Photo-activated microtubule targeting drugs: Advancing therapies for colorectal cancer.

Over the years immunotherapy has demonstrably improved the field of cancer treatment. However, achieving long-term survival for colorectal cancer (CRC) patients remains a significant unmet need. Combination immunotherapies incorporating targeted drugs like MEK or multi-kinase inhibitors have offered some palliative benefit. Nevertheless, substantial gaps remain in the current therapeutic armamentarium for CRC. In recent years, there has been a surge of interest in exploring novel treatment strategies, including the application of light-activated drugs in conjunction with optical devices. This approach holds promise for achieving localized and targeted delivery of cytotoxic agents, such as microtubule-targeting drugs, directly to cancerous cells within the colon.

[Severe atopic dermatitis in childhood in the era of personalized medicine]. / Dermatitis atópica severa en la infancia en la era de la medicina personalizada.

Atopic dermatitis (AD) is a chronic, non-infectious inflammatory dermatosis, with increasing prevalence in recent decades. Due to its chronic and recurrent nature, it diminishes the quality of life of patients and their families. In recent years, advances in the understanding of AD's pathophysiology have driven the development of targeted therapies such as monoclonal antibodies (mAbs) and Janus kinase inhibitors (JAKis) which modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. Four targeted therapies have been approved in the USA for the treatment of severe/refractory cases: dupilumab, tralokinumab, abrocitinib, and upadacitinib. This manuscript aims to present an update on the pathophysiology of AD, describe the new treatments available, and provide an analysis of the initial results of the use of these treatments in the pediatric population. We concluded that the high cost of these treatments often limits their prescription to situations where cases of atopic dermatitis are resistant to other conventional therapeutic options or when the disease reaches a severe degree. This underscores the importance of careful and accurate decision-making in the medical management of AD to ensure the efficient use of these therapeutic resources.

The cGAS-STING pathway in COPD: targeting its role and therapeutic potential.

Chronic obstructive pulmonary disease(COPD) is a gradually worsening and fatal heterogeneous lung disease characterized by airflow limitation and increasingly decline in lung function. Currently, it is one of the leading causes of death worldwide. The consistent feature of COPD is airway inflammation. Several inflammatory factors are known to be involved in COPD pathogenesis; however, anti-inflammatory therapy is not the first-line treatment for COPD. Although bronchodilators, corticosteroids and roflumilast could improve airflow and control symptoms, they could not reverse the disease. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway plays an important novel role in the immune system and has been confirmed to be a key mediator of inflammation during infection, cellular stress, and tissue damage. Recent studies have emphasized that abnormal activation of cGAS-STING contributes to COPD, providing a direction for new treatments that we urgently need to develop. Here, we focused on the cGAS-STING pathway, providing insight into its molecular mechanism and summarizing the current knowledge on the role of the cGAS-STING pathway in COPD. Moreover, we explored antagonists of cGAS and STING to identify potential therapeutic strategies for COPD that target the cGAS-STING pathway.

Targeting the Hippo/YAP1 signaling pathway in hepatocellular carcinoma: From mechanisms to therapeutic drugs (Review).

The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yes­associated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1­targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.

A fractional-order model for optimizing combination therapy in heterogeneous lung cancer: integrating immunotherapy and targeted therapy to minimize side effects.

This research presents a novel approach to address the complexities of heterogeneous lung cancer dynamics through the development of a Fractional-Order Model. Focusing on the optimization of combination therapy, the model integrates immunotherapy and targeted therapy with the specific aim of minimizing side effects. Notably, our approach incorporates a clever fusion of Proportional-Integral-Derivative (PID) feedback controls alongside the optimization process. Unlike previous studies, our model incorporates essential equations accounting for the interaction between regular and mutated cancer cells, delineates the dynamics between immune cells and mutated cancer cells, enhances immune cell cytotoxic activity, and elucidates the influence of genetic mutations on the spread of cancer cells. This refined model offers a comprehensive understanding of lung cancer progression, providing a valuable tool for the development of personalized and effective treatment strategies. the findings underscore the potential of the optimized treatment strategy in achieving key therapeutic goals, including primary tumor control, metastasis limitation, immune response enhancement, and controlled genetic mutations. The dynamic and adaptive nature of the treatment approach, coupled with economic considerations and memory effects, positions the research at the forefront of advancing precision and personalized cancer therapeutics.

Exploring novel drug targets for atopic dermatitis through plasma proteome with genome.

Atopic dermatitis (AD) is a chronic inflammatory disease with a complex and heterogeneous clinical presentation, leading to treatment limitations. Therefore, there is an urgent demand for new therapeutic drug targets. This study utilized Summary-data-based Mendelian randomization (SMR) to identify potential drug targets for AD. Summary statistics for 2,940 human plasma proteins were obtained from the UK Biobank, while AD statistics came from the Early Genetics and Epidemiology of Life Processes consortium and the FinnGen consortium. Furthermore, subsequent colocalization analyses confirmed the causal roles of candidate proteins. Moreover, Phenome-Wide Association Studies (PheWAS), protein-protein interaction (PPI), enrichment analysis, and single cell-type expression analysis provided additional insights. Additionally, drug prediction, druggability prediction, and molecular docking informed the discovery of novel drug targets. SMR analysis showed that eight plasma proteins were causally associated with AD: PVALB and TST were associated with a reduced risk of AD, while CA14, ECM1, IL22, IL6R, IL18R1, and MMP12 were associated with an increased risk of AD. Colocalization analysis confirmed significant associations for TST, IL22, and CA14. PheWAS further revealed that candidate drug targets were mainly linked to other allergic diseases. The corresponding protein-coding genes are predominantly expressed in melanocytes, T cells, and macrophages in skin tissue. Importantly, these proteins were identified to be involved in cytokine-cytokine receptor interaction, Th17 cell differentiation, and the JAK-STAT signaling pathway. All of these proteins are druggable, and six of them show great potential as drug targets. In conclusion, this study identified eight plasma proteins causally associated with AD and provided new insights into the etiology and potential drug targets for AD.

Evaluation of Efficacy and Safety in First-Line Treatment Methods for Extensive-Stage Small Cell Lung Cancer: A Comprehensive Comparative Study of Chemotherapy, Targeted Therapy Combined With Chemotherapy, and Immunotherapy Combined With Chemotherapy.

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive tumor with limited effectiveness in its standard chemotherapy treatment. Targeted antiangiogenic therapy and immune checkpoint inhibitors (ICIs) have demonstrated potential as alternative treatments for extensive-stage SCLC (ES-SCLC). However, there is insufficient comparative evidence available to determine the optimal first-line treatment option between ICIs plus chemotherapy and targeted antiangiogenic therapy plus chemotherapy. OBJECTIVE: This study is aimed at analyzing clinical data from ES-SCLC patients treated at the First Affiliated Hospital of Bengbu Medical College between June 2021 and June 2023. The study compared the efficacy and safety of three first-line treatment regimens: standard chemotherapy, antiangiogenic therapy combined with chemotherapy, and immune combination therapy. METHODS: Patients who met the inclusion criteria were divided into three groups: chemotherapy, immune combination therapy, and antiangiogenic therapy combined with chemotherapy. The study collected data on clinical characteristics, treatment regimens, and adverse reactions. The analysis included objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and treatment safety. RESULTS: A total of 101 patients were included in the study, with 49 receiving chemotherapy alone, 19 receiving antiangiogenic therapy, and 33 receiving immune combination therapy. The ORRs were 78.9% for antiangiogenic therapy, 72.7% for immune combination therapy, and 42.9% for chemotherapy alone. The median PFS was 8.0 months for antiangiogenic therapy, 7.8 months for immune combination therapy, and 5.2 months for chemotherapy alone. Both combination therapy groups demonstrated superior efficacy compared to chemotherapy alone. CONCLUSION: Targeted combined chemotherapy and immune combination chemotherapy showed superior efficacy as first-line treatments for ES-SCLC compared to chemotherapy alone, with manageable adverse reactions.

Exploring New Frontiers: Innovations and Therapeutic Targets in Dermatology.

The focus of dermatology has increasingly shifted towards exploring new and innovative approaches [...].

Highlights on Future Treatments of IPF: Clues and Pitfalls.

Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease characterized by irreversible scarring of lung tissue, leading to death. Despite recent advancements in understanding its pathophysiology, IPF remains elusive, and therapeutic options are limited and non-curative. This review aims to synthesize the latest research developments, focusing on the molecular mechanisms driving the disease and on the related emerging treatments. Unfortunately, several phase 2 studies showing promising preliminary results did not meet the primary endpoints in the subsequent phase 3, underlying the complexity of the disease and the need for new integrated endpoints. IPF remains a challenging condition with a complex interplay of genetic, epigenetic, and pathophysiological factors. Ongoing research into the molecular keystones of IPF is critical for the development of targeted therapies that could potentially stop the progression of the disease. Future directions include personalized medicine approaches, artificial intelligence integration, growth in genetic insights, and novel drug targets.

Tata-box-binding protein-associated factor 15 as a new potential marker in gastrointestinal tumors.

In this editorial, the roles of tata-box-binding protein-associated factor 15 (TAF15) in oncogenesis, tumor behavior, and as a therapeutic target in cancers in the context of gastrointestinal (GI) tumors are discussed concerning the publication by Guo et al. TAF15 is a member of the FET protein family with a comprehensive range of cellular processes. Besides, evidence has shown that TAF15 is involved in many diseases, including cancers. TAF15 contributes to carcinogenesis and tumor behavior in many tumors. Besides, its relationship with the mitogen-activated protein kinases (MAPK) signaling pathway makes TAF15 a new target for therapy. Although, the fact that there is few studies investigating the expression of TAF15 constitutes a potential limitation in GI system, the association of TAF15 expression with aggressive tumor behavior and, similar to other organ tumors, the influence of TAF15 on the MAPK signaling pathway emphasize that this protein could serve as a new molecular biomarker to predict tumor behavior and target therapeutic intervention in GI cancers. In conclusion, more studies should be performed to better understand the prognostic and therapeutic role of TAF15 in GI tumors, especially in tumors resistant to therapy.

Determinants of resistance and response to melanoma therapy.

Metastatic melanoma is among the most enigmatic advanced cancers to clinically manage despite immense progress in the way of available therapeutic options and historic decreases in the melanoma mortality rate. Most patients with metastatic melanoma treated with modern targeted therapies (for example, BRAFV600E/K inhibitors) and/or immune checkpoint blockade (for example, anti-programmed death 1 therapy) will progress, owing to profound tumor cell plasticity fueled by genetic and nongenetic mechanisms and dichotomous host microenvironmental influences. Here we discuss the determinants of tumor heterogeneity, mechanisms of therapy resistance and effective therapy regimens that hold curative promise.

A comprehensive overview of the molecular features and therapeutic targets in BRAFV600E-mutant colorectal cancer.

As one of the most prevalent digestive system tumours, colorectal cancer (CRC) poses a significant threat to global human health. With the emergence of immunotherapy and target therapy, the prognosis for the majority of CRC patients has notably improved. However, the subset of patients with BRAF exon 15 p.V600E mutation (BRAFV600E) has not experienced remarkable benefits from these therapeutic advancements. Hence, researchers have undertaken foundational investigations into the molecular pathology of this specific subtype and clinical effectiveness of diverse therapeutic drug combinations. This review comprehensively summarised the distinctive molecular features and recent clinical research advancements in BRAF-mutant CRC. To explore potential therapeutic targets, this article conducted a systematic review of ongoing clinical trials involving patients with BRAFV600E-mutant CRC.

Exploring Glypican-3 as a Molecular Target in Hepatocellular Carcinoma: Perspectives on Diagnosis and Precision Immunotherapy Strategies.

Liver cancer, primarily hepatocellular carcinoma (HCC), is the second leading cause of cancer-related deaths globally. It is typically characterized by rapid progression, poor prognosis, and high mortality rates. Given these challenges, the search for molecular targets aiding early diagnosis and targeted therapy remains imperative. Glypican 3 (GPC3), a cell-surface glycoprotein, emerges as a promising candidate for addressing HCC Overexpressed in HCC tissues; GPC3 is a credible immunohistochemical marker for liver cancer diagnosis and a potential marker for liquid biopsy through soluble GPC3 in serum. Various immunotherapies targeting GPC3 have been developed, including vaccines, anti-GPC3 immunotoxins, and chimeric antigen receptor-modified cells. This review comprehensively covers the structure, physicochemical properties, biological functions, and clinical applications of GPC3. It explores diagnostic and treatment strategies centered around GPC3, offering hope for improved early detection and targeted therapies in the challenging landscape of HCC.

Prospective therapeutic targets and recent advancements in the treatment of inflammatory bowel disease.

OBJECTIVE: Inflammatory Bowel Disease (IBD) poses a persistent challenge in the realm of gastroenterology, necessitating continual exploration of innovative treatment strategies. The limited efficacy and potential side effects associated with existing therapeutic modalities underscore the urgent need for novel approaches in IBD management. This study aims to examine potential therapeutic targets and recent advancements in understanding the disease's intricate pathogenesis, with a spotlight on the gut microbiome, immune dysregulation, and genetic predispositions. METHODS: A comprehensive review was conducted to delve into the pressing demand for new avenues in IBD treatment. The study examined potential therapeutic targets such as phosphodiesterase 4 (PDE4) inhibitors, immune system modulators, Tyrosine kinase receptors (TYK), Toll-like receptors (TLRs), modulation of the gut microbiota, stem cell therapy, fibrosis management, interleukins (ILs) regulation, and oxidative stress mitigation. Additionally, advances in precision medicine, biologics, small molecule inhibitors, and microbiome modulation techniques were explored. RESULTS: The investigation unveiled promising therapeutic targets and provided insights into recent breakthroughs that herald a transformative era in the therapeutic landscape for IBD. Advances in precision medicine, biologics, small molecule inhibitors, and the exploration of microbiome modulation techniques stood out as pivotal milestones in the field of gastroenterology. CONCLUSIONS: The findings offer renewed hope for enhanced efficacy, reduced side effects, and improved patient outcomes in the treatment of IBD. These innovative approaches necessitate continual exploration and underscore the urgent need for novel strategies in IBD management, potentially revolutionizing the realm of gastroenterology.

Recent Advances in Targeted Cancer Therapy: Are PDCs the Next Generation of ADCs?

Antibody-drug conjugates (ADCs) comprise antibodies, cytotoxic payloads, and linkers, which can integrate the advantages of antibodies and small molecule drugs to achieve targeted cancer treatment. However, ADCs also have some shortcomings, such as non-negligible drug resistance, a low therapeutic index, and payload-related toxicity. Many studies have focused on changing the composition of ADCs, and some have even further extended the concept and types of targeted conjugated drugs by replacing the targeted antibodies in ADCs with peptides, revolutionarily introducing peptide-drug conjugates (PDCs). This Perspective summarizes the current research status of ADCs and PDCs and highlights the structural innovations of ADC components. In particular, PDCs are regarded as the next generation of potential targeted drugs after ADCs, and the current challenges of PDCs are analyzed. Our aim is to offer fresh insights for the efficient design and expedited development of innovative targeted conjugated drugs.

Integrating Molecular Insights into Biliary Tract Cancer Management: A Review of Personalized Therapeutic Strategies.

Biliary tract cancers (BTCs) are rare and aggressive malignancies with an increasing incidence and poor prognosis. The standard systemic treatment for BTCs has evolved to include immune checkpoint inhibitors associated with gemcitabine-cisplatin as first-line therapies. However, survival rates remain low, highlighting the critical need for personalized treatment strategies based on molecular profiling. Currently, significant advancements have been made in the molecular characterization of BTCs, where genetic alterations, such as IDH1 mutations and FGFR2 fusions, provide targets for therapy. Molecular profiling is crucial early in the management process to identify potential candidates for clinical trials and guide treatment strategy. The integration of these molecular insights into clinical practice has allowed for the development of targeted therapies, although many of them are still in the phase 2 trial stage without definitive survival benefits demonstrated in phase 3 trials. This integration of comprehensive molecular profile insights with traditional treatment approaches offers a new horizon in the personalized medicine landscape for BTCs, with the aim of significantly improving patient outcomes through precision oncology.

Incorporating Tumor Genomic Profiling and Circulating Tumor Cell-derived Organoids into Clinical Practice for Gastrointestinal Cancers.

BACKGROUND/AIM: Precision medicine aims to revolutionize healthcare by tailoring treatment regimens. This study aimed to integrate comprehensive tumor genomic profiling (CTGP) by targeted-gene panel sequencing and drug screening by circulating tumor cell-derived organoids (CTOs) into clinical practice for the treatment of gastrointestinal (GI) cancers. PATIENTS AND METHODS: Nine patients with various GI cancers underwent CTGP and CTO drug sensitivity testing. CTGP results guided targeted therapy and immunotherapy, while CTO drug sensitivity predicted response to chemotherapy and targeted agents. The drug recommendations from two platforms were correlated with the treatment response to the suggested medications retrospectively. RESULTS: Five patients received therapies aligned with CTGP, including HER2-targeted treatment, immunotherapy, and BRAF/MEK dual inhibition, showing positive responses. CTO drug sensitivity predicted progression under regorafenib (low potential benefit) and good response to chemotherapy with high potential benefit. The combination of CTGP and CTO drug sensitivity may exhibit significant correlation with clinical outcomes during treatment with candidate drugs, demonstrating a sensitivity of 79% and an accuracy of 75%. This encompasses various treatment modalities, such as chemotherapy, targeted therapy, and immunotherapy. CONCLUSION: The present investigation elucidated the integration of CTGP and CTO drug sensitivity screening into clinical practice in a complementary manner, showcasing a significant correlation between treatment response and testing outcomes. Additional prospective evaluation of these two testing modalities in a large cohort is warranted to confirm whether the inclusion of CTO drug sensitivity screening confers enhanced survival benefits compared to utilizing CTGP alone.

Clinical Effectiveness of Targeted Therapies Following Nivolumab Therapy in Patients with Metastatic Renal Cell Carcinoma: A Real-World Study.

Background: The treatment and escape for metastatic renal cell carcinoma (RCC) has rapidly evolved, particularly with the integration of immune therapies into first-line regimens. However, optimal strategies following progression in first-line immunotherapy remain uncertain. This study aims to evaluate the efficacy and safety of axitinib and cabozantinib as third-line therapies after progression on nivolumab following first-line VEGF-TKI therapy. Methods: Patients with metastatic RCC who progressed on prior nivolumab treatment after receiving first-line VEGF-TKI therapy were included. Data on patient characteristics, treatment regimens, response rates, progression-free survival (PFS), and overall survival (OS) were collected. Statistical analyses were conducted to assess the prognostic factors and treatment outcomes. Results: A total of 46 patients were included who were predominantly male (83%) with clear-cell histology (89%). The median PFS on first-line TKI therapy was 10.2 months. All the patients received nivolumab as a second-line therapy, with a median of 12 cycles. The median second-line PFS was seven months. Third-line therapies included axitinib (24 patients) and cabozantinib (20 patients). The median PFS for axitinib and cabozantinib was six months, with comparable survival outcomes. The IMDC risk group and treatment tolerability were significant predictors of survival in multivariate analysis. Adverse events were manageable, with hypertension, fatigue, and diarrhea being the most common. Conclusion: Axitinib and cabozantinib show promise as third-line therapies post-nivolumab progression in metastatic RCC, though prospective validation is warranted. This study underscores the need for further research to establish treatment standards in this evolving landscape.

Just scratching the surface: novel treatment approaches for multiple myeloma targeting cell membrane proteins.

A better understanding of the roles of the adaptive and innate immune systems in the oncogenesis of cancers including multiple myeloma (MM) has led to the development of novel immune-based therapies. B cell maturation antigen (BCMA), G protein-coupled receptor family C group 5 member D (GPRC5D) and Fc receptor-like protein 5 (FcRL5, also known as FcRH5) are cell-surface transmembrane proteins expressed by plasma cells, and have been identified as prominent immunotherapeutic targets in MM, with promising activity demonstrated in patients with heavily pretreated relapsed and/or refractory disease. Indeed, since 2020, antibody-drug conjugates, bispecific T cell engagers and autologous chimeric antigen receptor T cells targeting BCMA or GPRC5D have been approved for the treatment of relapsed and/or refractory MM. However, responses to these therapies are not universal, and acquired resistance invariably occurs. In this Review, we discuss the various immunotherapeutic approaches targeting BCMA, GPRC5D and FcRL5 that are currently either available or in clinical development for patients with MM. We also review the mechanisms underlying resistance to such therapies, and discuss potential strategies to overcome these mechanisms and improve patient outcomes.