Pulmonary fibrosis is a disease that leads to respiratory failure and death. There has been little progress in therapeutic strategies for pulmonary fibrosis. There have been several reports on the cytokines associated with pulmonary fibrosis, including IL-6 and TGF-β1. Angiogenesis is one of the most important phenomena in the pathogenesis of pulmonary fibrosis. Previously, we reported the preventive effects of thalidomide against pulmonary fibrosis via the inhibition of neovascularization by angiogenic factors such as VEGF. Regorafenib is a multikinase inhibitor, which inhibits tyrosine kinase receptors such as VEGFR1-3 and TIE2. In the clinical setting, regorafenib has been widely used for anti-cancer therapy for metastatic colorectal cancer. In this study, we examined the preventive effects of regorafenib against pulmonary fibrosis.

We investigated whether regorafenib had an inhibitory effect on the proliferation, viability, and production of several cytokines in lung fibroblasts.

We demonstrated an inhibitory effect of regorafenib on the proliferation and viability of lung fibroblasts. Moreover, regorafenib reduced the production of several cytokines associated with the pathogenesis of pulmonary fibrosis, including IL-6, VEGF and TGF- β1, and collagen synthesis from lung fibroblasts.

These data suggest that regorafenib may have potential clinical applications in the prevention of pulmonary fibrosis.

Osteosarcoma is the most common bone malignancy in children and adolescents. Patients with metastatic and recurrent osteosarcoma have poor prognosis. Regorafenib is a multi-kinase inhibitor recommended as a complement to standard chemotherapy in the treatment of advanced osteosarcoma. The mechanisms associated with regorafenib resistance remains unclear. In this study we performed transcriptomics, proteomics and phosphorylated proteomics using regorafenib-treated osteosarcoma cell lines (MG-63, HOS-MNNG for transcriptomics, HOS-MNNG for proteomics and phosphorylated proteomics). After comprehensive multiomics and verification analyses of differentially expressed genes, essential genes for the malignancy of osteosarcoma cells were identified. The effects of essential genes on the proliferation, invasion, and migration of osteosarcoma were determined. The study also evaluated their role in the apoptosis of osteosarcoma cells. The up-regulation of essential genes was determined by immunohistochemistry assays. Using comprehensive multiomics and verification analyses we found that the CTDSPL2 gene might play a role in the malignancy and Regorafenib resistance in osteosarcoma. In vitro and clinical specimen assays demonstrated that CTDSPL2 promotes the proliferation, invasion and metastasis of osteosarcoma cells, while inhibiting tumor cell apoptosis. In conclusion CTDSPL2 was identified as an essential gene for survival of osteosarcoma cells. Knockdown of CTDSPL2 expression significantly inhibited the proliferation, invasion, and metastasis of osteosarcoma cells, suggesting that it is involved in the formation and development of osteosarcoma tumors. Our data showed that CTDSPL2 is a potential therapeutic target for patients with osteosarcoma.

To determine if an alternating regimen of the tyrosine kinase inhibitors imatinib and regorafenib improved outcomes in patients with advanced gastrointestinal stromal tumors.

ALTGIST (NCT02365441) was a randomized phase II study of standard treatment of imatinib (Arm A) compared with an experimental alternating regimen of imatinib and regorafenib (Arm B). Primary outcome was best objective tumor response (OTR) at nine months.

Seventy-six eligible patients (Arm A 36, Arm B 40) enrolled were evaluable. Median follow-up was 46.0 months (range 6.5-64.6). Best responses and OTR were similar at 9 months. Eighteen (50.0%) Arm A patients and twelve (30.0%) Arm B patients discontinued treatment due to progressive disease. No Arm A patients stopped protocol therapy due to unacceptable toxicity, with 12 (30.0%) stopping in Arm B. Twelve (33.2%) Arm A patients and 12 (30.0%) Arm B patients experienced at least one serious adverse event, mostly grade 3. Secondary endpoints of PFS at 1 and OS at 1 year were not statistically different.

Alternation of imatinib and regorafenib did not impact on 9 months objective response nor on the secondary objectives of PFS and OS. Patients in the alternating arm experienced more toxicity and protocol discontinuations.

NCT02365441.

Hepatocellular carcinoma (HCC), the most common liver cancer, has limited treatment options. The author investigated novel combinations of regorafenib (Reg) with diosmin (Dio), sulfasalazine (SZZ), or rosuvastatin (Ros) to enhance anti-HCC efficacy. Each agent potentiated Reg activity via distinct pathway modulation: Reg/Dio inhibited Akt/m-TOR and RAF/ERK; Reg/SZZ suppressed Akt/m-TOR and NF-κB; and Reg/Ros suppressed JAK/STAT3 and RAF/ERK. These findings demonstrate synergistic potential by combining Reg with drugs possessing complementary anti-inflammatory, cholesterol-lowering, or cytotoxic activities, offering promising multi-targeted therapeutic strategies for HCC.

Regorafenib, an antiangiogenic multikinase inhibitor (MKI), showed antitumour activity in the second line of treatment for sarcomas in the phase II, randomised versus placebo, multicentre clinical trials REGOSARC (NCT01900743) and REGOBONE (NCT02389244). MKIs are drugs with a narrow therapeutic index subject to drug-drug interactions. The co-medications were not included in the trials' analyses.

We conducted an ancillary exploratory analysis of the two trials to evaluate the interactions between regorafenib and patients' co-medications administered at baseline in terms of efficacy [progression-free survival (PFS)] and toxicity. The efficacy analysis was stratified according to histology groups.

Overall, 289 patients were included in the efficacy analysis and 339 in the toxicity analysis. Of the entire population, 71.7% of patients had at least one co-medication (median = 2, range 0-14). Overall, we found an improvement in PFS with regorafenib versus placebo (hazard ratio 0.40, 95% confidence interval 0.30-0.53, P < 0.0001). In the multivariate model adjusted on sex, histological grade, and performance status, we did not find any significant interaction between treatment effect (regorafenib versus placebo) and the co-medications on PFS. In the safety analysis, we observed no significant interaction analysis between treatment effect (regorafenib versus placebo) and the co-medications, for all the adverse events, even when considering co-medications with treatments known to be at risk of similar toxicities, or with co-medications at risk of pharmacological overdose (like cytochrome P-450 3A4 inhibitors, organic anion-transporting polypeptide inhibitors, UDP-glucuronosyltransferase inhibitors, treatments competing on protein binding). We did not find any significant interaction between regorafenib and anti-acid drugs either in the efficacy analysis (P = 0.35) or in the toxicity analysis (P = 0.53).

We did not find any significant unfavourable interaction between regorafenib and patients' co-medications, from any pharmacological class (e.g. anti-acid), either in terms of efficacy or regarding the occurrence of adverse events. These results are reassuring for the safety of regorafenib administered in association with co-medications.

Registered systemic treatment options for glioblastoma patients are limited. The phase II REGOMA trial suggested an improvement of median overall survival in progressive glioblastoma by the multi-tyrosine kinase inhibitor regorafenib. This has not been confirmed by GBM AGILE. So far, regorafenib has been administered as monotherapy or as an addition to standard of care in newly diagnosed glioblastoma. Rational combination therapies involving regorafenib might be a reasonable strategy. Here, we aimed at identifying functionally instructed combination therapies involving regorafenib.

We applied a genome-wide CRISPR-Cas9-based functional genomics target discovery approach using activation and knockout screens followed by genetic, pharmacological, functional validations. Regorafenib-induced molecular alterations were assessed by RNA sequencing and DigiWest. We investigated selected functionally instructed combination therapies in three orthotopic glioma mouse models in vivo (syngeneic SMA560/VM/Dk model and two xenograft models) and performed immunohistochemistry of post-treatment brains.

We identified potential modifiers of regorafenib response, including BCL2, BCL2L1, ITGB3, FOXC1, SERAC1, ARAF, and PLCE1. The combination of regorafenib with Bcl-2/Bcl-xL inhibition was superior to both monotherapies alone in vitro, ex vivo, and in vivo. We identified regorafenib-induced regulations of the Bcl-2 downstream target chemokine receptor 1 (CCR1) as one potential underlying molecular mediator. Furthermore, regorafenib led to changes in the myeloid compartment of the glioma-associated microenvironment.

This preclinical study uses a functional genomics-based target discovery approach with subsequent validations involving regorafenib. It serves as a biological rationale for clinical translation. Particularly, an investigation of the combination of regorafenib plus navitoclax within a clinical trial is warranted.

This study aimed to evaluate the prognostic effect of the cumulative dose (CD) of regorafenib on survival in patients with metastatic colorectal cancer (mCRC).

This retrospective study utilized the Taipei Medical University Clinical Research Database for analysis. Patients aged ≥ 20 years with mCRC who were prescribed regorafenib between January 2014 and December 2021 were identified and then divided into low- and high-CD groups (≤ 4200 mg vs. > 4200 mg). Overall survival (OS), time-to-treatment discontinuation (TTD), and the incidence of five common adverse events were compared between groups. In addition, natural cubic splines were employed to examine the non-linear relationship between cumulative doses and survival in the multivariate Cox regression model.

A total of 259 patients were enrolled, with 130 in the low-CD group and 129 in the high-CD group; the median OS was 4.6 months and 9.8 months, respectively (p < 0.01). The median TTD was 51.5 days for the low-CD group and 72.0 days for the high-CD group (p < 0.01). No significant difference in drug-related adverse events was observed between groups. In the multivariate Cox analysis, a CD ≤ 4200 mg was a negative prognostic factor (hazard ratio 1.41 [95% confidence interval 1.08-1.84], p = 0.01). In addition, patients on a dose range between 4368 and 5376 mg exhibited minimal mortality risk.

The cumulative doses of regorafenib > 4200 mg were associated with improved survival. The suggested optimal dose range serves as a reference for dose modification in clinical practice.

Several options have been evaluated in metastatic gastro-oesophageal adenocarcinomas (mGA) after failure of first-line fluoropyrimidine and platinum-based chemotherapy. Regorafenib (REGO), a receptor tyrosine kinase inhibitor, has shown promising activity as second- and third-line treatment of mGA.

PRODIGE58-UCGI35-REGIRI was a comparative, prospective, phase II, open-label study evaluating the safety and efficacy of REGO [160 mg/day on day 2 (D2)-D8/D16-D22] plus irinotecan (IRI: 180 mg/m2 intravenously on D1/D15 every 28 days) versus IRI alone in patients with mGA (gastric or gastro-oesophageal junction/tumour Siewert II and III) after failure of first-line fluoropyrimidine and platinum-based chemotherapy. Primary endpoint was overall survival (OS).

Forty-four patients were included in the REGIRI arm and 45 in the IRI arm, primary tumours (67.4%) were mainly localised in the gastro-oesophageal junction, and 60.7% patients had synchronous metastases. With a median follow-up of 19.4 months [95% confidence interval (CI) 16.8-29.9 months], median OS was 6.3 months (95% CI 5.2-7.1 months) versus 8.2 months (95% CI 5.2-9.7 months) in the REGIRI versus IRI arms (hazard ratio 1.11, 95% CI 0.70-1.74, P = 0.66). Median progression-free survival was 2.2 months versus 1.9 months, objective response rate 15.9% versus 13.3%, and disease control rate 45.5% versus 33.3%. Grade 3 treatment-related adverse events (AEs) were reported for 52.3% of patients in the REGIRI arm versus 23.3% in the IRI arm with four toxic deaths (two homozygous UGT1A1∗28 patients died from sepsis and thrombotic microangiopathy, and two heterozygous UGT1A1∗1/∗28 patients from diarrhoea and pulmonary embolism), versus one (UGT1A1∗1 wild-type patient died from primary tumour perforation). Main grade ≥3 AEs were diarrhoea (18.2% versus 7.0%), hypertension (9.1% versus 0.0%), asthenia (6.8% versus 0.0%), febrile neutropenia (6.8% versus 0.0%), neutropenia (6.8% versus 11.6%), and weight decrease (6.8% versus 0.0%).

The study was stopped early because of limited efficacy and increased toxicities in the REGIRI arm, possibly due to drug interactions. No optimal sub-population that could benefit from a REGIRI regimen exposure was identified.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality, with limited therapeutic options available for advanced stages of the disease. Treatment strategies for HCC are multimodal and largely depend on the disease stage, liver function, and individual patient factors. Based on the WHO's VigiAccess database, this study employed a retrospective descriptive analysis of adverse drug reaction (ADR) reports associated with four widely used tyrosine kinase inhibitors (TKIs) for HCC, including Sorafenib, Cabozantinib, Lenvatinib, and Regorafenib. The analysis included demographic data such as patient age, gender, and geographical distribution, alongside clinical information on the systems and symptoms associated with ADR reports. A total of 112,975 ADR reports related to the four TKI-targeted drugs were identified. Sorafenib exhibited the highest ADR reporting rate (30.7%), followed by Cabozantinib (29.4%), Lenvatinib (24.5%), and Regorafenib (15.4%). The odds ratio method was employed to assess the statistical correlation between the use of these targeted drugs and the occurrence of ADRs. Notably, Sorafenib (3,746) and Regorafenib (2,496) served to have the highest number of reported palmar-plantar erythrodysaesthesia syndrome. Chi-square analyses suggested that ADRs related to Lenvatinib were reported significantly more frequently in female patients compared to their male counterparts. The findings of this study can enhance public awareness of drug-related adverse events and provide an evidence-based foundation for prioritizing the management of ADRs associated with TKIs in second-line HCC therapy.

Cancer is one of the leading causes of death worldwide. Recent advances in precision oncology have enabled many specific cancer patient populations to respond well and achieve longer survival with small-molecule kinase inhibitors, which have become a new therapeutic strategy for tumors. Since 2001, the Food and Drug Administration has approved 108 and 63 new anticancer drugs for treating solid tumors and hematological malignancies, respectively, 89 of which belong to the large group of small-molecule kinase inhibitors (SMKIs). Compared to conventional chemotherapeutic agents such as cyclophosphamide, doxorubicin, and 5-FU, SMKIs offer better efficacy with fewer toxic side effects. Nevertheless, with the development of more novel SMKIs and their wider clinical application to a larger population of cancer patients, variable degrees of cardiotoxic adverse events have emerged for some SMKIs during cancer therapy. This review comprehensively summarizes the most updated progress in the cardiotoxicity of SMKIs in cancer therapy and discusses the new findings and mechanisms, which will provide emerging strategies for the prevention of cardiotoxicity caused by small molecule targeted drugs and the design of the next generation of low cardiotoxicity targeted drugs.

This meta-analysis and trial sequential analysis (TSA) aimed to evaluate the efficacy and safety of triple therapy with tyrosine kinase inhibitors (TKIs) combined with transcatheter arterial chemoembolization (TACE) plus programmed death 1 (PD-1) inhibitors (T-T-P) and dual therapy with TKIs combined with TACE (T-T) for the treatment of advanced unresectable hepatocellular carcinoma (uHCC).

Literature related to the efficacy of TKIs combined with TACE plus PD-1 inhibitors in uHCC was searched using the Embase, PubMed, and Cocrane libraries. TSA was used to reduce false positive results due to random error.

Seventeen articles were included in this meta-analysis, including 2,561 patients. In the T-T-P group, OS [HR 0.45, 95% confidence interval (CI) 0.39-0.52; p = 0.000], PFS [HR 0.43, 95% CI 0.38 - 0.48; p = 0.000], were significantly prolonged compared to those in the T-T group; ORR (RR 1.59 [95% CI 1.39-1.81]; p = 0.000) and DCR (RR 1.26 [95% CI 1.15-1.37]; p = 0.000) were significantly higher. TSA analysis showed early results without further testing. Prognostic factor analysis demonstrated that portal vein tumor thrombus (PVTT) and extrahepatic metastasis were common independent risk factors for OS and PFS. Regarding grade 3/4 adverse events results showed no statistically significant differences in any of them.

Compared with T-T treatment group, the T-T-P treatment group exhibited a notable improvement in OS and PFS, particularly in cases of PVTT and extrahepatic metastasis. Furthermore, it can markedly enhance the ORR and DCR in patients with uHCC.

Pulmonary metastasis frequently complicates osteosarcoma, making the investigation of its mechanisms and therapeutic strategies a focal point in both clinical medicine and biosciences. The explosive growth of the relevant literature has still not been systematically sorted out and summarized.

Bibliometric methods were used in this study, Literature was retrieved from the Web of Science Core Collection, SCOPUS, and PubMed up until July 1, 2024. Bibliometric indicators were analyzed and research trends and hotspots in the field visualized using the Bibliometrix package, VOSviewer 1.6.19 and Citespace 6.3.R1 software.

A total of 1148 publications were reviewed, revealing that over the past five decades, the cumulative number of publications on pulmonary metastasis of osteosarcoma has gradually increased. China leads in the number of published papers, while the United States exhibits the most collaborative relationships with other countries. Italy is noted for the highest quality of research. Sun Yat-sen University is the most prolific institution, and the most productive author is Eugenie S. Kleinerman from the University of Texas MD Anderson Cancer Center. "Cancer" is the journal with the most publications, and Zhou Yan's 2020 paper received the highest local citations. Keywords such as "angiogenesis," "tumor microenvironment," and "surgery" appeared frequently, suggesting these topics are current research hotspots.

"Immunotherapy", "survival", "chemotherapy", "prognosis", "biomarkers", "metastasectomy", "microRNA", "angiogenesis", "tumor microenvironment", and "surgery" define key research areas. Current hot topics include tumor-associated macrophages and the tumor microenvironment, which may hold the key to future therapeutic breakthroughs.

A novel series of quinoxaline derivatives was designed and synthesized to target VEGFR-2, a receptor critical in cancer progression, with a focus on favorable pharmacophoric features. Among these derivatives, compound 11d emerged as a promising candidate, exhibiting potent cytotoxicity against MDA-MB-231 and MCF-7 cancer cell lines, with IC50 values of 21.68 μM and 35.81 μM, respectively, while displaying significantly reduced toxicity in normal cell lines WI-38 and WISH (IC50 values of 82.46 μM and 75.27 μM). Compared to standard treatments doxorubicin and sorafenib, compound 11d demonstrated a favorable therapeutic window. Inhibition assays showed that 11d inhibits VEGFR-2 with an IC50 of 62.26 nM ± 2.77, comparable to sorafenib. Mechanistically, treatment with 11d upregulated pro-apoptotic markers BAX, caspase-8, and caspase-9, while downregulating the anti-apoptotic marker Bcl-2, resulting in a significant BAX/Bcl-2 ratio increase (16.11). A wound healing assay confirmed 11d's anti-migratory effects, limiting wound closure in MDA-MB-231 cells to 27.51% compared to untreated cells. Additionally, flow cytometry revealed that 11d induced both early (46.43%) and late apoptosis (31.49%) in MDA-MB-231 cells, alongside G1 phase cell cycle arrest, reducing S and G2/M phase progression. Molecular docking and dynamics simulations over 200 ns demonstrated stable binding of compound 11d to VEGFR-2, with docking scores superior and comparable to sorafenib. Density Functional Theory (DFT) calculations underscored 11d's stability and reactivity, while in silico ADMET analysis predicted a favorable safety profile over sorafenib, particularly with respect to carcinogenic and chronic toxicity risks. These findings indicate that quinoxaline derivative 11d holds potential as a selective and effective VEGFR-2 inhibitor with promising antitumor and anti-metastatic properties, warranting further investigation.

Ewing's sarcoma (ES) is a highly aggressive primary bone malignancy that primarily affects children and adolescents. Several tyrosine kinase receptors (RTKs) have been found to be overexpressed in ES samples, and it was demonstrated that some play significant roles in driving the malignant phenotype of ES. Specifically, ES with insulin-like growth factor 1 (IGF1R) or vascular endothelial growth factor (VEGFR) overexpression were correlated with more aggressive ES and worse outcomes. Other RTKs that were determined to be overexpressed in ES include platelet-derived growth factor receptor, stem cell factor receptor, and hepatocyte growth factor. Overexpression of these molecules suggests their possible tumor-driving role, making them potential targets for intervention. Various tyrosine kinase inhibitors (TKIs), including apatinib, anlotinib, and cabozantinib have shown clinical promise in patients with recurrent ES who have progressed on previous lines of therapy. The findings reported in this review emphasize the importance of assessing IGF1R-focused inhibitors and combinational therapeutic regimens in future research. Furthermore, biomarkers predictive of response are necessary to improve patient outcomes. In order to optimize ES care, considerations for patient eligibility on the basis of positivity for biomarkers predictive of response, and the inclusion of quality-of-life evaluations in studies must be addressed.

Tyrosine kinase inhibitors (TKIs) can treat various cancers, primarily through their antiangiogenic effects. However, as angiogenesis is crucial for successful wound healing, TKIs may adversely impact wound repair. This review analysed all 63 FDA-approved TKIs and identified evidence for wound healing and repair implications in 24 agents. The primary mechanism contributing to impaired wound healing appears to be the inhibition of vascular endothelial growth factor receptors, with secondary targets, such as epidermal growth factor receptors and platelet-derived growth factor receptors, potentially playing a role. Information from safety package inserts, preclinical studies, case reports and clinical trials suggests that these TKIs can cause delayed or impaired wound healing. The safety information generally recommends discontinuing treatment for at least one to 2 weeks before elective surgery and resuming treatment only after adequate wound healing has occurred. Neoadjuvant therapy with TKIs may be feasible if sufficient time is allowed between the cessation of the TKI and the onset of surgery. As the use of TKIs continues to increase, healthcare professionals should be aware of their potential impact on wound healing and take appropriate precautions to minimise the risk of wound-related complications.

Vascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role in suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 inhibitors with promising anticancer activity.

The synthesized compounds were evaluated for anti-proliferative activity against human cancer cell lines (HCT-116, MCF-7, and HepG-2), and WI-38 as normal cells. Sorafenib was used as a reference drug. VEGFR-2 inhibitory activity was determined, followed by cell cycle analysis, apoptosis assays, Q-RT-PCR analysis, and wound-healing assays. In silico molecular docking was conducted to explore binding interactions.

Among the tested compounds, 13b exhibited potent anti-proliferative activity (IC50: 3.98-11.81 µM) and strong VEGFR-2 inhibition (IC50: 41.51 nM), surpassing sorafenib (IC50: 53.32 nM). Cell cycle analysis revealed that 13b induced G2/M phase arrest in MCF-7 cells. Apoptosis levels increased from 2% to 52%, accompanied by a > 12-fold rise in the Bax/Bcl-2 ratio and activation of caspase-8/9. Additionally, 13b significantly suppressed MCF-7 cell migration, with only 5.28% wound closure. In silico studies confirmed its strong VEGFR-2 binding interactions.

Thiadiazole-based derivatives, particularly compound 13b, exhibit potent VEGFR-2 inhibition, anti-proliferative effects, apoptosis induction, and anti-migratory activity, supporting their potential as promising anticancer agents.

Gastrointestinal stromal tumors (GIST) are the most common gastrointestinal soft tissue sarcomas, with an incidence of about 15 cases per million person-years. Approximately 15% of GIST develop due to succinate dehydrogenase deficiency (SDH-Def), and such tumors do not respond well to the tyrosine kinase inhibitors (TKIs) used to treat other GIST. Due to its indolent nature SDH-Def GIST can often be surveilled if asymptomatic. In our current practice we typically treat advanced symptomatic SDH-Def GIST with the anti-angiogenic TKIs, sequentially treating with sunitinib, regorafenib and pazopanib. This practice is based on limited data. This systematic review provides an update on new data (12/21/2021 to 9/26/2024) for systemic treatment of SDH-Def GIST, both with agents generally used to treat other GIST subtypes and with agents approved in other malignancies. Olverembatinib and rogaratinib have shown promising activity in pre-clinical models and small SDH-Def GIST cohorts. Other agents whose benefits are explored here include the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab and temozolomide, whether as monotherapy or in combination with INBRX-109 (a pro-apoptotic antibody) or olaparib. Additional research into TKI agents with anti-vascular endothelial growth factor receptor (VEGFR) and anti-fibroblast growth factor receptor (FGFR) activity in this clinical setting is needed. Patients with SDH-Def will benefit more broadly from ongoing explorations of treatments with alternative mechanisms of action, especially those that exploit cellular pathways involved in SDH-Def GIST tumorigenesis.

This study aimed to develop a quantitative intratumoral heterogeneity (ITH) model for assessing the risk of early recurrence (ER) in pre-treatment multimodal imaging for hepatocellular carcinoma (HCC) patients undergoing ablation treatments.

This multi-centre study enrolled 633 HCC patients who underwent ultrasound-guided local ablation between January 2015 and September 2022. Among them, 422, 85, 57 and 69 patients underwent radiofrequency ablation (RFA), microwave ablation (MWA), laser ablation (LA) and irreversible electroporation (IRE) ablation, respectively. Vision-Transformer-based quantitative ITH (ViT-Q-ITH) features were extracted from the US and MRI sequences. Multivariable logistic regression analysis was used to identify variables associated with ER. A combined model integrated clinic-radiologic and ViT-Q-ITH scores. The prediction performance was evaluated concerning calibration, clinical usefulness and discrimination.

The final training cohort and internal validation cohort included 318 patients and 83 patients, respectively, who underwent RFA and MWA. The three external testing cohorts comprised of 106 patients treated with RFA, 57 patients treated with LA and 69 patients who underwent IRE ablation. The combined model showed excellent predictive performance for ER in the training (AUC: .99, 95% CI: .99-1.00), internal validation (AUC: .86, 95% CI: .78-.94), external testing (AUC: .83, 95% CI: .73-.92), LA (AUC: .84, 95% CI: .73-.95) and IRE (AUC: .82, 95% CI: .72-.93) cohorts, respectively. Decision curve analysis further affirmed the clinical utility of the combined model.

The multimodal-based model, incorporating clinic-radiologic factors and ITH features, demonstrated superior performance in predicting ER among early-stage HCC patients undergoing different ablation modalities.

RAF1 is a key player in growth factor receptor signaling, which has been linked to multiple viral infections, including human cytomegalovirus (HCMV) infection. Although HCMV remains latent in most individuals, it can cause acute infection in immunocompromised populations, such as transplant recipients, neonates, and cancer patients. Current treatments are suboptimal, highlighting the need for novel therapies. Multiple points in the growth factor signaling pathway are important for HCMV infection, but the relationship between HCMV and RAF1, a component of the mitogen-activated protein kinase (MAPK) cascade, is not well understood. The AMP-activated protein kinase (AMPK) is a known regulator of RAF1, and AMPK activity is induced by HCMV infection, which is important for productive HCMV replication. Our data indicate that HCMV infection induces AMPK-specific changes in RAF1 protein phosphorylation, including increasing phosphorylation at RAF1-Ser621, a known AMPK phospho-site, which results in increased binding to the 14-3-3 scaffolding protein, an important aspect of RAF1 protein activation. Inhibition of RAF1, either pharmacologically or via shRNA or CRISPR-mediated targeting, inhibits viral replication and spread in both fibroblasts and epithelial cells. Collectively, our data indicate that HCMV infection and AMPK activation modulate RAF1 activity, which is important for viral replication.

Human cytomegalovirus (HCMV) infection is a widespread infection impacting approximately 60-90% of the global population. Although latent in healthy individuals, acute infection in immunocompromised populations, such as neonates, transplant recipients, and cancer patients, can result in retinal and gastrointestinal problems, hearing loss, and even death. Current antivirals are suboptimal due to the development of viral resistance or toxicity in patients, highlighting the need for novel treatments. Our research suggests a new potential target, RAF1, which is a regulator of cellular growth and proliferation. We find that RAF1 is phosphorylated by AMP-activated protein kinase, and that inhibition of RAF1 negatively impacts viral infection. Furthermore, drugs currently used to treat certain cancers also inhibit RAF1 and may have an additional anti-HCMV therapeutic effect in HCMV-susceptible cancer patients.

Fruquintinib is a highly selective, oral inhibitor of all 3 VEGF receptors. The global, randomized, double-blind phase 3 FRESCO-2 trial (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival in patients with refractory metastatic colorectal cancer (mCRC) who received fruquintinib plus best supportive care (BSC) versus placebo plus BSC. Here we report detailed safety data from FRESCO-2 including an analysis of treatment-related adverse events of special interest (AESIs).

Patients with mCRC eligible for FRESCO-2 had received all standard chemotherapies and prior anti-VEGF and anti-EGFR therapies if indicated, and displayed progression on, or intolerance to, TAS-102 and/or regorafenib. Prespecified AESIs based on VEGFR tyrosine kinase inhibitor drug classes were evaluated.

Incidences of treatment-related AESIs were 64.9% with fruquintinib + BSC versus 23.0% with placebo + BSC. The most frequent all-grade treatment-related AESIs for fruquintinib were hypertension (28.9%; grade ≥3 10.7%), palmar-plantar erythrodysesthesia syndrome/hand-foot skin reaction (PPE 18.6%; grade ≥3 6.1%), and hypothyroidism (15.6%; grade ≥3 0.4%). Dose reductions due to treatment-related AESIs were reported in 10.3% of patients who received fruquintinib + BSC versus 0.4% with placebo + BSC. The most common treatment-related AESIs resulting in dose reduction for fruquintinib were PPE syndrome (5.0%), hypertension (2.9%), and proteinuria (1.3%). Overall, 5.9% versus 0.9% had treatment-related AESIs resulting in study drug discontinuation.

Fruquintinib + BSC demonstrated a predictable and manageable safety profile in pretreated patients with mCRC and is a novel oral treatment option that prolongs survival and enriches the continuum of care in this population.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, necessitating the continuous evolution of therapeutic approaches. Despite advancements in early detection and localized treatments, metastatic colorectal cancer (mCRC) poses significant challenges due to low survival rates and resistance to conventional therapies. This review highlights the current landscape of CRC treatment, focusing on chemotherapy and targeted therapies. Chemotherapeutic agents, including 5-fluorouracil, irinotecan, and oxaliplatin, have significantly improved survival but face limitations such as systemic toxicity and resistance. Targeted therapies, leveraging mechanisms like VEGF, EGFR, and Hedgehog pathway inhibition, offer promising alternatives, minimizing damage to healthy tissues while enhancing therapeutic precision. Furthermore, future directions in CRC treatment include exploring innovative targets such as Wnt/β-catenin, Notch, and TGF-β pathways, alongside IGF/IGF1R inhibition. These emerging strategies aim to address drug resistance and improve patient outcomes. This review emphasizes the importance of integrating molecular insights into drug development, advocating for a more personalized approach to combat CRC's complexity and heterogeneity.

Mesenchymal stem cells (MSCs) transplantation is a promising therapeutic strategy for ischemic stroke. However, the survival of transplanted MSCs is often compromised by the excessive levels of reactive oxygen species (ROS) and calcium ions (Ca2+) in the ischemic microenvironment following blood flow occlusion. In this study, a protective strategy is developed using functional nanomaterials to escort and shield MSCs. Specifically, NaGdF4@PDA-ALD nanoparticles (NPANs) are synthesized, featuring a NaGdF4 core coated with polydopamine (PDA) for ROS scavenging and further modified with alendronate sodium (ALD) for Ca2+ chelation. The internalization of NPANs by MSCs protected them from oxidative damage and calcium overload, thereby promoting their viability and functionality. Furthermore, NaGdF4 generated T1 signal enhancement, enabling in vivo tracking of MSCs via magnetic resonance imaging. The NPANs-treated MSCs demonstrated improved survival and migration to the ischemic region, promoting blood flow restoration and angiogenesis. These findings confirm the feasibility of employing functional nanoparticles to augment MSCs-based therapies, offering a promising strategy to improve their therapeutic efficacy in ischemic stroke treatment.

Colorectal cancer, ranking as the third most prevalent malignancy globally, substantially benefits from both immunotherapy and VEGF/VEGFR inhibitors. Nevertheless, the use of monotherapy proves inadequate in effectively tackling the heterogeneity of tumors and the intricacies of their microenvironment, frequently leading to drug resistance and immune evasion. This situation underscores the pressing need for innovative strategies aimed at augmenting the effectiveness and durability of treatments. Clinical research demonstrates that the combination of VEGF/VEGFR inhibitors (primarily including VEGF/VEGFR-targeted drugs and multi-kinase inhibitors) with immune checkpoint inhibitors creates a synergistic effect in the treatment of colorectal cancer. Our analysis explores how VEGF/VEGFR inhibitors recalibrate the tumor microenvironment, modulate immune cell functions, and influence the expression of immune checkpoints and cytokines. Furthermore, we critically evaluate the preclinical and clinical feasibility of these combined therapeutic approaches. Despite the potential for toxicity, the significant benefits and prospective applications of these strategies warrant thorough exploration. Exploring the synergistic mechanisms of these combined treatments has the potential to inaugurate a new paradigm in oncology, enabling more personalized and efficacious treatment modalities. Additionally, the synergy between VEGF/VEGFR inhibitors and nascent immunotherapies emerges as a promising field of inquiry.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.

Neovascularization is an important process in brain tumor development, invasion and metastasis. Several research studies have indicated that the VEGF signaling target has potential for reducing angiogenesis in brain tumors. However, targeting VEGF signaling has not met the expected efficacy, despite initial enthusiasm. This is partly because tumors cleverly use alternative growth factor pathways, other than VEGF signaling, to restore angiogenesis. Multi-target inhibitors have been developed to inhibit several receptor kinases that play a role in the development of angiogenesis. By simultaneously affecting various receptor kinases, these treatments can potentially obstruct various angiogenic pathways that are involved in brain cancer advancement, often offering a more holistic strategy than treatments focusing on just one kinase. Since 2009, the FDA has approved a number of multi-kinase inhibitors that target angiogenic growth factor receptors (e.g., VEGFR, PDGFR, FGFR, RET, c-KIT, MET, AXL and others) for treatment of malignant diseases, including brain cancer. Here, we present some recent results from the literature regarding the preclinical and clinical effects of these inhibitors on brain tumors.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. Despite progress in therapeutic strategies, the median overall survival remains approximately 15 months. A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-κB, and TGF-β, critical to tumor growth, invasion, and treatment resistance. This review examines the epidemiology, molecular mechanisms, and therapeutic prospects of targeting these pathways in GBM, highlighting recent insights into pathway interactions and discovering new therapeutic targets to improve patient outcomes.

In recent years, the standard treatment for hepatocellular carcinoma (HCC) has changed dramatically due to the emergence of potent systemic treatment options. These advanced therapies have led to increased survival benefits for patients with advanced or intermediate-stage HCC. Advancements in HCC treatments also offer the possibility of conversion therapy for initially unresectable HCC. However, the treatment of HCC is becoming increasingly complex, due to the expanding availability of systemic therapies, their use in combination with locoregional therapies, and their perioperative applications. Patient characteristics such as liver function, esophageal and gastric variceal status, and treatment goal (downstaging resection or long-term maintenance treatment), are the most critical factors when selecting a systemic treatment strategy. Consequently, the necessity to tailor a personalized and comprehensive treatment strategy for individual patients is growing. This review briefly summarizes the current systemic treatment regimens for HCC from a surgeon's perspective. It is based on results from clinical studies as well as personal experience and introduces the concept of a patient-centered, treatment goals-driven, individualized systemic treatment strategy for managing HCC.

Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.

STC1 is a protein secreted by intratumor endothelial cells in which plasma concentrations increase in patients with chemorefractory mCRC. Based on analyses of patients with refractory mCRC in the TEXCAN and CORRECT trials, we found that STC1 plasma levels had a prognostic role for OS, with high levels associated with poor outcome. A predictive role for baseline STC1 levels was pointed out for regorafenib efficacy.

Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.

We explored the rationale for treating glioblastoma (GBM) with regorafenib. In 103 newly diagnosed GBM patients, we assessed mutations, copy number variants (CNVs), fusions, and overexpression in 46 genes encoding protein kinases (PKs) potentially targeted by regorafenib or its metabolites and performed a functional enrichment analysis to assess their implications in angiogenesis. We analyzed regorafenib's binding inhibitory activity and target affinity for these 46 PKs and focused on a subset of 18 genes inhibited by regorafenib at clinically achievable concentrations and on 19 genes involved in angiogenesis. Putative oncogenic alterations were defined as oncogenic/likely oncogenic mutations, oncogenic fusions, CNVs > 5, and/or gene overexpression. Regorafenib did not target all 46 PKs. For the 46-gene set, 40 genes (86.9%) and 73 patients (70.8%) harbored at least one alteration in genes encoding targetable PKs, but putative oncogenic alterations were present in only 34 patients (33%). In the 18-gene set, 18 genes (100%) and 48 patients (46.6%) harbored alterations, but putative oncogenic alterations were detected in only 26 patients (25.2%). Thirty patients (29.1%) had oncogenic alterations in the 18-gene set and/or in angiogenesis-related genes. Around 33% of patients had oncogenic alterations in any of the 46 potential targets. Additionally, the suboptimal dosing of regorafenib, due to its poor penetration of the blood-brain barrier, may reduce the likelihood of effectively targeting certain PKs. Future use of multi-target drugs must be guided by a thorough understanding of target presence, effective inhibition, and the drug's ability to reach brain tumors at adequate concentrations.

Sorafenib is currently the first choice for the treatment of patients with advanced hepatocellular carcinoma, but its therapeutic effect is still limited.

This study aims to examine whether WEE family kinase inhibitors can enhance the anticancer effect of sorafenib.

We analyzed the expression levels of PKMYT1 kinase and WEE1 kinase in HCC, studied the inhibitory effect of PKMYT1 kinase inhibitor RP-6306, WEE1 kinase inhibitor adavosertib combined with sorafenib on the proliferation of HCC cells, and detected the effect of drug combination on CDK1 phosphorylation.

We found that PKMYT1 and WEE1 were upregulated in HCC and were detrimental to patient survival. Cell experiments showed that both RP-6306 and adavosertib (1-100 μM) inhibited the proliferation of HCC cell lines in a dose-dependent manner alone, and the combination of the two drugs had a synergistic effect. In HCC cell lines, sorafenib combined with RP-6306 or adavosertib showed a synergistic antiproliferation effect and less toxicity to normal cells. Sorafenib combined with RP-6306 and adavosertib further inhibited the proliferation of HCC cells and caused complete dephosphorylation of CDK1.

Taken together, our findings provide experimental evidence for the future use of sorafenib in combination with RP-6306 or adavosertib for the treatment of HCC.

Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR-2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR-2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well-tolerated sunitinib and sorafenib, have been approved as VEGFR-2 inhibitors. However, the widespread side effects linked to these VEGFR-2 inhibitors-hypertension, epistaxis, proteinuria, and upper respiratory infection-motivate researchers to search for new VEGFR-2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer-aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure-based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR-2 inhibitor design. Future VEGFR-2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors.

High grade gliomas are characterized by a very poor prognosis due to fatal relapses after surgery. Current chemotherapy is only a palliative care, while potential drug candidates are limited by poor overcoming of the blood-brain barrier.

A suitable chemotherapeutic approach should be engineered to overcome both the altered blood-brain barrier in the glioma site, as well as the intact one in the brain adjacent to tumor zone, and to target the multiple factors influencing glioma proliferation, differentiation, migration, and angiogenesis.

In this experimental research, ultrasmall solid lipid nanoparticles were prepared owing to the temperature phase inversion technology and loaded with a specific drug combination made of paclitaxel, regorafenib, and nanoceria.

Such solid lipid nanoparticles demonstrated capability to inhibit glioma cell proliferation and migration, as well as angiogenesis in vitro. Moreover, relevant in vivo evidence assessed the accumulation of solid lipid nanoparticles in the glioma site of the F98/Fischer rat model, without causing any off-target toxicity.

Thus, promising results for glioma treatment were obtained with a technology characterized by safety and economy, allowing the perspective of successful scalability.