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Notch1 and Notch2, transmembrane receptors belonging to the Notch family, are pivotal mediators of intercellular communication and have profound implications including cell fate determination, embryonic development, and tissue homeostasis in various cellular processes. Despite their structural homology, Notch1 and Notch2 exhibit discrete phenotypic characteristics and functional nuances that necessitate their individualized targeting in specific medical scenarios. Aberrant Notch signaling, often driven by the dysregulated activity of one receptor over the other, is implicated under various pathological conditions. Notch1 dysregulation is frequently associated with T-cell acute lymphoblastic leukemia, whereas Notch2 perturbations are linked to B-cell malignancies and solid tumors, including breast cancer. Hence, tailored therapeutic interventions that selectively inhibit the relevant Notch receptor need to be devised to disrupt the signaling pathways driving the specific disease phenotype. In this review, we emphasize the importance of distinct tissue-specific expression patterns, functional divergence, disease-specific considerations, and the necessity to minimize off-target effects that collectively underscore the significance of "individualized" targeting for Notch1 and Notch2. This comprehensive review sheds light on the receptor-specific characteristics of Notch1 and Notch2, providing insights into their roles in cellular processes and offering opportunities for developing tailored therapeutic interventions in the fields of biomedical research and clinical practice., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The prognosis of adult patients with acute lymphoblastic leukemia (ALL) has improved in the last decades. This has been due to the sum of several factors including more precise recognition of the ALL subtypes, refinement of the assessment of prognostic factors, improvement in pediatric-inspired chemotherapy regimens and especially to the incorporation of novel targeted and immune therapeutics, as well as engineered cellular therapies, among others. These therapies were initially developed for relapsed or refractory patients but are now being incorporated into frontline treatment and represent a major step forward in ALL therapy. This review focuses on the recent advances in ALL characterization and especially on the treatment of ALL in adults.

Metastasis is a major cause of cancer-related deaths. Similar to the tumor microenvironment formation, the premetastatic niche develops in distant organs before the arrival of tumor cells. Elucidating the mechanism(s) underlying premetastatic niche formation could contribute to the establishment of effective therapeutic targets for metastasis. Our research indicates that primary tumors hijack Toll-like receptor 4 (TLR4) signaling to establish a premetastatic niche in the lungs by utilizing an endogenous ligand S100A8. S100A8 is expressed not only in immune cells but also in various types of tumor cells. By focusing on S100A8 as a therapeutic target, we identified at least three multivalent S100A8 inhibitory peptides. Here, we review the tumor-promoting role of S100A8-mediated TLR4 signaling and propose S100A8 as a potential therapeutic target for aggressive cancer., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cancer genomics plays a crucial role in oncology by enhancing our understanding of how genes drive cancer and facilitating the development of improved treatments. This field meticulously examines various cancers' genetic makeup through various methodologies, leading to groundbreaking discoveries. Innovative tools such as rapid gene sequencing, single-cell studies, spatial gene mapping, epigenetic analysis, liquid biopsies, and computational modeling have significantly progressed the field. These techniques uncover genetic alterations, tumor heterogeneity, and the evolutionary dynamics of cancers. Genetic abnormalities and molecular markers that initiate and propagate distinct cancer types are classified according to tumor type. The integration of precision medicine with cancer genomics emphasizes the significance of utilizing genetic data in treatment decision-making, enabling personalized care and enhancing patient outcomes. Critical topics in cancer genomics encompass tumor diversity, alterations in non-coding DNA, epigenetic modifications, cancer-specific proteins, metabolic changes, and the impact of inherited genes on cancer risk., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: Provide the most up-to-date information on the dynamic landscape of antibody-drug conjugates (ADCs) in gynecologic cancers. We discuss the latest research that supports the approved ADCs and outline the ongoing trials and preliminary results that may lead to ADC approvals in the future. Current gaps in knowledge and areas for future research are discussed., Recent Findings: ADCs are rapidly changing the landscape of gynecologic cancer care. Three ADCs are currently FDA approved and used routinely in clinical practice, with many more currently in clinical development. The most common ADC target is folate receptor alpha of which there are 8 different folate receptor targeting ADCs in development. Other targets under investigation include trophoblast cell surface antigen-2 (Trop-2), claudin-6 (CLDN6), cadherin-6 (CDH6), nectin-4, HER-2 and B7-H4. ADCs can cause new and unique adverse effects, including ocular toxicities and interstitial lung disease., Summary: ADCs offer the opportunity for a more effective and personalized treatment approach for gynecologic cancer patients. Side effects must be closely monitored, and preventive measures must be followed to maximize benefit and minimize toxicity. A better understanding of the role of target proteins as biomarkers to predict response to ADCs will be critical for successful clinical implementation of ADCs and further research in this area is necessary., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Kirsten Rat Sarcoma (KRAS) is a potent target for cancer therapy because it acts as a signaling hub, engaging in various signaling pathways and regulating a number of cellular functions like cell differentiation, proliferation, and survival. Recently, an emergency approval from the US-FDA has been issued for KRAS G12C inhibitors (sotorasib and adagrasib) for metastatic lung cancer treatment. However, clinical studies on covalent KRAS G12C inhibitors have rapidly confronted resistance in patients. Many methods are being assessed to overcome this resistance, along with various combinatorial clinical studies that are in process. Moreover, because KRAS G12D and KRAS G12V are more common than KRAS G12C , focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRAS G12C inhibitors., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Despite significant progress in managing multiple myeloma (MM) in recent years, certain patients still have a short duration of therapeutic response, often relapsing within 18 months. These patients typically have high‑risk genetic mutations and may show little to no response to current treatments, highlighting the need for further exploration of optimal therapeutic targets for MM. B‑cell maturation antigen (BCMA), highly expressed in mature B lymphocytes and plasma cells and upregulated in MM, is a promising therapeutic target. Various BCMA‑targeted strategies, including antibody‑drug conjugates, bispecific T‑cell engagers and chimeric antigen receptor T‑cell therapy, are under clinical evaluation to optimize efficacy and safety. This review summarizes the latest clinical updates on these strategies, highlights their effectiveness in MM and relapsed/refractory MM and provides future perspectives and recommendations for overcoming current challenges.

The progression-free-survival ratio is a popular endpoint in oncology trials, which is frequently applied to evaluate the efficacy of molecularly targeted treatments in late-stage patients. Using elementary calculations and simulations, numerous shortcomings of the current methodology are pointed out. As a remedy to these shortcomings, an alternative methodology is proposed, using a marginal Cox model or a marginal accelerated failure time model for clustered time-to-event data. Using comprehensive simulations, it is shown that this methodology outperforms existing methods in settings where the intrapatient correlation is low to moderate. The performance of the model is further demonstrated in a real data example from a molecularly aided tumor trial. Sample size considerations are discussed., (© 2024 The Author(s). Biometrical Journal published by Wiley‐VCH GmbH.)

Background: Breast mucinous carcinoma (MC) is typically positive for estrogen receptor (ER) and progesterone receptor (PR) expressions and negative for human epidermal growth factor receptor (HER2) overexpression. HER2 positive MC is a rare entity; its response to neoadjuvant HER2-targeted therapy remains unclear., Methods: Four cases of HER2 positive MC and seven cases of HER2 positive invasive ductal carcinoma with mucinous features (MCF) were identified. Clinicopathologic features were collected. Patients' germline data was gathered if available. Tumor's response to HER2-directed treatment were recorded and compared., Results: Two HER2 positive MCs were treated with neoadjuvant HER2-directed treatment and showed no response in the subsequent surgical resection specimens including one positive lymph node showing no treatment effect. One patient had upfront surgery. The fourth patient presented with advanced stage and showed progression on HER2-directed treatment. Six HER2 positive MCFs received neoadjuvant HER2-directed therapy; two cases showed complete pathologic response and four had only minimal residual carcinomas in the breast. Two cases with positive lymph nodes had complete response in the lymph nodes. The seventh patient presented at an advanced stage and was stable on HER2-directed treatment., Conclusions: Our findings suggest that HER2 positive MCs may be resistant to HER2-directed treatment. This is in contrast with the excellent treatment response observed in HER2 positive MCFs. It is important to report mucinous carcinoma percentage in biopsies on HER2 positive tumors as it may be related to treatment response. Further investigation of the underlying mechanisms may help optimize clinical management in this patient population., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The discovery of the association between EGFR mutations and the efficacy of EGFR tyrosine-kinase inhibitors (TKIs) has revolutionized the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Currently, third-generation EGFR TKIs, which are often characterized by potent central nervous system penetrance, are the standard-of-care first-line treatment for advanced-stage EGFR-mutant NSCLC. Rational combinations of third-generation EGFR TKIs with anti-angiogenic drugs, chemotherapy, the EGFR-MET bispecific antibody amivantamab or local tumour ablation are being investigated as strategies to delay drug resistance and increase clinical benefit. Furthermore, EGFR TKIs are being evaluated in patients with early stage or locally advanced EGFR-mutant NSCLC, with the ambitious aim of achieving cancer cure. Despite the inevitable challenge of acquired resistance, emerging treatments such as new TKIs, antibody-drug conjugates, new immunotherapeutic approaches and targeted protein degraders have shown considerable promise in patients with progression of EGFR-mutant NSCLC on or after treatment with EGFR TKIs. In this Review, we describe the current first-line treatment options for EGFR-mutant NSCLC, provide an overview of the mechanisms of acquired resistance to third-generation EGFR TKIs and explore novel promising treatment strategies. We also highlight potential avenues for future research that are aimed at improving the survival outcomes of patients with this disease., Competing Interests: Competing interests: S.R.R. works in an institution that receives grant support from AstraZeneca for specific clinical trials. F.Z., H.G., Y.X., X.L., D.S.W.T. and C.Z. declare no competing interests., (© 2024. Springer Nature Limited.)

Molecular targeted cancer therapy is a rapidly developing field, driving progress toward greater treatment efficacy. However, targeted monotherapy often fails due to the development of multidrug resistance in tumors. The combination of multiple targeted agents emerges as a possible solution to enhance treatment outcomes by activating different signaling pathways. This study systematically investigates the combined effect of targeted agents for the oncomarkers HER2 and EpCAM on cancer cells. Specifically, the study examined the impact of anti-HER2 (DARP_9.29-LoPE) and anti-EpCAM (DARP_EC1-LoPE) immunotoxins on a panel of cancer cells expressing various levels of HER2 and EpCAM. Using the Chou-Talalay combination indices, the study revealed that cells with low HER2 expression and high EpCAM expression are not optimal targets for combined HER2/EpCAM therapy. In contrast, the most effective approach involves the usage of an equimolar ratio of immunotoxins for cells exhibiting high HER2 and moderate EpCAM expression, resulting in a synergistic therapeutic effect. These findings provide significant insights into optimizing combination anti-HER2/EpCAM therapies and hold promise for the development of more effective cancer treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This comprehensive review explores the transformative potential of PROTAC (Proteolysis-Targeting Chimeras) therapy as a groundbreaking approach in the landscape of lung cancer treatment. The introduction provides a succinct overview of current challenges in lung cancer treatment, emphasizing the significance of targeted therapies. Focusing on PROTAC therapy, the article elucidates its mechanism of action, comparing it with traditional targeted therapies and highlighting the key components and design principles of PROTAC molecules. In the context of lung cancer, the review meticulously summarizes preclinical evidence, emphasizing efficacy and specificity gleaned from studies evaluating PROTAC therapy. It delves into the implications of this preclinical data, discussing potential advantages over existing targeted therapies. An update on ongoing clinical trials involving PROTAC therapy for lung cancer offers a snapshot of the current progress, with a summary of key outcomes and advancements in early-phase trials. The mechanistic insights into PROTAC therapy's impact on lung cancer cells are explored, alongside a discussion on potential biomarkers for patient stratification and response prediction. The influence of tumor heterogeneity on PROTAC therapy outcomes is also addressed. Safety and tolerability assessments, encompassing preclinical and clinical studies, are comprehensively evaluated, including a comparative analysis with traditional targeted therapies and strategies to mitigate side effects. Looking forward, the article discusses the future perspectives of PROTAC therapy in lung cancer treatment and addresses ongoing challenges, providing a nuanced exploration of potential combination therapies and synergistic approaches. In conclusion, the review summarizes key findings and insights, underscoring the tremendous potential of PROTAC therapy as a promising and innovative avenue in pursuing more effective lung cancer treatments., Competing Interests: Declaration of competing interest We declare no conflicts of interest regarding the publication of this review manuscript entitled "Revolutionizing Lung Cancer Treatment: Introducing PROTAC Therapy as a Novel Paradigm in Targeted Therapeutics." None of the authors have financial or personal relationships with other people or organizations that could potentially influence the work presented in the manuscript. This work has not been submitted to any other journal for consideration. We affirm that the manuscript represents original work, and all sources used have been appropriately cited., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nasopharyngeal carcinoma (NPC) is a distinctive epithelial cancer closely associated with Epstein-Barr Virus (EBV) infection, posing significant challenges in diagnosis and treatment due to its resistance to conventional therapies and high recurrence rates. Current therapies, including radiotherapy and chemotherapy, exhibit limited efficacy, particularly in recurrent or metastatic cases, highlighting the urgent need for novel therapeutic strategies. Targeting EBV oncoproteins, such as Epstein-Barr Virus encoded Nuclear Antigen 1 (EBNA1), Latent Membrane Protein 1 (LMP1), and Latent Membrane Protein 2 (LMP2), presents a promising therapeutic avenue in NPC treatment. This review discusses the latest advancements in drug discovery targeting EBV oncoproteins, emphasizing the identification of inhibitors for specific functional regions of oncoproteins EBNA1, LMP1, and LMP2. Particular attention is given to the molecular mechanisms of these inhibitors and their preclinical or clinical potential in treating EBV-positive NPC. These developments highlight a promising future for targeted therapies in improving outcomes for NPC patients., Competing Interests: Declarations. Competing Interest: The authors declare no competing interests. Ethical approval: This article does not contain studies with human or animal subjects performed by any of the authors., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Alzheimer's disease (AD) is a complex neurodegenerative disorder that currently lacks effective treatment options. This study aimed to identify potential therapeutic targets for the treatment of AD using comprehensive bioinformatics methods and machine learning algorithms. By integrating differential gene expression analysis, weighted gene co-expression network analysis, Mfuzz clustering, single-cell RNA sequencing, and machine learning algorithms including LASSO regression, SVM-RFE, and random forest, five hub genes related to AD, including PLCB1, NDUFAB1, KRAS, ATP2A2, and CALM3 were identified. PLCB1, in particular, exhibited the highest diagnostic value in AD and showed significant correlation with Braak stages and neuronal expression. Furthermore, Noscapine, PX-316, and TAK-901 were selected as potential therapeutic drugs for AD based on PLCB1. This research provides a comprehensive and reliable method for the discovery of AD therapeutic targets and the construction of diagnostic models, offering important insights and directions for future AD treatment strategies and drug development., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Multiple studies have demonstrated that the abundance and functionality of γδ T cells are favorable prognostic indicators for prolonged survival in cancer patients. However, the association between the immunophenotype of circulating γδ T cells and the therapeutic response in NSCLC patients undergoing chemotherapy or targeted therapy remains unclear., Methods: Patients with EGFR wild-type (EGFR-WT) or mutant (EGFR-Mut) non-small cell lung cancer (NSCLC), diagnosed between January 2020 and January 2024, were included in this study. Clinicopathological characteristics, treatment regimens, and follow-up data were retrospectively collected. Peripheral blood samples from 52 NSCLC patients were analyzed for the immunophenotypes of αβ T cells and γδ T cells using full-spectrum flow cytometry., Results: No significant differences were observed in the proportions of αβ T cells or γδ T cells, nor in the expression of immune exhaustion markers, between epidermal growth factor receptor wild-type and mutant NSCLC patients. Notably, NSCLC patients with a high clinical benefit rate (responder, R) exhibited a higher proportion of circulating Vδ2 T cells compared to non-responders (NR), in both EGFR-Mut (NR vs. R, P = 0.0437) and EGFR-WT groups (NR vs. R, P = 0.0180). Additionally, the expression of the immune exhaustion marker PD-1 on Vδ2 T cells was significantly lower in the responder group (NR vs. R, EGFR-Mut, P = 0.0050; EGFR-WT, P = 0.0180). Moreover, responder patients exhibited elevated levels of TNF-α compared to non-responders, irrespective of EGFR mutation status (NR vs. R, EGFR-Mut, P = 0.0055; EGFR-WT, P = 0.0007)., Conclusions: These findings collectively suggest that circulating Vδ2 T cells with low levels of immune exhaustion are critical contributors to the effectiveness of chemotherapy and targeted therapies in NSCLC. Targeting Vδ2 T cells may represent a promising strategy for enhancing therapeutic clinical benefit rates in NSCLC patients., Competing Interests: Declarations. Ethics approval and consent to participate: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Research Ethics Committee of the First Affiliated Hospital, Jinan University, Guangzhou, China and the need of informed consent for this study was exempted in the ethical approval documents (approval numbers KY-2020-10 and KY-2020-11). Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Oxidative stress is key in inflammatory airway diseases. Heme oxygenase 1 (HMOX1) regulates oxidative stress, but its role in airway diseases needs exploration., Methods: Differentially expressed genes (DEGs) between healthy nasal mucosa and chronic rhinosinusitis with nasal polyps (CRSwNP) were identified from Gene Expression Omnibus (GEO). Candidate genes were further screened using Gene Set Enrichment Analysis (GSEA) and Random Forest (RF) algorithms. Causal inference between candidate genes and upper and lower airway diseases (CRSwNP, allergic rhinitis (AR), and asthma (AS)) was conducted using bidirectional two-sample Mendelian randomization (TwoSampleMR) analysis. Single-cell RNA sequencing (scRNA-seq) data were used to determine the cellular localization and intercellular interactions of candidate genes. Molecular docking was used to identify potential therapeutic agents., Results: HMOX1 expression was significantly elevated in CRSwNP. TwoSampleMR analysis indicated a negative causal relationship between HMOX1 exposure and the occurrence of upper and lower airway diseases (CRSwNP [(odds ratio (OR)/95% confidence interval (CI): 0.945/(0.893-0.999), P = 0.044], AR [OR/95% CI: 0.997/(0.994-0.999), P = 0.007], and AS [OR/95% CI: 0.935/(0.895-0.977), P = 0.003]). scRNA-seq data revealed HMOX1 localization in M2 macrophages. Molecular docking identified 15 antioxidants, including Acetylcysteine and Quercetin, that can upregulate HMOX1 expression., Conclusion: HMOX1 may have a protective role in the pathogenesis of upper and lower airway diseases (CRSwNP, AR, and AS) by modulating oxidative stress. Antioxidants that increase HMOX1 expression could offer new therapeutic avenues for these diseases., Clinical Trial: Not applicable., Competing Interests: Declarations. Ethics approval and consent to participate: All experimental protocols were approved by the Ethics Committee of Union Hospital (wuhan union hospital), Tongji Medical College, Huazhong University of Science and Technology (UHCT-IEC-SOP-016-03-01). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Osteoarthritis (OA) is a chronic joint condition affecting millions worldwide, characterized by the gradual degeneration of joint cartilage, leading to pain, stiffness, and functional impairment. Although the pathogenesis of OA is not fully understood, the roles of inflammation, metabolic dysregulation, and biomechanical stress are increasingly recognized. Current treatments, including pharmacotherapy, physical therapy, and surgical interventions, aim to alleviate symptoms and improve quality of life, yet they face limitations and challenges. In recent years, researchers have explored a variety of new treatment strategies, such as molecular targeted therapy, biologic treatments, regenerative medicine, and lifestyle modifications, aiming to directly address the root causes and complex mechanisms of OA. This review aims to summarize the latest research advancements to provide fresh perspectives for clinical treatment and lay the foundation for future research and development of treatment strategies for OA., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2025 the Author(s). Published by Wolters Kluwer Health, Inc.)

Osteoporosis is a systemic skeletal disorder characterized by reduced bone density and an increased risk of fractures, particularly prevalent in the aging population. Osteoporotic complications, including vertebral compression fractures, hip fractures, and distal forearm fractures, affect over 8.9 million individuals globally, placing a significant economic strain on healthcare systems. Recent advances have expanded our understanding of the mechanisms underlying osteoporosis, particularly the intricate regulatory networks involved in bone metabolism. A central player in these processes is ubiquitin-mediated proteasomal degradation, a crucial post-translational modification system that involves ubiquitin, the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), ubiquitin ligase (E3), deubiquitinating enzymes, and the proteasome. Among the various E3 ligases, the NEDD4 family has emerged as a key regulator of both bone development and osteoporotic pathology. This review delineates the role of NEDD4 family in osteoporosis and identifies potential drug targets within these pathways, offering insights into novel therapeutic approaches for osteoporosis through targeted intervention., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Conflict of interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2025. The Author(s).)

Background: Nasopharyngeal carcinoma (NPC) is one of the most common head and neck cancers worldwide. The majority of the new cases were from Asia and are the leading cause of cancer in China. The main treatment is surgery and radiotherapy with chemotherapy for advanced cases. With the advancement of targeted therapies, the objective of this study was to investigate the efficacy and safety of targeted therapies in NPC., Methods: Databases were searched from inception to Aug 2023, comparing molecular targeted therapies (MTT) with conventional chemotherapy, chemotherapy or surgery. Study screening, data extraction, and data analysis were conducted independently by two investigators. The Cochrane Risk of Bias tool 1.0 was used for the quality of the studies., Results: There was a total of ten eligible studies with 471 participants in the treatment arm and 469 participants in the control arm. Most studies had an unclear risk of bias assessment. Upon network meta-analysis, cetuximab was found to be the most effective regimen for complete response (CR), bevacizumab was found to be the most effective regimen for partial response (PR), nimotuzumab was found to be the most effective regimen for overall survival rate (OS) and progression-free survival (PFS). Pairwise meta-analysis showed that MTT had a significantly better response than conventional therapies in complete response. GRADE analysis reported low certainty of evidence for CR and very low certainty of evidence for other efficacy outcomes. There was a higher chance of bleeding with MTT and was statistically significant., Conclusion: It was observed that targeted therapies were found to be a promising strategy for NPC especially recurrent and/or metastatic NPC, but the most appropriate therapy still needs to be evaluated., Trial Registration: This study was registered with the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY) with a registration number of INPLASY202380024., Competing Interests: Declarations. Ethics approval and consent to participate: Not relevant. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Liver cancer, and in particular hepatocellular carcinoma (HCC) is a disease of rising prevalence and incidence. To date, definitive treatment options include either surgical excision or ablation of the affected area. With increasing research on several pathways that could be involved in the progression of HCC, new elements within these pathways emerge as potential targets for novel therapies. The WNT/β-catenin pathway favors the presence of M2 tumor-associated macrophages which in turn promote tumor growth and metastasis. The inhibition of this pathway is considered a good candidate for such targeted therapeutic interventions. Interestingly, as Huang et al show in their recently published article, Calculus bovis which is used in traditional Chinese medicine can exert an inhibitory effect on the β-catenin pathway and become a potential candidate for targeted pharmacotherapy against liver cancer., Competing Interests: Conflict-of-interest statement: The authors have nothing to disclose., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

Systemic sclerosis (SSc) is considered a rare autoimmune disease in which there are alterations of both the innate and adaptive immune response resulting in the production of autoantibodies. Abnormalities of the immune system compromise the normal function of blood vessels leading to a vasculopathy manifested by Raynaud's phenomenon, an early sign of SSc . As a consequence of this reactive picture, the disease can evolve leading to tissue fibrosis. Several SSc-specific autoantibodies are currently known and are associated with specific clinical manifestations and prognosis. Although the pathogenetic role of these autoantibodies is still unclear, their production by B cells and plasma cells suggests the importance of these cells in the development of SSc. This review narratively examines B-cell dysfunctions and their role in the pathogenesis of SSc and discusses B-cell-targeted therapies currently used or potentially useful for the management of end-organ complications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)

Small cell lung cancer (SCLC) is an intractable disease with rapid progression and high mortality, presenting a persistent obstacle impeding clinical management. Although recent advancements in immunotherapy have enhanced the response rates of platinum-based chemotherapy regimens, the emergence of acquired resistance invariably leads to recurrence and metastasis. Consequently, there is an urgent necessity to explore novel therapeutic targets and optimize existing treatment strategies. This article comprehensively reviews the currently available therapeutic modalities for SCLC. It delves into the immunologic prognostic implications by analyzing selected immune-related signatures. Moreover, it conducts an in-depth exploration of the molecular subtyping of SCLC and the associated molecular pathways to identify potential therapeutic targets. Specifically, the focus is on clinical interventions targeting delta-like ligand 3 (DLL3), elucidating its resistance mechanisms and demonstrating its notable antitumor efficacy. Furthermore, the study examines the mechanisms of chimeric antigen receptor (CAR) T and antibody-drug conjugate (ADC), covering resistance issues and strategies for optimizing resistance management, with particular emphasis being placed on analyzing the prospects and clinical value of CAR T therapy in the context of SCLC. Moreover, the effectiveness of poly ADP-ribose polymerase and ataxia telangiectasia and rad3/checkpoint kinase 1 inhibitors is discussed and underscores the advantages of combining these inhibitors with standard chemotherapy to combat chemoresistance and enhance the antitumor effects of immunotherapies. Overall, this study investigates emerging strategies for targeted therapies and optimized combination regimens to overcome resistance in SCLC and highlights future strategies for new therapeutic technologies for SCLC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Endometrial Cancer (EC) is one of the most common gynecological malignancies, ranking first in developed countries and regions. The occurrence and development of EC is closely associated with genetic mutations. TP53 mutation, in particular, can lead to the dysfunction of numerous regulatory factors and alteration of the tumor microenvironment (TME). The changes in the TME subsequently promote the development of tumors and assist in immune escape by tumor cells, making it more challenging to treat EC and resulting in a poor prognosis. Therefore, it is important to understand the effects of TP53 mutation in EC and to conduct further research in relation to the targeting of TP53 mutations. This article reviews current research progress on the role of TP53 mutations in regulating the TME and in the mechanism of EC tumorigenesis, as well as progress on drugs that target TP53 mutations., (© 2025 The Author(s). Published by IMR Press.)

Dipeptidyl peptidase 4 (DPP4) is a serine protease widely distributed in membrane-bound and soluble forms in various tissues and organs throughout the body. DPP4 plays a role in inflammation, immune regulation, cell growth, migration and differentiation. The role of DPP4 in tumors has garnered increasing attention. Previous research has demonstrated that DPP4 contributes to the promotion of cancer in most cancers, and it may play a specific biological function through the variation in tumor cell types and expression forms. However, the expression of DDP4 in different tumor types and its specific mechanism remains unclear. In this review, we describe the structure of DPP4, summarize the recent research progress of its expression and potential mechanisms in common tumors, and discuss the development prospects of DPP4 inhibitors in tumor therapy. Although current research emphasizes the potential of DPP4 as a drug target, the incomplete understanding of its regulatory mechanisms impedes the discovery and development of new therapies against it. Further research on DPP4-related tumors is anticipated to promote its clinical application as a potential therapeutic target., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Hepatocellular carcinoma (HCC) is a global health issue due to its late diagnosis and high recurrence rate. The early detection and diagnosis of HCC with specific and sensitive biomarkers and using novel treatment approaches to improve patient outcomes are essential. Glypican-3 (GPC-3) is a cell surface proteoglycan that is overexpressed in many tumors, including HCC. GPC-3 could be used as a specific biomarker for HCC early detection and could be a potential target for precise therapeutic strategies. Effective identification of GPC-3 could improve both diagnosis and targeted therapy of HCC. Moreover, targeted therapy using GPC-3 could result in a better treatment outcome. Recently, GPC3-targeted therapies have been used in different investigational therapeutic approaches like bi-specific/monoclonal antibodies, peptide vaccines, and CAR T cell therapies. This study aims to highlight the theranostic potential of GPC-3 as a novel biomarker for early detection and as a potential molecular target for HCC treatment as well., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neurodegenerative disorders are characterized by a progressive decline of specific neuronal populations in the brain and spinal cord, typically containing aggregates of one or more proteins. They can result in behavioral alterations, memory loss and a decline in cognitive and motor abilities. Various pathways and mechanisms have been outlined for the potential treatment of these diseases, where redox regulation is considered as one of the most common druggable targets. For example, in amyotrophic lateral sclerosis (ALS) with superoxide dismutase-1 (SOD1) pathology, there is a downregulation of the antioxidant response nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. TDP-43 proteinopathy in ALS is associated with elevated levels of reactive oxygen species and mitochondrial dyshomeostasis. In ALS with mutant FUS, poly ADP ribose polymerase-dependent X ray repair cross complementing 1/DNA-ligase recruitment to the sites of oxidative DNA damage is affected, thereby causing defects in DNA damage repair. Oxidative stress in Huntington's disease (HD) with mutant huntingtin accumulation manifests as protein oxidation, metabolic energetics dysfunction, metal ion dyshomeostasis, DNA damage and mitochondrial dysfunction. The impact of oxidative stress in the progression of these diseases further warrants studies into the role of antioxidants in their treatment. While an antioxidant, edaravone, has been approved for therapeutics of ALS, numerous antioxidant molecules failed to pass the clinical trials despite promising initial studies. In this review, we summarize the oxidative stress pathways and redox modulators that are investigated in ALS and HD using various models., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats., Competing Interests: Declarations. Ethics approval and consent to participate: Not Applicable. Consent for publication: We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all the authors. All figures are original and were drawn using BioRender by the authors for this review. Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work in this paper. M.H.A. is founder, shareholder and scientific advisor of IO Biotech ApS. LMC is a consultant for Evergreen Theragnostics. S.K. has consulted for Telix Pharmaceuticals Ltd., acknowledges support for investigator services from RayzeBio and holds the following patent: PCT/US2021/039418 (THOR cell (tumor homing radio-emitting cell)., (© 2025. The Author(s).)

Tumor-agnostic US Food and Drug Administration approvals are transforming oncology. They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAF V600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms. The genomically driven tissue-agnostic approach has a strong biological rationale (cancer is a disease of the genome), yields remarkably high response rates, and provides drug access to patients with an unmet need (rare/ultra-rare malignancies). Despite the solid tumor focus, both solid and hematologic cancers can harbor identical driver molecular abnormalities and respond to cognate therapies. For example, BRAF V600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers., Competing Interests: Declaration of interests J.J.A. serves on the advisory board of CureMatch, Inc., and as a consultant for Datma. J.L.M. has served as a consultant for Pharmacyclics/Abbvie, Bayer, Gilead/Kite, Beigene, Pfizer, Janssen, Celgene/BMS, Kyowa, Alexion, Fosunkite, Seattle Genetics, Karyopharm, Aurobindo, Verastem, Genmab, Genentech/Roche, ADC Therapeutics, Epizyme, Beigene, Novartis, Morphosys/Incyte, MEI, TG Therapeutics, AstraZeneca, and Eli Lilly; received research funding from Bayer, Gilead/Kite, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, Millennium, Novartis, and Beigene; and received honoraria from Targeted Oncology, OncView, Curio, Physicians' Education Resource, and Seattle Genetics. R.K. has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, TopAlliance, and the NCI; has received consultant and/or speaker fees and/or served on an advisory board/acted as a consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, and X-Biotech; has equity interest in CureMatch, Inc., and IDbyDNA; serves on the boards of CureMatch and CureMetrix; and is a co-founder of CureMatch., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pescadillo ribosomal biogenesis factor 1 (PES1), a nucleolar protein initially identified in zebrafish, plays an important role in embryonic development and ribosomal biogenesis. Notably, PES1 has been found to be overexpressed in a number of cancer types, where it contributes to tumorigenesis and cancer progression by promoting cell proliferation, suppressing cellular senescence, modulating the tumor microenvironment (TME) and promoting drug resistance in cancer cells. Moreover, recent emerging evidence suggests that PES1 expression is significantly elevated in the livers of Type 2 diabetes mellitus (T2DM) and obese patients, indicating its involvement in the pathogenesis of metabolic diseases through lipid metabolism regulation. In this review, we present the structural characteristics and biological functions of PES1, as well as complexes in which PES1 participates. Furthermore, we comprehensively summarize the multifaceted role of PES1 in various diseases and the latest insights into its underlying molecular mechanisms. Finally, we discuss the potential clinical translational perspectives of targeting PES1, highlighting its promising as a therapeutic intervention and treatment target., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: More than a decade following the discovery of Calreticulin (CALR) mutations as drivers of myeloproliferative neoplasms (MPN), advances in the understanding of CALR-mutant MPN continue to emerge. Here, we summarize recent advances in mehanistic understanding and in targeted therapies for CALR-mutant MPN., Recent Findings: Structural insights revealed that the mutant CALR-MPL complex is a tetramer and the mutant CALR C-terminus is exposed on the cell surface. Targeting mutant CALR utilizing antibodies is the leading therapeutic approach, while mutant CALR-directed vaccines are also in early clinical trials. Additionally, chimeric antigen receptor (CAR) T-cells directed against mutant CALR are under evaluation in preclinical models. Approaches addressing the cellular effects of mutant CALR beyond MPL-JAK-STAT activation, such as targeting the unfolded protein response, proteasome, and N-glycosylation pathways, have been tested in preclinical models. In CALR-mutant MPN, the path from discovery to mechanistic understanding to direct therapeutic targeting has advanced rapidly. The longer-term goal remains clonally-selective therapies that modify the disease course in patients., Competing Interests: Declarations. Competing Interests: In the last 24 months, AM has received research funding from Relay and Morphic and consulted for Morphic, BioMarin, Protagonist, Incyte, Nuvalent, PharmaEssentia and Cellarity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Colorectal cancer (CRC) is a prevalent malignancy with high morbidity and mortality rates globally. Advances in single-cell sequencing technology have enabled comprehensive analyses of tumor cells at single-cell resolution, providing valuable insights into the molecular mechanisms underlying CRC initiation and progression. In this study, we integrated single-cell sequencing data with the TCGA database to identify key molecular pathways involved in CRC pathogenesis. Our analysis revealed that dysregulation of phospholipid metabolism, particularly sphingolipid metabolism, plays a crucial role in CRC development. Specifically, we observed aberrant expression of genes involved in sphingolipid biosynthesis and degradation, as well as altered levels of various sphingolipid metabolites in CRC cells. Furthermore, we identified several potential therapeutic targets, including SMPD1 , GLTP , B3GALT4 , and ST8SIA6 , within the sphingolipid metabolism pathway that could be exploited for the development of novel CRC treatments. Overall, our findings provide novel insights into the molecular mechanisms underlying CRC and highlight the importance of targeting phospholipid metabolism, specifically sphingolipid metabolism, as a potential therapeutic strategy for CRC., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cancer remains a leading cause of mortality globally and a major health burden, with chemotherapy often serving as the primary therapeutic option for patients with advanced-stage disease, partially compensating for the limitations of non-curative treatments. However, the emergence of chemotherapy resistance significantly limits its efficacy, posing a major clinical challenge. Moreover, heterogeneity of resistance mechanisms across cancer types complicates the development of universally effective diagnostic and therapeutic approaches. Understanding the molecular mechanisms of chemoresistance and identifying strategies to overcome it are current research focal points. This review provides a comprehensive analysis of the key molecular mechanisms underlying chemotherapy resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular drug metabolism, and the role of cancer stem cells (CSCs). We also examine specific causes of resistance in major cancer types and highlight various molecular targets involved in resistance. Finally, we discuss current strategies aiming at overcoming chemotherapy resistance, such as combination therapies, targeted treatments, and novel drug delivery systems, while proposing future directions for research in this evolving field. By addressing these molecular barriers, this review lays a foundation for the development of more effective cancer therapies aimed at mitigating chemotherapy resistance., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no conflict of interest., (© 2025. The Author(s).)

Ovarian cancer remains the most lethal gynecological malignancy. Despite the approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target the pivotal hallmarks of cancer. This review is giving an updated overview of innovative and upcoming therapies for the treatment of ovarian cancer that focuses specific on the hallmarks of cancer. The hallmarks of cancer constitute a broad concept to reenact complexity of malignancies and furthermore identify possible targets for new treatment strategies. For this purpose, we analyzed approvals and current clinical phase III studies (registered at ClinicalTrials.gov (National Library of Medicine, National Institutes of Health; U.S. Department of Health and Human Services, 2024)) for new drugs on the basis of their mechanisms of action and identified new target approaches. A broad spectrum of new promising drugs is currently under investigation in clinical phase III studies targeting mainly the hallmarks "self-sufficiency in growth signals," "genomic instability," and "angiogenesis." The benefit of immune checkpoint inhibitors in ovarian cancer has been demonstrated for the first time. Besides, targeting the tumor microenvironment is of growing interest. Replicative immortality, energy metabolism, tumor promoting inflammation, and the microbiome of ovarian cancer are still barely targeted by drugs. Nevertheless, precision medicine, which focuses on specific disease characteristics, is becoming increasingly important in cancer treatment., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis. Recent advances in targeted therapies have opened new avenues for intervention in PDAC, focusing on key genetic and molecular pathways that drive tumor progression., Methods: In this review, we provide an overview on advances in novel targeted therapies in pancreatic adenocarcinoma., Results: Here, we explore the latest development in targeting the KRAS pathway, a historically "undruggable" target crucial to PDAC pathogenesis. Strategies to inhibit KRAS include direct KRAS-targeted therapies, modulation of upstream and downstream signaling, KRAS-specific siRNA, and novel combination therapies integrating KRAS inhibitors with immune checkpoint blockade, PARP inhibitors, chemotherapy, CDK4/6 inhibitors, and autophagy modulators. Beyond KRAS, emerging targets such as NRG1 fusions, NTRK/ROS1 fusions, RET alterations, and the PRMT5/CDKN2A/MAT2A axis, along with EGFR and Claudin18.2 inhibitors, are also discussed as promising therapeutic strategies. Additionally, the review highlights novel approaches for microsatellite instability-high (MSIH) PDAC and emerging therapies, including adoptive cell therapies (CAR-T, TCR, TIL), cancer vaccines, and strategies to modify the tumor microenvironment., Conclusion: Overall, the rapid evolution of targeted therapies offers renewed optimism in the fight against pancreatic cancer, a malignancy with historically poor outcomes., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Colorectal cancer (CRC) is a heterogeneous group of diseases comprising several molecular subtypes. Comprehensive DNA sequencing is now standard practice to identify these subtype. Until recently, KRAS mutation status in metastatic CRC was primarily used as a biomarker to predict resistance to EGFR inhibition. However, with up to 40% of CRC cases harboring KRAS mutations, therapeutic targeting of RAS has been an area of great need. The development of KRASG12C inhibitors has led to the FDA approval of drugs for treating non-small cell lung cancer. Recently, these and other newly developed inhibitors have been investigated as monotherapies and in combination for metastatic KRASG12C-mutant CRC. This review examines the development of these inhibitors and highlights data supporting the inclusion of sotorasib and adagrasib, in combination with either panitumumab or cetuximab, in the NCCN Guidelines for CRC for the treatment of refractory metastatic disease.

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide [...].

Extramammary Paget disease (EMPD) is a rare skin cancer that typically occurs in the anogenital area of older people. Since efficacy of treatments for metastatic or unresectable EMPD remains poor, development of a novel therapeutic approach is strongly desired. However, the lack of EMPD models has hampered investigation of EMPD. Here we investigated whether trophoblast cell surface antigen 2 (TROP2) could be a promising therapeutic target for EMPD. We retrospectively collected 108 samples from 54 patients with primary and metastatic EMPD from 10 Japanese institutions, and compared TROP2 expression between primary and metastatic lesions of each paired sample. In vitro assays were performed using a newly established EMPD cell line, KS-EMPD-1. TROP2 was strongly and homogeneously expressed in patient tissues, regardless of primary or metastatic lesions. The KS-EMPD-1 cells were treated with a TROP2-targeted antibody-drug conjugate (ADC), sacituzumab govitecan, and it significantly reduced cell viability in a dose-dependent manner compared with that of the cells treated with sacituzumab alone. Knockdown of TROP2 reduced cell viability and cell migration, and caused slight upregulation of the apoptosis-related factors, together with downregulation of the epithelial-to-mesenchymal transition-related factors. These findings suggest that a TROP2-targeted ADC may be a promising treatment option for unresectable EMPD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Progressive multiple sclerosis (MS) represents the worsening phase of the disease, characterized by increasing neurodegeneration and disability and mainly refractory to current treatments. Finding therapeutic options remains challenging partially not only because of the lack of understanding of pathogenic mechanisms but also because the early dogma was centered on neuroinflammation, overshadowing the critical role of the tissue repair process. The tissue repair target should start early in disease development, and therapeutic strategies for progressive MS should combine anti-inflammatory and neuroprotective aspects. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, has shed light on some ligand receptor pairs, such as growth-arrest-specific 6 (GAS6)/protein tyrosine kinase receptor (TYRO3) and protein S (PROS1)/AXL receptor tyrosine kinase (AXL), required to dampen inflammation, promote tissue repair, and engage remyelination. Understanding the role of these proteins in the early stages of MS is a critical step toward preventing or stopping neurodegeneration. Herein, we will discuss the receptor/ligand pairs that might be targetable for therapeutic intervention in progressive MS. SIGNIFICANCE STATEMENT: The aim for progressive multiple sclerosis treatment should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. Targeting the TYRO3, AXL, and MER tyrosine kinase receptor (TAM) signaling axis, particularly as growth-arrest-specific 6/TYRO3 and protein S/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients in the early stages of progressive multiple sclerosis., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

There has been over 130 years of research into the treatment of breast cancer using approaches that target oestrogen receptor signalling. Here, we summarise the development of the key pillars of such endocrine therapy, namely, oestrogen deprivation, achieved through ovarian suppression and/or aromatase inhibition, and oestrogen receptor blockade, through selective oestrogen receptor modulators, downregulators and novel compounds entering early phase development. The translation of these compounds from advanced to early breast cancer settings is discussed with a focus on the placebo-controlled breast cancer prevention studies to most accurately describe the side effect profiles of the main approaches., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

HER2-positive (+) breast cancer is an aggressive disease with poor prognosis, a narrative that changed drastically with the advent and approval of trastuzumab, the first humanized monoclonal antibody targeting HER2. In addition to another monoclonal antibody, more classes of HER2-targeted agents, including tyrosine kinase inhibitors, and antibody-drug conjugates were developed in the years that followed. While these potent therapies have substantially improved the outcome of patients with HER2+ breast cancer, resistance has prevailed as a clinical challenge ever since the arrival of targeted agents. Efforts to develop new treatment regimens to treat/overcome resistance is futile without a primary understanding of the mechanistic underpinnings of resistance. Resistance could be attributed to mechanisms that are either specific to the tumor epithelial cells or those that emerge through changes in the tumor microenvironment. Reactivation of the HER receptor layer due to incomplete blockade of the HER receptor layer or due to alterations in the HER receptors is one of the major mechanisms. In other instances, resistance may occur due to deregulations in key downstream signaling such as the PI3K/AKT or RAS/MEK/ERK pathways or due to the emergence of compensatory pathways such as ER, other RTKs, or metabolic pathways. Potent new targeted agents and approaches to target key actionable drivers of resistance have already been identified, many of which are in early clinical development or under preclinical evaluation. Ongoing and future translational research will continue to uncover additional therapeutic vulnerabilities, as well as new targeted agents and approaches to treat and/or overcome anti-HER2 treatment resistance., (© 2025. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

The tumor microenvironment (TME) is involved in cancer initiation and progression. With advances in the TME field, numerous therapeutic approaches, such as antiangiogenic treatment and immune checkpoint inhibitors, have been inspired and developed. Nevertheless, the sophisticated regulatory effects on the biological balance of the TME remain unclear. Decoding the pathological features of the TME is urgently needed to understand the tumor ecosystem and develop novel antitumor treatments. Protein serine/threonine phosphatases (PSPs) are responsible for inverse protein phosphorylation processes. Aberrant expression and dysfunction of PSPs disturb cellular homeostasis, reprogram metabolic processes and reshape the immune landscape, thereby contributing to cancer progression. Some therapeutic implications, such as the use of PSPs as targets, have drawn the attention of researchers and clinicians. To date, the effects of PSP inhibitors are less satisfactory in real-world practice. With breakthroughs in sequencing technologies, scientists can decipher TME investigations via multiomics and higher resolution. These benefits provide an opportunity to explore the TME in a more comprehensive manner and inspire more findings concerning PSPs in the TME. The current review starts by introducing the canonical knowledge of PSPs, including their members, structures and posttranslational modifications for activities. We then summarize the functions of PSPs in regulating cellular homeostasis. In particular, we specified the up-to-date roles of PSPs in modulating the immune microenvironment, adopting hypoxia, reprogramming metabolic processes, and responding to extracellular matrix remodeling. Finally, we introduce preclinical PSP inhibitors with translational value and conclude with clinical trials of PSP inhibitors for cancer treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Abstract: There is major interest in deintensifying therapy for isocitrate dehydrogenase-mutant low-grade gliomas, including with single-agent cytostatic isocitrate dehydrogenase inhibitors. These efforts need head-to-head comparisons with proven modalities, such as chemoradiotherapy. Ongoing clinical trials now group tumors by intrinsic molecular subtype, rather than classic clinical risk factors. Advances in imaging, surgery, and radiotherapy have improved outcomes in low-grade gliomas. Emerging biomarkers, targeted therapies, immunotherapy, radionuclides, and novel medical devices are a promising frontier for future treatment. Diverse representation in glioma research and clinical trials will help to ensure that advancements in care are realized by all groups., Competing Interests: Conflicts of Interest and Source of Funding: M.P.M. reported receiving personal fees from Xoft, Novocure, Kazia, Telix, and Zap and stock ownership in Chimerix. C.J.K. has disclosed that he has no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2025 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Many patients with cancer exhibit primary or rapid secondary resistance to targeted therapy (TT). We hypothesized that a higher number of altered oncogenic signaling pathways [pathway alteration load (PAL)] would reduce the benefit of TT which only intervenes in one pathway. This hypothesis was tested in the Drug Rediscovery Protocol (DRUP)., Patients and Methods: DRUP is a prospective, pan-cancer, non-randomized clinical trial (NCT02925234) that treats patients with therapy-refractory metastatic cancer and an actionable molecular profile using matched off-label targeted and immunotherapies. All patients treated with TT with available clinical outcomes and whole genome sequencing were included. PAL was determined based on driver gene alterations and correlated with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Outcomes were validated in the independent Hartwig Medical database of metastatic cancers., Results: In 154 patients treated with TT, the median PAL was 3. Patients with a PAL below median (n = 60) demonstrated a higher CBR (41.7% versus 25.5%, odds ratio 0.48, P = 0.051), longer PFS [median 4.7 versus 2.9 months, adjusted hazard ratio (aHR) 1.70, P = 0.020] and OS (median 13.7 versus 5.6 months, aHR 3.80, P < 0.001) compared with those with PAL ≥3. Two hundred and fifty-eight patients in the Hartwig database showed similar results for CBR (54.2% versus 36.7%, odds ratio 2.04, P = 0.009) and PFS (7.0 versus 4.2 months, aHR 1.55, P = 0.009)., Conclusions: In our population, PAL emerged as a pan-cancer determinant of outcome to TT. Our findings support refined patient selection for TT and highlight the rationale for combinatorial treatment strategies in patients with multiple affected pathways., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6) are important regulators of the cell cycle. Selective CDK4/6 small-molecule inhibitors have shown clinical activity in hormonal receptor-positive (HR + ) metastatic breast cancer, but their effectiveness remains limited in other cancer types. CDK4/6 degradation and improved selectivity across CDK paralogs are approaches that could expand the effectiveness of CDK4/6 targeting. Recent studies also suggest the use of CDK4/6-targeting agents in cancer immunotherapy. In this Review, we highlight recent advancements in the mechanistic understanding and development of pharmacological approaches targeting CDK4/6. Collectively, these developments pose new challenges and opportunities for rationally designing more effective treatments., Competing Interests: Competing interests: X.W. and P.I.P. hold a patent on CDK4/6-directed degradation (WO/2018/106870). P.I.P reports research funding to his institution by Verastem Oncology and Enliven Therapeutics for projects unrelated to this work and consulting fees from Nuvalent, Blueprint Medicines, Belharra Therapeutics and Fore-Bio. E.G. reports compensation for consulting or equity ownership from BaxGen Therapeutics, BeanPod Biosciences, Comorin Therapeutics, Life Biosciences and Stelexis Biosciences for projects unrelated to this work. All other authors declare no competing interests., (© 2025. Springer Nature America, Inc.)

Cancers affecting women, such as breast, uterine, ovarian, endometrial, and cervical cancers, have become increasingly prevalent. The growing incidence and death rates associated with these cancers warrant the development of innovative and alternative approaches to current treatments. This article investigates the association of women's cancers with a molecular target known as protease-activated receptor 2 (PAR2), a G protein-coupled receptor that is expressed on the surface of cancer cells. Expression levels of the PAR2 gene were curated from publicly available databases, and PAR2 was found to be significantly overexpressed in tissues from patients with breast, uterine, ovarian, endometrial, or cervical cancer compared with normal tissues. PAR2 overexpression has been previously linked to tumor progression and, in some cases, tumor growth. Activation of PAR2 by either endogenous proteases or synthetic agonists triggers certain downstream intracellular signaling pathways that have been associated with tumor progression, cell migration and invasion, angiogenesis, and apoptosis of cancer cells. Although recent advances have led to identification of several PAR2 antagonists, none has yet been developed for human use. Additionally, PAR2 inhibition has been shown to increase the efficacy of chemotherapeutic drugs, allowing them to be potentially used at less toxic doses in combination therapies for cancer. The present work briefly summarizes the current status of PAR2 as a potential therapeutic target for treating women's cancers. SIGNIFICANCE STATEMENT: This article highlights potential roles for protease-activated receptor 2 (PAR2) in cancers affecting women. Overexpression of the PAR2 gene in women's cancers is associated with various oncogenic processes, such as tumor progression, cell migration, and invasion, ultimately contributing to poorer patient prognoses. Given the increasing incidence of women's cancers, there is an urgent need to develop novel therapeutic drugs, and PAR2 represents a promising target for developing new treatments., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Molecular docking is a structure-based computational technique that plays a major role in drug discovery. Molecular docking enhances the efficacy of determining the metabolic interaction between two molecules, i.e., the small molecule (ligand) and the target molecule (protein), to find the best orientation of a ligand to its target molecule with minimal free energy in forming a stable complex. By stimulating drug-target interactions, docking helps identify small molecules that might inhibit cancer-promoting proteins, aiding in the development of novel targeted therapies. Molecular docking enables researchers to screen vast reorganization, identifying potential anti-cancer drugs with enhanced specificity and reduced toxicity. The growing importance of molecular docking underscores its potential to revolutionize cancer treatment by accelerating the identification of novel drugs and improving clinical outcomes. As a wide approach, this computational drug design technique can be considered more effective and timesaving than other cancer treatment methods. In this review, we showcase brief information on the role of molecular docking and its importance in cancer research for drug discovery and target identification. Therefore, in recent years, it can be concluded that molecular docking can be scrutinized as one of the novel strategies at the leading edge of cancer-targeting drug discovery.

Circulating tumor DNA (ctDNA) consists of DNA fragments released from cancer cells into the blood circulation with quick clearance. Analysis of ctDNA can enable real-time assessment of the presence of cancer cells and their genomic characteristics. Therefore, ctDNA is expected to be one of the most useful biomarkers for cancer. In recent years, several ultra-sensitive assays for ctDNA analysis have been developed, and many clinical trials are using these assays to investigate the efficacy of ctDNA-based therapeutic strategies. In the perioperative phase, real-time identification of minimal residual disease at the molecular level with ctDNA analysis can help evaluate the risk of recurrence to inform escalation or de-escalation of perioperative drug therapy. Many trials have examined whether therapeutic strategies using ctDNA analysis to predict treatment efficacy or resistance to molecular targeted agents can improve prognosis in metastatic breast cancer. In this review, we discuss the most recent ctDNA assays, the significance of introducing ctDNA assays to clinical practice, and the research on their application in perioperative and metastatic phases., Competing Interests: Declarations. Conflict of interest: T.Y. received honoraria from Pfizer, Chugai, Eli Lilly, MSD, Astra Zeneca, Kyowa-Kirin and Eisai. Research involving human participants: Not applicable. Informed consent: For this type of study, formal consent is not required., (© 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society.)

Purpose: Pediatric gliomas are the most common brain tumor in children, encompassing both low-grade glioma (pLGG) and high-grade glioma (pHGG). Alterations in the RAS/MAPK pathway are the driver event in the majority of pLGG and account for a subset of pHGG. Identification of these alterations has resulted in the transition to targeted therapy as a treatment option., Results: In pLGG, multiple trials have demonstrated superior outcomes using targeted therapy compared to traditional chemotherapy regimens. This has transformed care for these patients over the past decade with targeted therapy moving into front-line treatment regimens in certain scenarios. Despite these advances, novel targeted therapy approaches continue to present unique challenges to patient care, including optimal duration of therapy, distinct toxicity profiles and the unknown potential impact on the natural history of disease. While targeted therapy has revolutionized treatment of pLGG, additional questions remain in regard to pHGG including the role of targeted therapy in combination with other treatments, such as chemotherapy/radiation, and mechanisms of resistance. These developments are promising treatment options for pediatrics gliomas, enabling a move towards precision medicine., Conclusion: Herein, we review the role of RAS/MAPK targeted therapy for treatment of pediatric glioma along with the current controversies and outstanding questions., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Consent to participate: Not applicable as this is a review paper., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The purpose of this review is to explore the molecular foundations of ocular surface squamous neoplasia (OSSN), focusing on the genetic and epigenetic aspects. While current management strategies include surgical excision and medical therapies, the understanding of OSSN's molecular basis remains limited, hindering the development of targeted treatments., Methods: A comprehensive MEDLINE search was conducted for literature published between January 1993 and October 2023. Only studies with original data on molecular, genetic, or epigenetic mechanisms, such as mutations, gene expression, and genetic predispositions were included. Articles were excluded if they focused solely on clinical management without addressing these factors, or if they were reviews, editorials, or opinion pieces., Results: The search yielded a total of 108 articles, out of which 39 articles met the criteria for further analysis. Investigations into OSSN have identified key DNA mutations in the TP53, HGF, EGFR, TERT, and CDKN2A genes, indicating common oncogenic pathways shared with other squamous cell carcinomas (SCCs). Significant epigenetic changes were identified, including DNA methylation, histone modifications, and altered miRNA expression patterns. Epigenetic dysregulation of critical tumor suppressors and oncoproteins, further highlight the complex genetic landscape of OSSN., Conclusion: The molecular alterations identified in OSSN not only enhance our understanding of its biology but also have potential as novel biomarkers for early detection, prognostic evaluation, and as therapeutic targets. The identification of genetic and epigenetic markers in OSSN signifies progress towards personalized medicine approaches. Further studies and collaborative efforts are essential to validate these molecular markers and translate them into clinical practice, potentially revolutionizing OSSN management and improving patient outcomes., Competing Interests: Conflicts of interest Dr. Palioura is a consultant for Alcon. The authors declare no other conflict of interest related to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Castration-resistant prostate cancer (CRPC) presents significant challenges in clinical management due to its resistance to conventional androgen receptor (AR)-targeting therapies. The advent of proteolysis targeting chimeras (PROTACs) has revolutionized cancer therapy by enabling the targeted degradation of key molecular players implicated in CRPC progression. In this review we discuss the developments of PROTACs for CRPC treatment, focusing on AR and other CRPC-associated regulators. We provide an overview of the strategic trends in AR PROTAC development from the aspect of targeting site selection and preclinical antitumor evaluation, as well as updates on AR degraders in clinical applications. Additionally, we briefly address the current status of selective AR degrader development. Furthermore, we review new developments in PROTACs as potential CRPC treatment paradigms, highlighting those targeting chromatin modulators BRD4, EZH2, and SWI/SNF; transcription regulator SMAD3; and kinases CDK9 and PIM1. Given the molecular targets shared between CRPC and neuroendocrine prostate cancer (NEPC), we also discuss the potential of PROTACs in addressing NEPC.