Dihydrolipoamide dehydrogenase (DLD) is a novel molecular target of bortezomib.

Proteasome inhibitors (PIs), such as bortezomib and calfizomib, were backbone agents in the treatment of multiple myeloma (MM). In this study, we investigated bortezomib interactors in MM cells and identified dihydrolipoamide dehydrogenase (DLD) as a molecular target of bortezomib. DLD catalyzes the oxidation of dihydrolipoamide to form lipoamide, a reaction that also generates NADH. Our data showed that bortezomib bound to DLD and inhibited DLD's enzymatic function in MM cells. DLD knocked down MM cells (DLD-KD) had decreased levels of NADH. Reduced NADH suppressed assembly of proteasome complex in cells. As a result, DLD-KD MM cells had decreased basal-level proteasome activity and were more sensitive to bortezomib. Since PIs were used in many anti-MM regimens in clinics, we found that high expression of DLD correlated with inferior prognosis of MM. Considering the regulatory role of DLD in proteasome assembly, we evaluated DLD targeting therapy in MM cells. DLD inhibitor CPI-613 showed a synergistic anti-MM effect with bortezomib in vitro and in vivo. Overall, our findings elucidated DLD as an alternative molecular target of bortezomib in MM. DLD-targeting might increase MM sensitivity to PIs.

Therapeutic advances of targeting receptor tyrosine kinases in cancer.

Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role in cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression of certain RTKs, are critical in creating environments conducive to tumor development. Following their discovery, extensive research has revealed how RTK dysregulation contributes to oncogenesis, with many cancer subtypes showing dependency on aberrant RTK signaling for their proliferation, survival and progression. These findings paved the way for targeted therapies that aim to inhibit crucial biological pathways in cancer. As a result, RTKs have emerged as primary targets in anticancer therapeutic development. Over the past two decades, this has led to the synthesis and clinical validation of numerous small molecule tyrosine kinase inhibitors (TKIs), now effectively utilized in treating various cancer types. In this manuscript we aim to provide a comprehensive understanding of the RTKs in the context of cancer. We explored the various alterations and overexpression of specific receptors across different malignancies, with special attention dedicated to the examination of current RTK inhibitors, highlighting their role as potential targeted therapies. By integrating the latest research findings and clinical evidence, we seek to elucidate the pivotal role of RTKs in cancer biology and the therapeutic efficacy of RTK inhibition with promising treatment outcomes.

Activity-based protein profiling and global proteome analysis reveal MASTL as a potential therapeutic target in gastric cancer.

BACKGROUND: Gastric cancer (GC) is a prevalent malignancy with limited therapeutic options for advanced stages. This study aimed to identify novel therapeutic targets for GC by profiling HSP90 client kinases. METHODS: We used mass spectrometry-based activity-based protein profiling (ABPP) with a desthiobiotin-ATP probe, combined with sensitivity analysis of HSP90 inhibitors, to profile kinases in a panel of GC cell lines. We identified kinases regulated by HSP90 in inhibitor-sensitive cells and investigated the impact of MASTL knockdown on GC cell behavior. Global proteomic analysis following MASTL knockdown was performed, and bioinformatics tools were used to analyze the resulting data. RESULTS: Four kinases-MASTL, STK11, CHEK1, and MET-were identified as HSP90-regulated in HSP90 inhibitor-sensitive cells. Among these, microtubule-associated serine/threonine kinase-like (MASTL) was upregulated in GC and associated with poor prognosis. MASTL knockdown decreased migration, invasion, and proliferation of GC cells. Global proteomic profiling following MASTL knockdown revealed NEDD4-1 as a potential downstream mediator of MASTL in GC progression. NEDD4-1 was also upregulated in GC and associated with poor prognosis. Similar to MASTL inhibition, NEDD4-1 knockdown suppressed migration, invasion, and proliferation of GC cells. CONCLUSIONS: Our multi-proteomic analyses suggest that targeting MASTL could be a promising therapy for advanced gastric cancer, potentially through the reduction of tumor-promoting proteins including NEDD4-1. This study enhances our understanding of kinase signaling pathways in GC and provides new insights for potential treatment strategies.

A Precision Oncology Platform to Support Genotype-Tailored Therapy Selection.

There is a critical need for a streamlined process to identify genotype-matched individuals eligible for enrollment into clinical trials and/or targeted therapies, as current methodologies face challenges in integrating diverse molecular data sources. We have developed a precision oncology platform to assist molecular tumor boards and community oncologists in reviewing patients' phenotypes, evaluating related knowledge, and identifying genotype-matched therapies.

Innovations in Rare Gynecologic Cancer: Melanoma, Neuroendocrine, and Low-Grade Serous Ovarian.

In the field of gynecologic cancer, low-grade serous ovarian cancer (LGSOC) has been poorly understood and underinvestigated until recently. Similarly, understanding of the distinct properties and therapeutic sensitivities of gynecologic melanoma and cervical neuroendocrine tumors has recently accelerated. For each of these rare cancers, we explore the epidemiology and natural history, discuss the prognosis, diagnostic testing, and contemporary molecular classification, and then deliberate existing and emerging therapeutic strategies. In LGSOC, we focus on the clinical relevance of recent molecular studies that shed light on the importance of mitogen-activated protein kinase (MAPK) pathway gene mutation and chromosome 1 copy-number change on prognosis and MEK inhibitor sensitivity. We also discuss the relative chemoresistance of this disease and the fact that attention is shifting to combinations of molecular therapies such as endocrine agents plus cyclin-dependent kinase 4/6 inhibitors or MEK inhibitors plus FAK inhibitors. Gynecologic tract melanomas harbor a lower frequency of canonical BRAF mutations, and have lower tumor mutational burden and immune cell infiltration than cutaneous melanomas (CMs). As a result, patients with this disease are less likely to respond to BRAF/MEK or immune checkpoint inhibition than patients with CM. Emerging strategies include the combination of antiangiogenic agents with immune checkpoint inhibitors and the use of adoptive cellular therapies. In cervical neuroendocrine cancer, we discuss the use of surgery in early-stage disease, and the uncertainties regarding the role of radiotherapy. We also explore the evidence for chemotherapy and emerging investigational strategies including the use of poly (ADP-ribose) polymerase inhibitors. For all situations, we explore the shared decision-making process with the patient.

Identification of molecular targets and small drug candidates for Huntington's disease via bioinformatics and a network-based screening approach.

Huntington's disease (HD) is a gradually severe neurodegenerative ailment characterised by an increase of a specific trinucleotide repeat sequence (cytosine-adenine-guanine, CAG). It is passed down as a dominant characteristic that worsens over time, creating a significant risk. Despite being monogenetic, the underlying mechanisms as well as biomarkers remain poorly understood. Furthermore, early detection of HD is challenging, and the available diagnostic procedures have low precision and accuracy. The research was conducted to provide knowledge of the biomarkers, pathways and therapeutic targets involved in the molecular processes of HD using informatic based analysis and applying network-based systems biology approaches. The gene expression profile datasets GSE97100 and GSE74201 relevant to HD were studied. As a consequence, 46 differentially expressed genes (DEGs) were identified. 10 hub genes (TPM1, EIF2S3, CCN2, ACTN1, ACTG2, CCN1, CSRP1, EIF1AX, BEX2 and TCEAL5) were further differentiated in the protein-protein interaction (PPI) network. These hub genes were typically down-regulated. Additionally, DEGs-transcription factors (TFs) connections (e.g. GATA2, YY1 and FOXC1), DEG-microRNA (miRNA) interactions (e.g. hsa-miR-124-3p and has-miR-26b-5p) were also comprehensively forecast. Additionally, related gene ontology concepts (e.g. sequence-specific DNA binding and TF activity) connected to DEGs in HD were identified using gene set enrichment analysis (GSEA). Finally, in silico drug design was employed to find candidate drugs for the treatment HD, and while the possible modest therapeutic compounds (e.g. cortistatin A, 13,16-Epoxy-25-hydroxy-17-cheilanthen-19,25-olide, Hecogenin) against HD were expected. Consequently, the results from this study may give researchers useful resources for the experimental validation of Huntington's diagnosis and therapeutic approaches.

Immune-targeted therapy with transarterial chemo(embolization) for unresectable HCC: a systematic review and meta-analysis.

Background: Transarterial chemo(embolization) is preferred for treating unresectable hepatocellular carcinoma (uHCC); however, because of emerging immune-targeted therapies, its efficacy is at stake. This systematic review pioneers to evaluate the clinical efficacy and safety of transarterial chemo(embolization) combined with immune-targeted therapy for uHCC patients. Methods: PubMed, Embase, and Cochrane Library were searched for studies comparing immune-targeted therapy with or without transarterial chemo(embolization) until 31 May 2024. The complete response (CR) rate, objective response rate (ORR), and disease control rate (DCR) were considered to be the primary outcomes calculated for the clinical outcomes of transarterial chemo(embolization) combined with immune-targeted therapy, along with progression-free survival (PFS) and overall survival (OS). The incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. Results: Sixteen studies, encompassing 1,789 patients receiving transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immune-targeted therapy alone, were considered eligible. The combination of transarterial chemo(embolization) and immune-targeted therapy demonstrated enhanced outcomes in CR (OR = 2.12, 95% CI = 1.35-3.31), ORR (OR = 2.78, 95% CI = 2.15-3.61), DCR (OR = 2.46, 95% CI = 1.72-3.52), PFS (HR = 0.59, 95% CI = 0.50-0.70), and OS (HR = 0.51, 95% CI = 0.44-0.59), albeit accompanied by a surge in ALT (OR = 2.17, 95% CI = 1.28-3.68) and AST (OR = 2.28, 95% CI = 1.42-3.65). The advantages of additional transarterial chemo(embolization) to immune-targeted therapy were also verified in subgroups of first-line treatment, intervention techniques, with or without extrahepatic metastasis, Child-Pugh grade A or B, and with or without tumor thrombus. Conclusion: The combination of transarterial chemo(embolization) and immune-targeted therapy seems to bolster local control and long-term efficacy in uHCC, albeit at the expense of hepatic complications. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier 474669.

Clinical value of guideline recommended molecular targets and genome targeted cancer therapies: cross sectional study.

OBJECTIVE: To assess the clinical benefit and actionability of molecular targets for genome targeted cancer drugs recommended for clinical practice by the National Comprehensive Cancer Network (NCCN). DESIGN: Cross sectional study. PARTICIPANTS/SETTING: Genome targeted cancer drugs recommended by NCCN guidelines in the advanced setting. MAIN OUTCOME MEASURES: Molecular target actionability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit of genome targeted oncology therapies was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets at ESCAT category level I associated with studies showing substantial clinical benefit by ESMO-MCBS (grades 4-5) were designated as high benefit, and those linked to studies achieving an ESMO-MCBS grade of 3 were categorized as being of promising but unproven benefit. RESULTS: 411 recommendations related to 74 genome targeted drugs targeting 50 driver alterations were examined. Most recommendations (346/411; 84%) were associated with clinical trials of various phases, but 16% (65/411) relied on only case reports or pre-clinical studies. However, clinical trials mostly comprised phase I or phase II (271/346; 78%), single arm (262/346; 76%) studies. The primary endpoint assessed in most trials was overall response rate (271/346; 78%) rather than survival. ESCAT tier I targetability encompassed 60% (246/411) of target recommendations, 35% (142/411) were classified as tier II or III, and 6% (23/411) had their relevance yet to be determined (tiers IV to X). When ESMO-MCBS was applied to 267 scorable trials, only 12% (32/267) showed substantial clinical benefit (grades 4-5) and 45% (121/267) were grade 3. When both frameworks were combined, 12% (32/267) of trials supported a determination of high benefit and 33% (88/267) indicated promising but unproven benefit. Of the 118 interventions endorsed by NCCN authors as preferred, 62 (53%) applied to treatments with high or promising but unproven benefit. CONCLUSION: According to the ESCAT and ESMO-MCBS frameworks, about one eighth of genome based treatments for solid cancer were rated as likely to offer a high benefit to patients, whereas around a third were identified as offering a promising but unproven substantial benefit. Ensuring that NCCN recommendations are aligned with expected clinical benefits is crucial for promoting informed, evidence based, genomic guided treatment decisions.

Targeted therapies and conventional care for the treatment of ankylosing spondylitis in China: a cost-effectiveness analysis based on the network-meta analysis.

OBJECTIVE: This study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)-namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib-from the perspective of the Chinese health care system. METHODS: The York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis. RESULTS: Compared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows: secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used. CONCLUSION: Targeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics.

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.

Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study.

BACKGROUND: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis. METHODS: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing. FINDINGS: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy. INTERPRETATION: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP. FUNDING: F Hoffmann-La Roche.

Gene regulatory networks reveal sex difference in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) has been observed to have significant sex differences in incidence, prognosis, and response to therapy. However, the molecular mechanisms responsible for these disparities have not been investigated extensively. METHODS: Sample-specific gene regulatory network methods were used to analyze RNA sequencing data from non-cancerous human lung samples from The Genotype Tissue Expression Project (GTEx) and lung adenocarcinoma primary tumor samples from The Cancer Genome Atlas (TCGA); results were validated on independent data. RESULTS: We found that genes associated with key biological pathways including cell proliferation, immune response and drug metabolism are differentially regulated between males and females in both healthy lung tissue and tumor, and that these regulatory differences are further perturbed by tobacco smoking. We also discovered significant sex bias in transcription factor targeting patterns of clinically actionable oncogenes and tumor suppressor genes, including AKT2 and KRAS. Using differentially regulated genes between healthy and tumor samples in conjunction with a drug repurposing tool, we identified several small-molecule drugs that might have sex-biased efficacy as cancer therapeutics and further validated this observation using an independent cell line database. CONCLUSIONS: These findings underscore the importance of including sex as a biological variable and considering gene regulatory processes in developing strategies for disease prevention and management.

Lung adenocarcinoma (LUAD) is a disease that affects males and females differently. Biological sex not only influences chances of developing the disease, but also how the disease progresses and how effective various therapies may be. We analyzed sex-specific gene regulatory networks consisting of transcription factors and the genes they regulate in both healthy lung tissue and in LUAD and identified sex-biased differences. We found that genes associated with cell proliferation, immune response, and drug metabolism are differentially targeted by transcription factors between males and females. We also found that several genes that are drug targets in LUAD, are also regulated differently between males and females. Importantly, these differences are also influenced by an individual's smoking history. Extending our analysis using a drug repurposing tool, we found candidate drugs with evidence that they might work better for one sex or the other. These results demonstrate that considering the differences in gene regulation between males and females will be essential if we are to develop precision medicine strategies for preventing and treating LUAD.

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.

Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.

The Phosphatidylinositol-3-kinase (PI3K) family is well-known to comprise three classes of intracellular enzymes. Class I PI3Ks primarily function in signaling by responding to cell surface receptor stimulation, while class II and III are more involved in membrane transport. Under normal physiological conditions, the PI3K signaling network orchestrates cell growth, division, migration and survival. Aberrant activation of the PI3K signaling pathway disrupts cellular activity and metabolism, often marking the onset of cancer. Currently, the Food and Drug Administration (FDA) has approved the clinical use of five class I PI3K inhibitors. These small-molecule inhibitors, which exhibit varying selectivity for different class I PI3K family members, are primarily used in the treatment of breast cancer and hematologic malignancies. Therefore, the development of novel class I PI3K inhibitors has been a prominent research focus in the field of oncology, aiming to enhance potential therapeutic selectivity and effectiveness. In this review, we summarize the specific structures of PI3Ks and their functional roles in cancer progression. Additionally, we critically evaluate small molecule inhibitors that target class I PI3K, with a particular focus on their clinical applications in cancer treatment. Moreover, we aim to analyze therapeutic approaches for different types of cancers marked by aberrant PI3K activation and to identify potential molecular targets amenable to intervention with small-molecule inhibitors. Ultimately, we propose future directions for the development of therapeutic strategies that optimize cancer treatment outcomes by modulating the PI3K family.

Circulating interleukin-8 and osteopontin are promising biomarkers of clinical outcomes in advanced melanoma patients treated with targeted therapy.

BACKGROUND: Circulating cytokines can represent non-invasive biomarkers to improve prediction of clinical outcomes of cancer patients. Here, plasma levels of IL-8, CCL4, osteopontin, LIF and BDNF were determined at baseline (T0), after 2 months of therapy (T2) and, when feasible, at progression (TP), in 70 melanoma patients treated with BRAF and MEK inhibitors. The association of baseline cytokine levels with clinical response, progression-free survival (PFS) and overall survival (OS) was evaluated. METHODS: Cytokine concentrations were measured using the xMAP technology. Their ability to discriminate between responding (Rs) and non-responding (NRs) patients was assessed by Receiver Operating Characteristics analysis. PFS and OS were estimated with the Kaplan-Meier method. The Cox proportional hazard model was used in the univariate and multivariate analyses to estimate crude and adjusted hazard ratios with 95% confidence intervals. RESULTS: CCL4 and LIF were undetectable in the majority of samples. The median osteopontin concentration at T0 and T2 was significantly higher in NRs than in Rs. The median T0 and T2 values of IL-8 were also higher in NRs than in Rs, although the statistical significance was not reached. No differences were detected for BDNF. In 39 Rs with matched T0, T2, and TP samples, osteopontin and IL-8 significantly decreased from T0 to T2 and rose again at TP, while BDNF levels remained unchanged. In NRs, none of the cytokines showed a significant decrease at T2. Only osteopontin demonstrated a good ability to discriminate between Rs and NRs. A high IL-8 T0 level was associated with significantly shorter PFS and OS and higher risk of progression and mortality, and remained an independent negative prognostic factor for OS in multivariate analysis. An elevated osteopontin T0 concentration was also significantly associated with worse OS and increased risk of death. Patients with high IL-8 and high osteopontin showed the lowest PFS and OS, and in multivariate analysis this cytokine combination remained independently associated with a three- to six-fold increased risk of mortality. CONCLUSION: Circulating IL-8 and osteopontin appear useful biomarkers to refine prognosis evaluation of patients undergoing targeted therapy, and deserve attention as potential targets to improve its clinical efficacy.

Toxicities associated with sequential or combined use of immune checkpoint inhibitors and small targeted therapies in non-small cell lung cancer: A critical review of the literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become standard-of-care at different stage disease in non-small cell lung cancer (NSCLC). Based on the increasing characterization of molecular aberrations and oncogenic drivers in NSCLC, it is expected that more and more patients will benefit from orally small targeted therapies in NSCLC. However, their concomitant or sequential use is associated with an increased risk of a various toxicity pattern. METHODS: Relevant publications were included if they reported data on the question of toxicities associated with sequential or combined use of ICIs and small targeted therapies used in NSCLC treatment. MEDLINE, Google Scholar, and the Cochrane Library were searched for the following request, from database inception until June 2023. RESULTS: This review highlighted a various pattern of toxicities (i.e., interstitial lung disease, hepatitis, dermatoses) in the context of both sequential and concomitant administration of ICIs and small targeted therapies. Such toxicities seem rather a "drug-effect" than a "class-effect" and some of these toxicities are more specific of a small targeted therapy. This review highlights on the impact of treatment sequence administration and emphasis for physicians to be particularly careful whether small targeted therapy is administered within one to three months after last ICIs injection. CONCLUSION: Physicians have to be aware of severe toxicities in case of both concomitant or sequential ICIs/small targeted therapies administration in NSCLC. Further studies are needed to better understand the mechanisms underlying these toxicities in order to prevent them and to refine ICIs and small targeted therapy sequencing strategy.

Mast cell stabilizers: from pathogenic roles to targeting therapies.

Mast cells (MCs) are bone-marrow-derived haematopoietic cells that are widely distributed in human tissues. When activated, they will release tryptase, histamine and other mediators that play major roles in a diverse array of diseases/disorders, including allergies, inflammation, cardiovascular diseases, autoimmune diseases, cancers and even death. The multiple pathological effects of MCs have made their stabilizers a research hotspot for the treatment of related diseases. To date, the clinically available MC stabilizers are limited. Considering the rapidly increasing incidence rate and widespread prevalence of MC-related diseases, a comprehensive reference is needed for the clinicians or researchers to identify and choose efficacious MC stabilizers. This review analyzes the mechanism of MC activation, and summarizes the progress made so far in the development of MC stabilizers. MC stabilizers are classified by the action mechanism here, including acting on cell surface receptors, disturbing signal transduction pathways and interfering exocytosis systems. Particular emphasis is placed on the clinical applications and the future development direction of MC stabilizers.

Targeting the Wnt/ß-catenin signal pathway for the treatment of gastrointestinal cancer: Potential for advancement.

Gastrointestinal cancers (GICs) are highly prevalent cancers that threaten human health worldwide. The Wnt/ß-catenin signaling pathway has been reported to play a pivotal role in the carcinogenesis of GICs. Numerous interventions targeting the Wnt/ß-catenin signaling in GICs are currently being tested in clinical trials with promising results. Unfortunately, there are no clinically approved drugs that effectively target this pathway. This comprehensive review aims to evaluate the impact of clinical therapies targeting the Wnt/ß-catenin signaling pathway in GICs. By integrating data from bioinformatics databases and recent literature from the past five years, we examine the heterogeneous expression and regulatory mechanisms of Wnt/ß-catenin pathway genes and proteins in GICs. Specifically, we focus on expression patterns, mutation frequencies, and clinical prognoses to understand their implications for treatment strategies. Additionally, we discuss recent clinical trial efforts targeting this pathway. Understanding the inhibitors currently under clinical investigation may help optimize foundational research and clinical strategies. We hope that elucidating the current status of precision therapeutic stratification for patients targeting the Wnt/ß-catenin pathway will guide future innovations in precision medicine for GICs.