Search Results (114)

Cancer reversion therapy represents a paradigm shift in oncology, focusing on reprogramming malignant cells to a non-malignant state rather than destroying them. This narrative review synthesizes current evidence, emerging technologies, and future directions in this promising field. Cancer reversion is founded on key biological observations: somatic cell reprogramming, spontaneous cancer regression, and microenvironmental influences on malignant behavior. Current approaches include epigenetic reprogramming using HDAC inhibitors and DNA methyltransferase inhibitors; microenvironmental modulation through extracellular matrix manipulation and vascular normalization; differentiation therapy exemplified by all-trans retinoic acid in acute promyelocytic leukemia; and targeting oncogene addiction as demonstrated in BCR-ABL-driven leukemias. Emerging technologies accelerating progress include single-cell analyses that reveal cancer heterogeneity and cellular state transitions; CRISPR-based approaches enabling precise genetic and epigenetic manipulation; patient-derived organoids that model tumor complexity; and artificial intelligence applications that identify novel reversion-inducing agents. Critical evaluation reveals that many reported “reversion” phenomena represent stimulus-dependent plasticity or transient growth arrest rather than stable phenotypic normalization. True cancer reversion requires durable, heritable phenotypic changes that persist after treatment withdrawal, with evidence of epigenetic consolidation and functional restoration. Despite promising advances, significant challenges remain: cancer cell plasticity facilitating therapeutic escape, difficulties in establishing stable reversion states, delivery challenges for solid tumors, and the need for combination approaches to address tumor heterogeneity. Future directions include integrated multi-omics analyses to comprehensively map cellular state transitions, studies of natural regression phenomena to identify reversion mechanisms, advanced nanodelivery systems for targeted therapy, and synthetic biology approaches creating intelligent therapeutic systems. By redirecting rather than destroying cancer cells, reversion therapy offers the potential for reduced toxicity and resistance, potentially transforming cancer from a deadly disease to a manageable condition. Full article

Lung cancer remains the most prevalent and deadliest malignancy worldwide. According to the European Society for Medical Oncology guidelines for non-oncogene-addicted metastatic non-small-cell lung cancer (NSCLC), patients with metastatic squamous-cell carcinoma (LUSC) or metastatic non-squamous NSCLC with performance status 2 and PD-L1 < 50% may receive single-agent chemotherapy with gemcitabine (GEM), docetaxel (DOC), or vinorelbine. Herein, we investigated the cellular effects of GEM/DOC as monotherapies in NSCLC cell lines—lung adenocarcinoma, A549 and CALU6; LUSC, H520 and H1703. Treatment with GEM/DOC may induce apoptotic cell death in all NSCLC cell lines at 48 h. GEM/DOC can affect cancer cell migration assessed by scratch assay. Both GEM/DOC may produce distinct effects on cell cycle arrest, consistent with their particular pharmacodynamic effects. Furthermore, GEM/DOC induced signals consistent with autophagic activity in LUSC cell lines, but only GEM triggered signals consistent with autophagic activity in the CALU6 cell line. Analysis of three key long non-coding RNAs (lncRNAs)—MALAT1, NEAT1, and HOTAIR—showed variable expression in the studied cell lines as a potential response to DOC and GEM treatment. Our findings indicate different cellular effects of GEM and DOC in NSCLC cell lines and provide an overview of how currently used chemotherapeutics may influence the expression of lncRNAs. Full article

Background/Objectives: Anti–PD-1/PD-L1 blockers have revolutionized the treatment landscape of non–small cell lung cancer (NSCLC) lacking oncogene-addicted alterations, particularly in tumors with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%). Cemiplimab is approved as first-line monotherapy in this setting. However, real-world data remain scarce. This study aimed to evaluate the efficacy and safety of single-agent cemiplimab in a multicenter Spanish cohort and compare outcomes with a historical pembrolizumab cohort. Methods: Cemi-SPA is a retrospective multicenter study including 150 patients with advanced NSCLC and PD-L1 ≥ 50% treated with cemiplimab as first-line monotherapy across 21 Spanish centers. Clinical outcomes were analyzed and compared with a historical cohort of 144 patients treated with pembrolizumab. Propensity score matching (PSM) was performed to adjust for baseline differences. Results: Median progression-free survival (PFS) and overall survival (OS) were 8.1 and 12.6 months, respectively. ECOG performance status ≥ 2 was independently associated with worse outcomes, whereas the development of immune-related adverse events correlated with improved PFS and OS. After PSM, no significant differences were observed between cemiplimab and pembrolizumab in terms of efficacy. Conclusions: Cemiplimab demonstrated comparable real-world efficacy and safety to pembrolizumab in patients with advanced NSCLC and PD-L1 ≥ 50%. ECOG performance status emerged as the strongest prognostic factor, highlighting the importance of patient selection in routine clinical practice. Full article

Molecular chaperones are crucial for maintaining protein homeostasis by assisting in the proper folding, stabilization, and function of proteins. Among them, Heat shock protein 90 (Hsp90), represents a highly conserved protein family of molecular chaperones that plays an essential role in diverse biological processes and is fundamental to cellular health and survival. As a highly abundant molecular chaperone, Hsp90 comprises 1–2% of cellular proteins, increasing to 4–6% under stress conditions. It interacts with client proteins, assisting them in proper folding and stability. Unlike classical chaperonins, Hsp90 operates through a highly regulated, ATP-dependent cycle that involves multiple co-chaperones. This process allows Hsp90 to selectively engage with numerous client proteins, including signaling proteins, kinases, hormone receptors, and transcription factors. Recent discoveries have revealed its involvement in processes beyond protein folding, demonstrating its role in diverse cellular functions such as epigenetic regulation, immune signaling, and oncogenic transformation. This current review highlighted the specific characteristics of cytoplasmic and endoplasmic reticulum (ER) as well as mitochondrial paralogs and functions, focusing on its contribution to buffering genetic variation, facilitating oncogene addiction, and modulating disease phenotypes in conditions such as cancer, neurodegeneration, cardiovascular diseases (CVD), and diabetes. We also discuss the therapeutic potential of targeting Hsp90 and its co-chaperones, outlining the challenges and prospects in drug development. These insights not only reshape our understanding of chaperone biology but also present opportunities for precision medicine in various human diseases. Full article

Reactive oxygen species (ROS) function as critical signaling molecules in cancer biology, promoting proliferation, angiogenesis, and metastasis at controlled levels while inducing lethal damage when exceeding the cell’s buffering capacity. To survive under this state of chronic oxidative stress, cancer cells become dependent on a hyperactive antioxidant shield, primarily orchestrated by the Nrf2, glutathione (GSH), and thioredoxin (Trx) systems. These defenses maintain redox homeostasis and sustain oncogenic signaling, notably through the oxidative inactivation of tumor-suppressor phosphatases, such as PTEN, which drives the PI3K/AKT/mTOR pathway. Targeting this addiction to a rewired redox state has emerged as a compelling therapeutic strategy. Pro-oxidant therapies aim to overwhelm cellular defenses, with agents like high-dose vitamin C and arsenic trioxide (ATO) showing significant tumor-selective toxicity. Inhibiting the master regulator Nrf2 with compounds such as Brusatol or ML385 disrupts the core antioxidant response. Disruption of the GSH system by inhibiting cysteine uptake with sulfasalazine or erastin potently induces ferroptosis, a non-apoptotic cell death driven by lipid peroxidation. Furthermore, the thioredoxin system is targeted by the repurposed drug auranofin, which irreversibly inhibits thioredoxin reductase (TrxR). Extensive preclinical data and ongoing clinical trials support the concept that this reliance on redox adaptation is a cancer-selective vulnerability. Moreover, novel therapeutic strategies, including the expanding field of redox-active metal complexes, such as manganese porphyrins, which strategically leverage the differential redox state of normal versus cancer cells through both pro-oxidant and indirect Nrf2-mediated antioxidative mechanisms (triggered by Keap1 oxidation), with several agents currently in advanced clinical trials, have also been discussed. Essentially, pharmacologically tipping the redox balance beyond the threshold of tolerance offers a rational and powerful approach to eliminate malignant cells, defining a novel frontier for targeted cancer therapy. Full article

Transcription is a core hallmark of cancer, wherein many different proteins assemble at specific sites in the nucleus and act in concert to transcribe functionally relevant genes. Central to this process are transcription factors that bind to their cognate DNA motifs on enhancers and super-enhancers to recruit cofactors, coactivators, and epigenetic modifiers, thereby inducing or repressing gene expression. Super-enhancers drive oncogenic transcription, to which cancer cells become highly addicted and confer tumor dependencies on super-enhancer-driven transcription machinery. Transcriptional condensates (TCs) are nuclear membrane-less assemblies of DNA-binding transcription factors, transcription co-activators, and the transcriptional machinery (such as RNA polymerases, non-coding RNAs) formed through liquid–liquid phase separation (LLPS). The function of transcriptionally active oncogenic proteins and their interplay with nucleic acids are carried out within these biomolecular condensates, allowing them to spatiotemporally regulate oncogene expression and lead to the induction and maintenance of cancer. With this growing understanding, specific inhibitors and strategies targeting TC assembly and activation should be considered promising therapeutic opportunities for treating various tumors, including hematological malignancies. Full article

Background/Objectives: Lung cancer (LC) remains one of the most lethal malignancies worldwide, with both environmental and occupational exposures contributing to its incidence. While oncogene-addicted tumors—defined by single driver mutations—have garnered attention due to their therapeutic implications, less is known about the mutational landscape of tumors potentially arising from occupational exposure to carcinogens. This real-life observational study aimed to assess whether previous occupational exposure to lung carcinogens correlates with distinct LC phenotypes, particularly non-oncogene-addicted (nOA) profiles. Methods: A total of 199 LC patients were enrolled across two specialized oncology centers in Northern Italy between 2021 and 2023. Each participant underwent detailed occupational history taking and molecular characterization using next-generation sequencing. Patients were stratified into nonexposed (NE), low exposed (LE), and high exposed (HE) to carcinogens for lung based on standardized questionnaires and sector-specific assessments. Results: No significant differences were found in histological subtypes across exposure groups. However, people with adenocarcinoma and high occupational exposure to lung carcinogens were more frequently characterized by a nOA phenotype compared to those with low occupational exposure. Logistic regression models—adjusted for age, sex, and smoking habits—confirmed that HE patients had a significantly higher likelihood of developing nOA tumors (OR = 3.07; 95% CI: 1.16–8.11; p = 0.023). This association persisted after adjusting for smoking habits Exposures occurring 5–10 years before diagnosis seemed to be associated with an increased nOA profile. Conclusions: These findings suggest that high levels of exposure to occupational carcinogens impact LC phenotypes. Indeed, these phenotypes are more complex to treat and show the worst prognosis. Assessing the occupational exposure to lung carcinogens during work may offer prognostic insights and support the request for more adequate compensation for the patients. Further studies are warranted to validate these results and to explain the mechanisms that produce the differences observed in LC phenotypes in people with high exposure to occupational carcinogens. Full article

Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the most frequently mutated genes in human cancer, including non-small cell lung carcinoma (NSCLC). Sustained expression of KRAS is required for survival in KRAS-dependent tumors. KRAS tumors can become independent upon bypassing this addiction. Tissue inhibitor of metalloproteinase-1 (TIMP-1) exhibits a range of novel functions in addition to its initially recognized activity as a physiological inhibitor of matrix metalloproteinases (MMPs). It has repeatedly been associated with cancer progression and poor prognosis in multiple cancers. This study investigates the relationship between TIMP-1 modulation and KRAS dependency in NSCLC. We found an inverse expression of KRAS and TIMP-1 in NSCLC lines. Modulating TIMP-1 levels altered KRAS expression and affected KRAS-dependency features. Overexpression of TIMP-1 decreases the KRAS levels in dependent cells and knocking-down TIMP-1 increases KRAS levels in independent cells with concomitant change in RAS-GTP levels. TIMP-1 modulation influenced apoptosis upon KRAS ablation, with TIMP-1 overexpression decreasing apoptosis in dependent cells and TIMP-1 knockdown increasing it in independent cells. Bioinformatic analysis depicted variant-specific perturbations between KRAS and TIMP-1 expression. Furthermore, EMT marker expression was altered upon TIMP-1 modulation, suggesting the role of TIMP-1 in EMT induction in KRAS-independent cells. These findings emphasize the intricate relationship between TIMP-1 and KRAS in NSCLC, shedding light on potential mechanisms underlying tumor behavior and response to therapy. Full article

MYCN amplification without concurrent RB1 mutations characterizes a rare yet highly aggressive subtype of retinoblastoma; however, its precise developmental origins and therapeutic vulnerabilities remain incompletely understood. Here, we modeled this subtype by lentiviral-mediated MYCN overexpression in human pluripotent stem cell-derived retinal organoids, revealing a discrete developmental window (days 70–120) during which retinal progenitors showed heightened susceptibility to transformation. Tumors arising in this period exhibited robust proliferation, expressed SOX2, and lacked CRX, consistent with origin from primitive retinal progenitors. MYCN-overexpressing organoids generated stable cell lines that reproducibly gave rise to MYCN-driven tumors when xenografted into immunodeficient mice. Transcriptomic profiling demonstrated that MYCN-overexpressing organoids closely recapitulated molecular features of patient-derived MYCN-amplified retinoblastomas, particularly through activation of MYC/E2F and mTORC1 signaling pathways. Pharmacological screening further identified distinct therapeutic vulnerabilities, demonstrating distinct subtype-specific sensitivity of MYCN-driven cells to transcriptional inhibitors (THZ1, Flavopiridol) and the cell-cycle inhibitor Volasertib, indicative of a unique oncogene-addicted state compared to RB1-deficient retinoblastoma cells. Collectively, our study elucidates the developmental and molecular mechanisms underpinning MYCN-driven retinoblastoma, establishes a robust and clinically relevant human retinal organoid platform, and highlights targeted transcriptional inhibition as a promising therapeutic approach for this aggressive pediatric cancer subtype. Full article

Worldwide, lung cancer is one of the most common cancers, with non-small cell lung cancer (NSCLC) including up to 80–85% of all lung cancer diagnoses. The landscape of NSCLC is characterized by a heterogeneous spectrum of gene alterations, with tyrosine kinase inhibitors (TKIs) and targeted treatments that significantly improve survival outcomes for patients with oncogene-addicted NSCLC, offering superior efficacy, and often favorable safety and tolerability profiles compared to chemotherapy-based treatments. However, the complexity of NSCLC extends to co-occurring genomic alterations or amplifications in tumor suppressors and other oncogenes, such as TP53, STK11, KEAP1, PIK3CA, RB1, and others, that significantly influence disease progression, therapeutic resistance, and clinical outcomes. These co-mutations often contribute to the development of primary and acquired resistance to targeted therapies, complicating decision-making strategies. This review provides a timely and comprehensive synthesis of current insights into co-mutations in NSCLC, with a particular focus on their clinical implications, and offers a novel perspective by integrating recent molecular insights with therapeutic challenges, addressing existing knowledge gaps through a more integrative and clinically oriented analysis of co-mutations. Advances in next-generation sequencing (NGS) and molecular profiling have enabled the identification of these co-alterations, paving the way for more personalized therapeutic approaches. However, challenges remain in interpreting the functional interplay of co-mutations and translating these insights into effective clinical interventions. This review also highlights the significance of co-mutations in shaping NSCLC biology, and discusses their impact on current therapeutic paradigms, emphasizing the need for integrative biomarker-driven approaches to improve outcomes in NSCLC. Full article

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives. Full article

MYC is an aberrantly regulated transcription factor implicated in approximately 70% of human tumors, where it extensively modulates signaling pathways associated with cancer progression. Inactivating MYC has been shown to inhibit tumor growth and even induce sustained tumor regression across various cancer types, a phenomenon referred to as oncogene addiction. However, in vitro studies reveal that the knockout or knockdown of MYC in numerous tumor cell lines does not necessarily result in cell death, despite these tumors exhibiting MYC addiction in vivo. This discrepancy suggests that the unique tumor microenvironment in vivo may play a critical role in facilitating MYC addiction in cancer cells. MYC is also widely acknowledged for its role in mediating the immune evasion of tumor cells. Nevertheless, due to the extensive regulation of cellular gene expression by MYC and the incomplete understanding of the mechanisms underlying tumor immune escape, the precise pathways through which MYC influences tumor immune evasion remain inadequately elucidated. Recent years have seen the identification of novel tumor immune escape mechanisms, some of which have been demonstrated to be directly or indirectly regulated by MYC. For instance, MYC may contribute to immune evasion by modulating the expression of argininosuccinate synthetase 1 (ASS1), a key enzyme involved in arginine biosynthesis. Herein, in this study, we explore some novel potential mechanisms through which MYC facilitates the immune evasion of tumor cells, alongside a combined therapeutic approach targeting MYC and employing immunotherapy based on this mechanism. Furthermore, we suggest that targeting proteins interacting with MYC to modulate its expression and function may serve as an alternative strategy to direct MYC targeting, thereby expediting the clinical translation of combination therapies. Full article

Heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) is a multifunctional RNA-binding protein (RBP) that plays a central role in post-transcriptional regulation. Through its quasi-RNA recognition motifs and low-complexity domains, hnRNPH1 specifically binds guanine-rich RNA sequences, including G-quadruplex structures, to precisely modulate multiple aspects of RNA metabolism, such as alternative splicing, mRNA stability, translation, and subcellular localization. Accumulating evidence has implicated hnRNPH1 dysfunction in the pathogenesis of several human diseases. In cancer, hnRNPH1 often acts as a pro-tumorigenic factor, albeit in a context-dependent manner, influencing the alternative splicing of crucial oncogenes, mRNA stability, and tumor cell sensitivity to therapeutic agents. In the nervous system, hnRNPH1 is involved in neurodevelopment, neurodegenerative diseases, and drug addiction and plays an essential role in maintaining neuronal function and homeostasis. Furthermore, it exerts regulatory functions in reproductive system development and fertility and in non-neoplastic pathologies, including cardiovascular diseases, autoimmune disorders, and viral hepatitis. Given its pathophysiological significance, hnRNPH1 has emerged as a promising biomarker and therapeutic target. This review provides an overview of the structural basis and core molecular function of hnRNPH1. Its mechanisms of action and pathological significance in various diseases have also been detailed. Additionally, this review summarizes the current therapeutic strategies targeting hnRNPH1, discusses the associated challenges, outlines optimization approaches, and considers future research directions. Overall, this review aims to deepen our understanding of hnRNPH1 biology and inspire the development of novel diagnostic and therapeutic interventions. Full article

Immunotherapy and chemoimmunotherapy are standard treatments for non-oncogene-addicted advanced non-small cell lung cancer (NSCLC). Currently, a limited number of biomarkers, including programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB), are used in clinical practice to predict benefits from immune checkpoint inhibitors (ICIs). It is therefore necessary to search for novel biomarkers that could be helpful to identify patients who respond to immunotherapy. In this context, research efforts are focusing on different cells and mechanisms involved in anti-tumor immune response. Herein, we provide un updated literature review on the role of eosinophils in cancer development and immune response, and the functions of some cytokines, including IL-31 and IL-33, in eosinophil activation. We discuss available data demonstrating a correlation between eosinophils and clinical outcomes of ICIs in lung cancer. In this context, we underscore the role of absolute eosinophil count (AEC) and tumor-associated tissue eosinophilia (TATE) as promising biomarkers able to predict the efficacy and toxicities from immunotherapy. The role of eosinophils and cytokines in NSCLC, treated with ICIs, is not yet fully understood, and further research may be crucial to determine their role as biomarkers of response. Artificial intelligence, through the analysis of big data, could be exploited in the future to elucidate the role of eosinophils and cytokines in lung cancer. Full article

Background/Objectives: Non-small cell lung cancer (NSCLC) patients without gene driver mutations receive anti-PD1 treatments either as monotherapy or in combination with chemotherapy based on PD-L1 expression in tumor tissue. Anti-PD1 antibodies target various immune system components, perturbing the balance between immune cells and soluble factors. In this study, we identified the immune signatures of NSCLC patients associated with different clinical outcomes through network analysis. Methods: Twenty-seven metastatic NSCLC patients were assessed at baseline for the levels of circulating CD137⁺ T cells (total, CD4⁺, and CD8⁺) via cytofluorimetry, along with 14 soluble checkpoints and 20 cytokines through Luminex analysis. Hierarchical clustering and connectivity heatmaps were executed, analyzing the response to therapy (R vs. NR), performance status (PS = 0 vs. PS > 0), and overall survival (OS < 3 months vs. OS > 3 months). Results: The clustering of immune checkpoints revealed three groups with a significant differential proportion of six checkpoints between patients with PS = 0 and PS > 0 (p < 0.0001). Furthermore, significant pairwise correlations among immune factors evaluated in R were compared to the lack of significant correlations among the same immune factors in NR patients and vice versa. These comparisons were conducted for patients with PS = 0 vs. PS > 0 and OS < 3 months vs. OS > 3 months. The results indicated that NR with PS > 0 and OS ≤ 3 months exhibited an inflammatory-specific signature compared to the contrasting clinical conditions characterized by a checkpoint molecule-based network (p < 0.05). Conclusions: Identifying various connectivity immune profiles linked to response to therapy, PS, and survival in NSCLC patients represents significant findings that can optimize therapeutic choices. Full article