Investigational New Drugs最新文献

To extend the short half-life of fluorouracil (Fu), enhance its tumor targeting, improve efficacy, and reduce side effects, providing a new approach for colorectal cancer treatment. Fluorouracil was hydroxylated and conjugated with methotrexate to form a 5-fluorouracil-methotrexate conjugate (MF). This was complexed with sulfobutyl ether-β-cyclodextrin (MF-SEBCD) using a stirring method to create an injectable formulation. In vitro studies assessed the conversion of MF-SEBCD in plasma and its antitumor activity. In vivo studies examined antitumor activity, preliminary safety, pharmacokinetics, and tissue distribution. MF was synthesized with a 25% yield and purity above 95%. The water solubility of MF increased by 92-fold with MF-SEBCD preparation. In vitro, MF-SEBCD effectively converted into Fu in plasma and showed strong antitumor activity, with IC50 values of 0.51, 1.29, and 1.26 µM for MC38, HT29, and 4T1 cells, respectively. In vivo, MF-SEBCD achieved a tumor inhibition rate of 57.08%. Pharmacokinetic studies showed that MF-SEBCD extended Fu's half-life to 47 min, nearly double that of Fu injection. Tissue distribution analysis confirmed improved tumor targeting. MF-SEBCD effectively prolongs Fu's half-life, enhances tumor targeting, increases antitumor efficacy, and reduces side effects, offering a promising approach for colorectal cancer treatment.

Currently, therapeutic combinations of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents have shown promising outcomes and have the potential to establish a new standard of care. The efficacy and safety of the first-line combination of envafolimab (an ICI) and lenvatinib (an anti-tumor angiogenesis drug) for the treatment of patients with inoperable hepatocellular carcinoma (HCC) have not been demonstrated. Unresectable HCC patients with an Eastern Cooperative Oncology Group (ECOG) physical status score ≤ 1 and a Child-Pugh score ≤ 7 who had not received systemic therapy were included in this single-arm, exploratory, multicentre phase II clinical study. All patients were required to meet the criteria of being at least 18 years of age, having no history of other malignancies, and existing at least one measurable lesion. The patients were treated with envafolimab (150 mg, QW, subcutaneous) in combination with lenvatinib (12 mg for patients weighing over 60 kg, 8 mg for patients weighing under 60 kg). The co-primary endpoint of the study was overall survival (OS), while surrogate endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. Between March 2022 and April 2023, 36 patients were enrolled, 30 of whom were treated with envafolimab plus lenvatinib. At data cutoff, the median follow-up duration was 20 months (95% CI 18.9-21.1). Among the 30 assessable patients (patients treated according to the trial protocol), the median overall survival (mOS) and median progression-free survival (mPFS) for the therapy comprising envafolimab alongside lenvatinib were 18.5 months (95% CI 13.2-23.8) and 9.4 months (95% CI 1.6-15.6), respectively. The ORR and the DCR (evaluated according to mRECIST criteria) reached 40% and 80%, respectively. In terms of safety, 23 patients (76.7%) experienced at least one treatment-related adverse event (TRAE), of which the most common was elevated aspartate aminotransferase (AST, 23.3%). Furthermore, grade 3 and higher TRAEs occurred in 30%. This study demonstrates that envafolimab in combination with lenvatinib exhibits favourable anti-cancer activity and a manageable safety profile for the first-line treatment of patients with unresectable HCC.

Sarcomas, including bone sarcomas and soft tissue sarcomas (STSs), are a heterogeneous group of mesenchymal malignancies. Recent advancements in next-generation sequencing (NGS) have enabled the identification of novel chromosomal translocations and fusion genes, which play a critical role in sarcoma subtypes. Our study focuses on gene fusions in sarcomas among Chinese patients, comparing their genomic profiles to those of Western populations. We analyzed 1048 sarcoma samples from Chinese patients using a panel of over 500 genes, identifying 481 gene fusions in 329 patients. The most common fusions included EWSR1, HMGA2, and SS18, with notable subtype-specific fusions such as EWSR1-FLI1 in Ewing sarcoma and NAB2-STAT6 in solitary fibrous tumors. In comparison to Chinese and Western populations, variations in fusion spectrum exist, potentially necessitating distinct treatment strategies; however, further validation of these fusions is warranted. Our findings highlight the importance of gene fusions as diagnostic markers and potential therapeutic targets. Actionable fusions, including kinase-related fusions like ALK, NTRK3, and BRAF, were detected in 67 patients (6.4%) and may guide precision therapies. Additionally, we observed the frequent co-occurrence of genomic alterations, particularly in cell cycle regulators such as CDK4 and MDM2. Genomic profiling of sarcomas offers valuable insights into their molecular drivers and can support personalized therapeutic approaches. Further research is needed to validate these findings and optimize treatment strategies for sarcoma patients.

The immune checkpoint inhibitor therapy represented by blocking programmed cell death protein 1/ programmed cell death-ligand 1 (PD-1/PD-L1) has made significant progress in melanoma treatment. However, the response rate and therapeutic effect of immunotherapy alone are still not ideal for melanoma. In this study, we aimed to evaluate the defects of treating anti-PD-L1 alone and the therapeutic effect and molecular mechanism of combined therapy with anti-PD-L1 and MnCl₂. We detected the changes of immune cell populations after anti-PD-L1 treatment in melanoma xenograft mouse model. Further, we evaluated the regulatory effect of MnCl₂ on dendritic cells (DCs) maturation in vitro. Next, we tested the therapeutic effect and regulatory effect on the tumor microenvironment with anti-PD-L1 and MnCl₂ via combining treatment with anti-PD-L1 and MnCl₂. Anti-PD-L1 therapy has a certain tumor suppressive function, but the effect is not ideal. The results of flow cytometry showed that the number of CD4⁺ T cells and CD8⁺ T cells significantly increased after anti-PD-L1 treatment. However, the number of DCs remained basically unchanged after anti-PD-L1 treatment. In vitro, we confirmed that MnCl₂ significantly promoted DCs maturation vis activating cGAS-STING signaling pathway. The combination of anti-PD-L1 and MnCl₂ displayed the best tumor suppression effect in melanoma xenograft mouse model. In tumor microenvironment, the infiltration of T cells and the maturation of DCs were significantly promoted, demonstrating a strong anti-tumor immune response. In summary, we conclude that combining anti-PD-L1 with MnCl₂ is a promising therapeutic strategy for melanoma.

Studies have shown that the Zinc finger homeobox 4 (ZFHX4) might be a factor in the prognosis of malignancies. However, little is known about the association between the ZFHX4 mutation and the effectiveness of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) and melanoma. Three public ICIs-treated NSCLC cohorts were divided into discovery cohort (n=75) and validation cohort (n=62), which were used to evaluate the relationship between ZFHX4 mutation and ICIs effectiveness in NSCLC. Seven ICIs-treated melanoma cohorts (n = 418) were used to analyze the relationship between ZFHX4 mutation and immunotherapy efficacy in melanoma. NSCLC and skin cutaneous melanoma (SKCM) cohorts from The Cancer Genome Atlas (TCGA) were used to investigate underlying mechanism. Patients with ZFHX4 mutant-type (ZFHX4-Mut) showed a superior objective response rate (ORR) (P < 0.01) and longer progression-free survival (PFS) (P < 0.05) than patients with ZFHX4 wild-type (ZFHX4-WT) in NSCLC cohorts. In the melanoma cohorts, patients carrying ZFHX4-Mut had a higher ORR (P = 0.042) and longer overall survival (OS) (P = 0.011). Besides, patients with NSCLC and melanoma harboring ZFHX4-Mut had a higher tumor mutation burden (TMB) (P<0.001) and tumor neoantigen burden (TNB) (P<0.001) than those harboring ZFHX4-WT. ZFHX4 mutation was associated with higher levels of plasma B cells, activated CD4+ memory T cells, and CD8+ T cells. Seven DNA damage repair pathways were significantly enriched in the ZFHX4-Mut group. ZFHX4 mutation could serve as a predicter for the efficacy of ICIs therapy in NSCLC and melanoma.

Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53. Reactivation of p53, which is encoded from the wild type TP53 but lost its function for several reasons, is an attractive therapeutic approach in cancer treatment. p53 can be activated in a non-genotoxic manner by targeting its primary repressor, the MDM2 protein. Clinical trials involving MDM2 inhibitors are currently being conducted in a growing body of investigation, reflecting of the interest in incorporating these treatments into cancer treatment strategies. Early-phase clinical trials have demonstrated the promise of idasanutlin (RG7388), one of the developed compounds. It is a second-generation MDM2-p53 binding antagonist with enhanced potency, selectivity, and bioavailability. The aim of this study is to evaluate the efficacy of RG7388 as a therapeutic strategy for ALL and to investigate its potential impact on improving treatment outcomes for high-risk patients. RG7388 potently decreased the viability in five out of six ALL cell lines with diverse TP53 mutation profiles, whereas only one cell line exhibited high resistance. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic and extrinsic pathways of apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.

Ovarian cancer is the fifth leading cause of cancer related death in the United States. Cisplatin is a platinum-based anti-cancer drug used against ovarian cancer that enters malignant cells and then damages DNA causing cell death. Typically, ovarian cancer cells become resistant to cisplatin making it necessary to increase subsequent dosage, which usually leads to side-effects including irreversible damage to kidney and auditory system tissue. Ovarian cancer resistance is often associated with upregulation of histone deacetylase (HDAC) enzymes that cause DNA to adopt a closed configuration which reduces the ability of cisplatin to target and damage DNA. Compound B, a platinum(IV) complex with two axial phenylbutyrate (PBA) HDAC inhibitor ligands attached to a cisplatin core, can simultaneously inhibit HDAC activity and damage DNA causing decreased cancer cell viability in cisplatin-sensitive (A2780) and -resistant (A2780cis) ovarian cancer cell lines. However, compound B was not previously evaluated in vivo. As simultaneously inhibiting HDAC-mediated resistance with cisplatin treatment could potentiate the platinum drug's effect, we first confirmed the anti-cancer effect of compound B in the A2780 and A2780cis cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide spectrophotometric assay. Then, we used zebrafish embryo and transgenic animal models to comparatively analyze the effect of cisplatin, compound B, and controls on general organismal, auditory, and renal system toxicity, and cancer metastasis. We found that lower dosages of compound B (0.3 or 0.6 µM) than of cisplatin (2.0 µM) could cause similar or decreased levels of general, auditory, and renal tissue toxicity, and at 0.6 µM, compound B reduces cancer metastasis more than 2.0 µM cisplatin.

Background: The efficacy of immune rechallenge in patients with advanced non-small cell lung cancer (NSCLC) who responded well to initial immune checkpoint inhibitor (ICI) treatment is becoming a research hotspot. This study was aimed at describing the survival and clinical characteristics after immune rechallenge in initial immunotherapy responders.

Patients and methods: We retrospectively identified 104 patients with advanced NSCLC who responded well in the first ICI and were rechallenged with immunotherapy to treat progression between January 2018 and June 2023 at Zhejiang Cancer Hospital. Progression-free survival (PFS) 2 and overall survival (OS) were defined as the time from the first day of the second ICI to the date of progression, death, or last follow-up.

Results: Of 104 enrolled patients, 33 received immune monotherapy, and 71 were rechallenged with combination therapy (34 combined with anti-angiogenesis therapy). Patients with an initial immunotherapy duration exceeding 12 months, compared with a duration within 12 months, achieved a significantly prolonged mPFS2 and mOS (PFS2: 9.2 vs. 3.4 months, P < 0.001; OS: 25.5 vs. 10.7 months, P = 0.006). Patients rechallenged with combination therapy had significantly longer PFS2 than those receiving monotherapy (5.8 vs. 2.5 months, P = 0.040), and showed a favorable OS trend (15.9 vs. 10.1 months, P = 0.301). A significant difference in PFS2, particularly for patients receiving combined treatment with anti-angiogenesis therapy (8.7 vs. 4.6 months, P = 0.011), and a tendency toward longer OS (25.3 vs. 13.7 months, P = 0.090), were observed. Multivariate analysis identified long-term treatment duration (P = 0.005) and combined treatment with anti-angiogenesis therapy (P = 0.030) as independent positive factors associated with PFS after rechallenge.

Conclusion: Immune rechallenge is recommend for responders with a prolonged initial immunotherapy duration. Combination therapy, particularly that including anti-angiogenic therapy, is an alternative effective approach to immune rechallenge.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.