Search Results (20)

Background/Objectives: Standard treatment of multiply relapsed Ewing sarcoma remains to be established. Recent studies evaluating tyrosine kinase inhibitors (TKIs) with anti-angiogenic properties have shown encouraging results. Therefore, we conducted a systematic review and meta-analysis to explore the efficacy and safety of TKIs in patients with Ewing sarcoma. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases for clinical trials (CTs) and cohort studies assessing TKIs in the treatment of advanced Ewing sarcoma patients who received at least one prior line of therapy. The main outcome was objective response rate (ORR). All analyses were conducted using R software (v.4.2.2), employing random effects models with 95% confidence intervals (CIs). Results: We included 14 studies (seven phase II CT and seven retrospective cohorts), comprising 257 patients. The following TKIs were evaluated: cabozantinib, regorafenib, apatinib, anlotinib, sorafenib, lenvatinib, sunitinib, fruquintinib, and imatinib. In a pooled analysis of all Ewing sarcoma patients treated with TKIs, the ORR was 23% (95% CI, 11.2–37.1%) and the DCR was 61.1% (95% CI, 47.3–74.2%). Responses were numerically higher but statistically nonsignificant between clinical trials and real-world studies. The analysis including only single-agent TKIs showed better responses for anlotinib and apatinib, yet these drugs are not available in Western countries. Among the FDA-approved TKIs, superior outcomes were noted with single-agent cabozantinib. (ORR: 21.6%) and regorafenib (ORR: 11.3%). Several studies did not report toxicity data exclusively for Ewing sarcoma patients; thus, conclusions about toxicity are mostly based on the general population of studies and may not be fully representative of Ewing sarcoma patients. Conclusions: Anti-angiogenic TKIs have shown important anti-tumoral activity in patients with Ewing sarcoma. Efficacy was consistently seen in both clinical trials and real-world studies. Nonetheless, there are important differences in study design and population that may limit our interpretation of efficacy and toxicity findings. Full article

Mesenchymal chondrosarcoma (MCS) is characterised by small round cell biology, frequent HEY1-NCOA2 fusion, and high vascularity. These features plausibly lessen extracellular matrix barriers and confer relative chemosensitivity. We synthesised peri-operative (preoperative/neoadjuvant; postoperative/adjuvant) and palliative chemotherapy outcomes separately across multiple cohorts and case reports as well as the summarised the guidelines (ESMO/NCCN) In localised disease, integrating multi-agent Ewing-type chemotherapy with complete resection is associated with improved disease control. Contemporary 5-year overall survival (OS) typically spans ~55–73% across studies, while event-free survival (EFS) gains are demonstrated more consistently than OS gains in pooled analyses. In advanced MCS, first-line polychemotherapy yields modest, non-curative activity, with objective response rates (ORRs) of ~25–35% in adults, median progression-free survival (PFS) of ~4.7–6.7 months, and median OS of ~18 months. Activity may be higher in younger patients and for platinum–anthracycline combinations. We also discussed emerging therapies. Trabectedin demonstrates low disease control rate in translocation-related sarcomas, including few MCS cases. Anti-angiogenic tyrosine kinase inhibitors, such as apatinib and pazopanib, demonstrate activity in chondrosarcoma, but MCS-specific data are lacking. IDH1 inhibition benefits conventional subtypes rather than MCS. Early immunotherapy experience is limited, but pathway-directed strategies targeting BCL2 and PI3K-mTOR warrant evaluation. Full article

Background: For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as a novel target in CRC immunotherapy. Methods: Human CRC cell lines (RKO, HCT116), normal intestinal epithelial cells (HIEC-6), and the murine CRC cell line MC38 were used to study the effects of apatinib and MYOF in CRC cells. RNA sequencing, the CPTAC and TCGA databases, and other molecular and cellular methods were applied to disclose the mechanisms involved. A series of mouse models were established to assess the effects of apatinib and MYOF knockdown on tumor progression, immune cell infiltration, and immune checkpoint protein response. Results: We found that MYOF is overexpressed in CRC and linked to immune cell infiltration and checkpoint expression. Suppression of MYOF expression significantly inhibited CRC cell proliferation and migration, as well as reduced PD-L1 protein levels. Integrative analysis showed that apatinib modulates MYOF expression via VEGFR2, resulting in decreased PD-L1 expression, increased CD8+ T cell infiltration, and reduced pro-tumor M2 macrophages. Animal experiments further revealed that apatinib treatment or MYOF knockdown enhanced the efficacy of immune checkpoint blockade (ICB) in CRC. Conclusions: These findings highlight novel antitumor mechanisms of MYOF and suggest that combining apatinib with ICB therapy may improve CRC treatment outcomes, offering a promising strategy to enhance immune responses. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) remains a significant global health concern, primarily due to the limited efficacy of targeted therapies, which are often compromised by drug resistance and adverse side effects. Methods: In this study, we utilized a Tandem Mass Tag (TMT)-based quantitative proteomic approach to analyze global protein expression and serine/threonine/tyrosine (S/T/Y) phosphorylation modifications in HepG2 cells following treatment with three clinically relevant hepatocellular carcinoma-targeted agents: apatinib, regorafenib, and lenvatinib. Results: Utilizing KEGG pathway enrichment analysis, biological process enrichment analysis, and protein interaction network analysis, we elucidated the common and specific metabolic pathways, biological processes, and protein interaction regulatory networks influenced by three liver cancer therapeutics. The study additionally proposed potential combinational treatment strategies, highlighting a possible synergistic interaction between HCC-targeted drugs and the DNA methyltransferase inhibitor. Furthermore, through the integration of clinical phosphorylation site data, we identified several phosphorylation sites that exhibited higher abundance in tumor tissues compared to adjacent non-tumor tissues. These sites were associated with poor prognosis and elevated functional scores. Conclusions: In summary, this study conducted an in-depth analysis of the molecular alterations in proteins and phosphorylation modifications induced by clinical HCC-targeted drugs, predicting drug combination strategies and therapeutic targets. Full article

Triple-negative breast cancer (TNBC) cells are devoid of estrogen receptors (ERs), progesterone receptor (PRs), and human epidermal growth factor receptor 2 (HER2), and it (TNBC) counts for about 10–15% of all breast cancers. TNBC is highly invasive, having a faster growth rate and a higher risk of metastasis and recurrence. Still, chemotherapy is one of the widely used options for treating TNBC. This study reviewed the histological and molecular characterization of TNBC subtypes, signaling pathways that are aberrantly expressed, and small molecules targeting these pathways, as either single agents or in combination with other therapeutic agents like chemotherapeutics, immunotherapeutics, and antibody–drug conjugates; their mechanisms of action, challenges, and future perspectives were also reviewed. A detailed analytical review was carried out using the literature collected from the SciFinder, PubMed, ScienceDirect, Google Scholar, ACS, Springer, and Wiley databases. Several small molecule inhibitors were found to be therapeutics for treating TNBC. The mechanism of action and the different signaling pathways through which the small molecules exert their effects were studied, including clinical trials, if reported. These small molecule inhibitors include buparlisib, everolimus, vandetanib, apatinib, olaparib, salidroside, etc. Some of the signaling pathways involved in TNBC, including the VEGF, PARP, STAT3, MAPK, EGFR, P13K, and SRC pathways, were discussed. Due to the absence of these biomarkers, drug development for treating TNBC is challenging, with chemotherapy being the main therapeutic agent. However, chemotherapy is associated with chemoresistance and a high toxicity to healthy cells as side effects. Hence, there is a continuous demand for small-molecule inhibitors that specifically target several signaling pathways that are abnormally expressed in TNBC. We attempted to include all the recent developments in this field. Any omission is truly unintentional. Full article

Angiogenesis significantly influences the carcinogenesis of thymic epithelial tumors (TET). Both thymomas and thymic carcinoma (TC) overexpress VEGF-A and VEGFR-1 and -2. This review aims to provide an appraisal of the use of anti-angiogenics in the treatment of TET. The literature research identified 16 studies that were deemed eligible for further analysis. Seven studies assessed the clinical efficacy of sunitinib and five studies the use of apatinib and/or anlotinib. The multicenter Japanese phase II REMORA trial investigated the efficacy of lenvatinib, which is a multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The objective response rate was 38% (25.6–52%), which is the highest documented in TET that progressed after first-line chemotherapy. Anti-angiogenic agents may be useful in the treatment of TET, which are not amenable to curative treatment. Their toxicity profile seems to be acceptable. However, angiogenesis inhibitors do not appear to have a major influence on either thymomas or TC, although multikinase inhibitors may have some effect on TC. The current evidence suggests that the most active agent is lenvatinib, whereas sunitinib could be proposed as an acceptable second-line therapy for TC. Further research concerning the combination of immune checkpoint inhibitors with anti-angiogenic drugs is warranted. Full article

Hepatocellular carcinoma (HCC), a highly malignant digestive system tumor, poses substantial challenges due to its intricate underlying causes and pronounced post-surgery recurrence. Consequently, the prognosis for HCC remains notably unfavorable. The endorsement of sorafenib and PD-L1 inhibitors for HCC signifies the onset of a new era embracing immunotherapy and targeted treatment approaches for this condition. Hence, comprehending the mechanisms underpinning targeted immune combination therapy has become exceedingly vital for the prospective management of HCC patients. This article initially presents a triumphant instance of curative treatment involving the combination of TKI and PD-1 inhibitor subsequent to liver resection, targeting an advanced stage HCC as classified by the BCLC staging system. The case patient carries a decade-long history of hepatitis B, having undergone a regimen of 20 courses of treatments involving apatinib and camrelizumab. Throughout the treatment period, no occurrences of grade 3 or 4 adverse events (AE) were noted. Subsequently, the patient underwent a left hepatectomy. Following the hepatectomy, their serum AFP levels have consistently remained within normal limits, and CT imaging has indicated the absence of tumor recurrence over a span of 36 months. The patient had been reviewed on time for two years after the operation. The last time a CT was performed for this patient in our hospital was 7 May 2021, and no new tumors were found. Follow-up is still ongoing. When applying combined targeted immune transformation therapy using TKI and ICI for a patient with BCLC advanced stage HCC, apatinib treatment serves a dual purpose. It inhibits the survival and angiogenesis of tumor cells, while also enhancing the efficacy of camrelizumab in obstructing the interaction between PD-1 and PD-L1. This restoration of T cell cytotoxicity subsequently facilitates the elimination of tumor cells, leading to an enhanced anticancer effect. Full article

Since bevacizumab was first approved by the U.S. Food and Drug Administration as an anti-angiogenic therapy in 2004, angiogenesis-targeted therapy has been developed for various types of solid tumors. To date, ramucirumab and apatinib are clinically available as treatments for metastatic advanced gastric cancer (AGC). Ramucirumab demonstrated prolonged survival as second-line therapy of metastatic AGC in the RAINBOW and REGARD trials. However, neither ramucirumab extended survival in treatment-naïve patients with AGC in the RAINFALL or RAINSTORM trials nor bevacizumab in the AVAGAST and AVATAR trials. Apatinib demonstrated superior efficacy over the best supportive care in a Chinese phase III trial but not in an international phase III (ANGEL) trial. Currently, combination therapy of ramucirumab with irinotecan or FTD/TPI is being evaluated in the third-line setting, assessing the efficacy of continuous angiogenesis inhibition from second- to third-line therapy. Recently, the role of angiogenesis inhibition via immunomodulators is attractive to clinicians. Emerging results of several early-phase clinical trials indicated the promising antitumor activity of angiogenesis inhibition in combination with immune therapy. This review offers an overview of the history of clinical trials focused on anti-angiogenic for patients with AGC and presents future perspectives in this area. Full article

Background: Transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) may enhance the efficacy of treatment for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT); however, it remains unclear. We aim to evaluate the efficacy of TACE combined with TKIs. Methods: A thorough literature search was performed on major databases since their inception until October 2022. Based on the eligibility criteria, eight studies (2103 patients) were included. Results: Meta-analysis showed that TACE+sorafenib/apatinib had a better tumor response (objective response rate (ORR): RR = 4.85, 95% CI 2.68–8.75, disease control rate (DCR): RR = 3.23, 95% CI 1.88–5.56), and prolonged OS (HR = 0.50, 95%CI 0.42–0.60, p < 0.00001) than TACE alone. TACE+lenvatinib was stronger than TACE+sorafenib in ORR (60.7% vs. 38.9%) and TTP (HR = 0.61, 95% CI 0.43–0.86), whereas it was similar in DCR (96.4% vs. 96.3%) and OS (HR = 0.70 95% CI 0.46–1.05). Conclusions: TACE plus sorafenib or apatinib was superior to TACE alone for hepatocellular carcinoma with PVTT; no significant advantage was found between TACE+lenvatinib and TACE+sorafenib, although TACE+lenvatinib performed better in terms of ORR and TTP. Full article

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies. Full article

Glioblastoma is the most common histologic type of all gliomas and contributes to 57.3% of all cases. Despite the standard management based on surgical resection and radiotherapy, it is related to poor outcome, with a 5-year relative survival rate below 6.9%. In order to improve the overall outcome for patients, the new therapeutic strategies are needed. Herein, we describe the current state of knowledge on novel targeted therapies in glioblastoma. Based on recent studies, we compared treatment efficacy measured by overall survival and progression-free survival in patients treated with selected potential antitumor drugs. The results of the application of the analyzed inhibitors are highly variable despite the encouraging conclusions of previous preclinical studies. This paper focused on drugs that target major glioblastoma kinases. As far, the results of some BRAF inhibitors are favorable. Vemurafenib demonstrated a long-term efficacy in clinical trials while the combination of dabrafenib and trametinib improves PFS compared with both vemurafenib and dabrafenib alone. There is no evidence that any MEK inhibitor is effective in monotherapy. According to the current state of knowledge, BRAF and MEK inhibition are more advantageous than BRAF inhibitor monotherapy. Moreover, mTOR inhibitors (especially paxalisib) may be considered a particularly important group. Everolimus demonstrated a partial response in a significant proportion of patients when combined with bevacizumab, however its actual role in the treatment is unclear. Neither nintedanib nor pemigatinib were efficient in treatment of GBM. Among the anti-VEGF drugs, bevacizumab monotherapy was a well-tolerated option, significantly associated with anti-GBM activity in patients with recurrent GBM. The efficacy of aflibercept and pazopanib in monotherapy has not been demonstrated. Apatinib has been proven to be effective and tolerable by a single clinical trial, but more research is needed. Lenvatinib is under trial. Finally, promising results from a study with regorafenib may be confirmed by the ongoing randomized AGILE trial. The studies conducted so far have provided a relatively wide range of drugs, which are at least well tolerated and demonstrated some efficacy in the randomized clinical trials. The comprehensive understanding of the molecular biology of gliomas promises to further improve the treatment outcomes of patients. Full article

In recent years, advances of anticancer and supportive therapies have determined a gradual improvement in survival rates and patients’ general conditions in metastatic gastric cancer (mGC), allowing them to receive further treatments. The choice of treatment is driven by performance status, age, stage of disease, number of metastatic sites and time from the first to third line of treatment. Targets such as microsatellite instability, PD-L1 expression, and HER2 overexpression or amplification may be addressed to personalise treatment and prolong survival. Despite a growing number of third line options that have provided clinicians with greater opportunities to customise treatments, up to date few agents have been demonstrated as effective after two standard lines for mGC; for these reasons, chemotherapy, immunotherapy, and targeted therapy were all widely investigated in both phase II and phase III studies. Overall, TAS-102, apatinib, regorafenib, nilotinib, trastuzumab, and pembrolizumab were demonstrated to be valid options in the third line scenario for mGC patient refractory to at least two lines of therapy. A multimodal approach based on chemotherapy, immunotherapy, targeted agents, a personalised nutritional programme as well as the research of new predictive biomarkers may pave the way to new strategies to identify the best treatment for each patient. Full article

Treatment options for human epidermal growth factor receptor (HER2)-negative breast cancer patients are limited in comparison to the HER2-positive patients, particularly for metastatic breast cancer patients. Apatinib is a small-molecule tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor 2 (VEGFR-2). Here, we reported the apatinib-based therapy data in HER2-negative metastatic breast cancer. Apatinib was taken at a dose of 250 mg orally once per day and combined with standard chemotherapy regimens. The PFS and OS of 128 patients were 4.7 months and 15.3 months, respectively. The objective response rate (ORR) and the disease control rate (DCR) were 22.7% and 80.5%, respectively. Patients with breast cancer susceptibility gene (BRCA) mutations were found to have a longer PFS and OS. Moreover, combination immunotherapy or paclitaxel-platinum regimens shared an improved response to other regimens. Most of the adverse effects (hypertension, anaemia, and hand-foot syndrome) were grade 1 to 2. Metastatic breast cancer patients could benefit from apatinib therapy at a low dosage, and the adverse effects are mild in real-world clinical practice. Furthermore, BRCA may be a putative biomarker for apatinib in HER2-negative breast cancer. Immunotherapy or paclitaxel-platinum regimens may be recommended to combine with apatinib therapy. Full article

For hundreds of years, Atractylodes chinensis (DC.) Koidz. (AK) has been widely used as a treatment for spleen and stomach diseases in China. The AK polysaccharides (AKPs) have been thought to be the important bioactive components. In this stud, the impacts of different extraction methods were analyzed. The differences between AKPs extracted by hot water extraction (HWE), AKPs extracted by ultrasonic extraction (UAE), and AKPs extracted by enzyme extraction (EAE) were compared in terms of yield, total carbohydrate content, molecular weight distribution, monosaccharide composition, and synergistic activity of the AKPs with apatinib were determined. The results indicated that the yield of the polysaccharide obtained from HWE was higher than that of UAE and EAE. However, activity assays indicated that UAE-AKPs and HWE-AKPs enhanced apoptosis of human gastric cancer cells (SGC-7901) treated with apatinib and UAE-AKPs showed the strongest synergistic activities. This is also in agreement with the fact that UAE-AKPs have a smaller molecular weight, β-configuration, and higher galactose content. These findings suggested that UAE is an efficient and environmentally friendly method for producing new polysaccharides from Atractylodes chinensis (DC.) Koidz. for the development of natural synergist and for the treatment of gastric cancer. Full article