ERBB) pathway in pre-invasive breast cancer. Full article

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality worldwide and is characterized by extensive vascularization, aggressive progression, and limited therapeutic responsiveness. Angiogenesis plays a central role in HCC development by supporting tumor growth, metabolic adaptation, invasion, and metastatic dissemination. Although anti-angiogenic therapies targeting the vascular endothelial growth factor (VEGF) pathway have improved clinical management, their overall survival benefit remains modest because of compensatory signaling, adaptive resistance, and the highly complex nature of the tumor microenvironment (TME). Astrocyte elevated gene-1/metadherin (AEG-1/MTDH) has emerged as a multifunctional oncogene that functions by orchestrating interconnected angiogenic, inflammatory, metabolic, and immune-regulatory programs within the hepatic tumor microenvironment. AEG-1 regulates angiogenesis through modulation of VEGF-family signaling, NF-κB activation, hypoxia-responsive pathways, PI3K/AKT signaling, endothelial remodeling, and translational control of pro-angiogenic mediators. Emerging evidence further implicates AEG-1 in hypoxia adaptation, immune evasion, extracellular vesicle signaling, and metabolic reprogramming, supporting its role as a systems-level regulator of HCC angiogenesis. This review summarizes the current understanding of the molecular mechanisms through which AEG-1 regulates angiogenesis in HCC, discusses its interactions with the TME and anti-angiogenic resistance pathways, and highlights future translational opportunities for developing multi-targeted therapeutic strategies beyond conventional VEGF-centric approaches. Full article

Nanotechnology has become an important platform in the fields of gene therapy and genome editing, providing delivery strategies that address persistent therapeutic challenges by improving the precision, efficiency, and safety of genetic modifications. This review highlights the central role of nanomaterials in overcoming persistent barriers to genetic interventions, including inefficient delivery, instability of genetic cargo, and off-target effects. Specifically, we emphasize the combined use of nanomaterials with clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR-Cas) systems, which can improve editing specificity and therapeutic efficacy. Beyond the classical CRISPR/Cas9 platform, this review also discusses next-generation modalities such as base editors, Cas13, prime editing, and the recently described Tandem Interspaced Guide RNA and TIGR-associated protein (TIGR-Tas) system, while considering their therapeutic potential and distinct delivery challenges. By using nanomaterials, the stability and intracellular delivery of genome-editing systems are improved, enabling more effective treatments for genetic disorders and acquired diseases such as cancer and infectious diseases. In addition, nanocarriers provide controlled release, protection from degradation, and better biocompatibility, thereby improving the safety and reliability of gene-editing therapies. Despite these advances, important translational challenges remain, including immunotoxicity, large-scale manufacturing, and regulatory integration. Overall, the continued convergence of nanotechnology and genome engineering may support the development of personalized medicine strategies that adapt genetic engineering tools for patient-specific applications. Full article

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies widely used for the treatment of colorectal cancers. However, due to various mechanisms of resistance to these targeted therapies, the patients’ responses vary. These resistances remain a major obstacle in treatment and overcoming them has become a key emphasis of current therapeutic strategies. Intrinsic and acquired resistance often lead to reactivation of downstream signaling pathways, mainly the RAS-RAF-MEK-ERK (MAPK pathway) and PI3K-AKT axes. Prior existing mutations in KRAS, NRAS, and BRAF result in primary resistance by constantly activating the signals, irrespective of EGFR inhibition. That said, acquired resistance manifests under therapeutic burden through the process of clonal evolution via KRAS and BRAF alterations, restoring MAPK pathway activity despite EGFR inhibition. In addition to those mutations, tumor cells exploit mechanisms independent of EGFR, such as the pathway bypass, which includes amplification of ERBB family receptors like HER2 (ERBB2) and activation of MET signaling. To overcome these resistances, novel strategies have emerged, which target multiple nodes within the oncogenic networks. Such methods include vertical pathway inhibition, multi-kinase inhibition, liquid-biopsy-guided therapy, and anti-EGFR rechallenge. Reactivation driven by secondary mutation can be prevented by targeting multiple nodes within the MAPK cascade simultaneously, which is referred to as the vertical pathway inhibition. Overall, this review underscores that overcoming therapeutic resistance requires a multidimensional approach that integrates molecular profiling, rational combination therapies, and adaptive treatment. Finally, these advances underscore the shift toward precision oncology, where therapy is tailored to tumor evolution, leading to improved response and patient outcome. Full article

Background: Despite the therapeutic advances made in castration-sensitive prostate cancer, progression to castration-resistant disease is inevitable. Lutetium-177 vipivotide tetraxetan (¹⁷⁷Lu-PSMA-617) is a novel radioligand approved for use in metastatic castration-resistant prostate cancer (mCRPC). With promising efficacy, it is not without numerous potential side effects, namely cytopenias, which are often a reason for early discontinuation of ¹⁷⁷Lu-PSMA-617. We sought to describe the incidence of cytopenias associated with permanent discontinuation of ¹⁷⁷Lu-PSMA-617 at our institution. Methods: We conducted a retrospective review of patients who received ¹⁷⁷Lu-PSMA-617at the University of Virginia Comprehensive Cancer Center from 2018 to 2025. From this we assessed for the incidence of toxicities resulting in permanent discontinuation of ¹⁷⁷Lu-PSMA-617, which we refer to as dose-limiting toxicities. Descriptive statistics were used to summarize characteristics of the study population. Median overall survival from time of initiation of ¹⁷⁷Lu-PSMA-617 was estimated using a Kaplan–Meier curve. Results: Of the patients who received ¹⁷⁷Lu-PSMA-617 (n = 64), grade 3 or greater anemia occurred in 36% (n = 23), thrombocytopenia in 3% (n = 2), leukopenia in 3% (n = 2), neutropenia in 0% (n = 0), and lymphopenia in 33% (n = 21). In our cohort, 10.9% (n = 7) developed toxicities necessitating permanent discontinuation. Of these, 9.3% (n = 6) were attributable to cytopenias. Those cytopenias consisted of anemias in 100% (n = 6) of cases, leukopenia in 83% (n = 5), thrombocytopenia in 67% (n = 4), lymphopenia in 100% (n = 6), and neutropenia in 33% (n = 2). Aside from cytopenias, the remaining 1.6% (n = 1) of dose-limiting toxicities were attributable to renal injury. In the VISION trial, the ¹⁷⁷Lu-PSMA-617 treatment arm reported dose-limiting toxicities necessitating permanent discontinuation in 11.9% of participants, but did not report if these were attributable to cytopenia or other toxicities. Notably, 2 patients developed grade 5 pancytopenia and 1 patient developed grade 5 bone marrow failure in the VISION ¹⁷⁷Lu-PSMA-617 treatment arm. Compared to the VISION ¹⁷⁷Lu-PSMA-617 treatment arm, our cohort differed in the distribution of organ metastases, younger median age of patients, and a higher portion of those with ECOG 2 functional status. From the time of ¹⁷⁷Lu-PSMA-617 initiation, median overall survival was estimated to be 18.5 months, compared to 15.3 months in the VISION ¹⁷⁷Lu-PSMA-617 treatment arm. Conclusions: In our real-world analysis, 85% of dose-limiting toxicities necessitating ¹⁷⁷Lu-PSMA-617 discontinuation were attributed to cytopenias. Though a direct comparison cannot be made with the VISION ¹⁷⁷Lu-PSMA-617 treatment arm in terms of dose-limiting toxicity attributable specifically to cytopenias, they reported total dose-limiting toxicity to a similar degree, and cytopenias were the most common causes of grade 3 or greater toxicities. Therefore, it is important to recognize the ubiquity of these adverse events as well as the role that they play in therapy-limiting toxicity. Full article

The bacterial and toxin methods of cancer treatment date back 130 years. This paradigm rests on nonspecific bacterial-toxin-generated immunotherapy. This high-risk oncology research is experiencing a renaissance of methods that are among the most effective yet. Glioblastomas and other resistant cancers are the modern touchpoint, because of remission history following sepsis. Spurred by recent research deaths, we discuss protocols IRBs should consider in live bacterial or synthetic immuno-stimulatory trials. Human systemic inflammatory response syndrome immunology is unique due to non-functioning SIGLEC-13 and 17, which control excessive Toll-like receptor 4 (TLR-4) signaling. This is not a technicality like human CD8+/CD4+ T cells. SIGLEC-13&17 consequences are profound; humans are ≈330–200,000 times more sensitive to LPS/endotoxin than mice and rats. This human TLR-4 difference also applies to gene therapy and should inform the results from any animal model, including non-human primates. Clinical TLR-4 stimulation takes two forms: bacterial infection and sterile TLR-4 stimulators, and treatments differ. The stereotactic injection of calculated amounts of adjuvants like endotoxin, venoms/components, or synthetic alternatives may be safer than live bacteria. Inadequate planning for risk elements, basic predictive models, and treatments will likely cause death. Full article