Investigational New Drugs最新文献

Wilms' tumor 1-associated protein 1 (WTAP) is an epitranscriptomic regulator with multifaceted roles in cancer biology. Acting beyond its function in the m6A methyltransferase complex, WTAP governs RNA splicing, stability, and translation, influencing oncogenic signaling, immune modulation, and therapy resistance. Recent evidence reveals its dynamic involvement in diverse malignancies, where it can act as both an oncogene and tumor suppressor depending on the cellular context. WTAP promotes tumor progression through epithelial-mesenchymal transition (EMT), metabolic reprogramming, angiogenesis, and immune evasion, and contributes to resistance against chemotherapy and immunotherapy by regulating DNA repair, ferroptosis, and immune checkpoint pathways. However, studies have also demonstrated that WTAP can exert tumor-suppressive effects under specific physiological conditions, such as hepatocyte-specific WTAP loss leading to extracellular-signal regulated kinases (ERK)-driven hepatocarcinogenesis, and WTAP-mediated m6A regulation restraining oncogenic signaling in some prostate cancers. Moreover, by enhancing ferroptosis resistance, WTAP may weaken ferroptosis-driven antitumor immunity and contribute to immune-checkpoint resistance. Understanding these mechanisms offers opportunities for exploiting WTAP as a biomarker and therapeutic target across multiple cancer types. This review explores the multifaceted role of WTAP in cancer, focusing on its mechanisms of action in tumorigenesis, immune modulation, and therapy resistance, and offers insights into potential therapeutic strategies targeting WTAP in cancer treatment.

IDH-wild-type glioblastoma (IDH-wildtype GB) is an aggressive and genetically heterogeneous tumor characterized by intrinsic resistance to radiotherapy and chemotherapy, while surgical resection remains inherently limited by its diffuse infiltrative growth, leading to poor clinical outcomes. Natural products such as solamargine (SM), a steroidal glycoalkaloid with cytotoxic and antitumor properties, have emerged as potential adjuvant strategies. Here, we investigated the effects of SM on proliferation, clonogenic survival, morphology and migration of IDH-wildtype GB cell lines (U-87MG, U-251MG and T98-G) and non-tumoral astrocytes under normoxic and hypoxic conditions, as well as its interaction with temozolomide (TMZ). Under normoxia, SM reduced cell viability in a dose- and time-dependent manner, with IC₅₀ values between 5.04 and 9.53 μM and showed enhanced cytotoxicity under hypoxia. TMZ alone displayed modest activity, and its combination with SM produced predominantly antagonistic effects. Clonogenic assays confirmed the antiproliferative potential of SM, with significant inhibition of colony formation at 2.5 μM. SM induced marked morphological alterations but did not significantly impair migration in wound-healing assays. In U-87MG cells, SM triggered G₂/M cell-cycle arrest, increased intracellular reactive oxygen species generation, and elevated γH2AX protein expression, indicating oxidative stress-associated DNA damage. However, cleaved caspase-3 and p53 were not detected, suggesting a predominantly non-apoptotic mode of cell death. Together, these findings support SM as a promising candidate for IDH-wildtype GB therapy and underscore the need for further studies to clarify its mechanisms of action and optimize its therapeutic use.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for novel and effective therapeutic agents. Conventional treatments, including chemotherapy, radiotherapy, and surgery, are often associated with significant adverse effects, prompting the exploration of alternative therapeutic strategies. This study aimed to evaluate the anticancer effects of Scorpio fuscus venom (SFV) on human colorectal cancer models using integrated in vitro and in vivo approaches. SFV constituents were characterized using gel electrophoresis, followed by high-performance liquid chromatography and UV-visible spectrometry. Identified peptides were subjected to structural modeling and in silico docking analyses against selected proteins associated with colorectal cancer and apoptosis-related pathways. The cytotoxic effects of SFV were assessed in human CRC cell lines (DLD-1, HT-29, and CaCo-2) and a healthy colon epithelial cell line (CCD-18Co) using Alamar Blue assays after 48-h treatment, and half-maximal inhibitory concentration (IC₅₀) values were determined. SFV treatment resulted in a dose-dependent reduction in cancer cell viability, accompanied by decreased migratory capacity and colony formation ability. Apoptotic responses were further evaluated by flow cytometry and gene expression analyses, indicating modulation of apoptosis-associated genes. For in vivo validation, subcutaneous and orthotopic xenograft colon cancer models were established in mice. SFV administration led to reduced tumor growth compared with control groups. Immunohistochemical analyses revealed altered expression patterns of selected tumor-related markers in SFV-treated tumors. Gene expression profiling demonstrated ≥ twofold changes in 51 genes, including downregulation of BAK1 and TRAF3, and upregulation of BIRC2, BIRC3, BIRC6, CASP8, TNFRSF8, TNFRSF11, and BOK. Collectively, these findings indicate that SFV exerts significant antitumor effects in colorectal cancer models and support its potential as a promising anticancer agent, warranting further mechanistic and translational investigation.

Breast cancer remains a leading global health challenge, driving the urgent need for innovative therapeutic strategies. This study presents the initial results of the design, synthesis, characterization, and in vitro evaluation of a novel fluorescent agent for breast cancer treatment, focusing on its subcellular localization and molecular docking. Seven novel fluorescent compounds (3a-g) were synthesized via isatin derivatives and 4-bromo 1,8-naphthalimide conjugation. The compounds were spectroscopically characterized and tested in MDA-MB-231 and MCF-7 cells using viability assays, Annexin-V and propidium iodide flow cytometry to define cytotoxic mechanisms, confocal microscopy with nuclear and mitochondrial markers for subcellular localization, and molecular docking to VEGFR2 (4AGD) and KIT (3G0E) as co-crystals. 3a (3,85 µM and 2,99 µM) and 3c (1,77 µM and 77,31 µM) emerged as two candidates with high cytotoxic potential, exhibiting the lowest IC₅₀ values in MCF-7 and MDA-MB-231 cell lines, respectively, at the 24^th hour. Several conjugates, particularly 3a (87.47 %) and 3 g (96.62 %) in MCF-7, induced late apoptosis, and 3c (98.57 %) in MDA-MB-231 induced the highest early apoptosis. Across both proteins (3G0E and 4AGD), 3c consistently shows stronger predicted binding than sunitinib, with more negative binding energies and lower Ki values in each case, supporting its promise as a lead together with 3a.

To explore the clinical characteristics of pembrolizumab induced autoimmune hemolytic anemia (AIHA) and to provide references for diagnosis, treatment and prognosis. Case reports and case series of pembrolizumab induced AIHA were collected by searching the database and the clinical data of patients were summarized for statistical analysis up to August 31, 2025. Sixteen cases (55.2%) of male patients and 13 cases (44.8%) of female patients were included, with a median age of 69 years (36,85). The median time to develop AIHA after the first administration was 30 days (range 10,780), and the median cycle was 2.5 cycles (range 1,33). Clinical symptoms can be manifested as fatigue (13.8%), shortness of breath (10.3%), dyspnea (10.3%) and dizziness (6.9%). Direct antiglobulin test showed negative results (17.2%). Warm AIHA accounted for 44.8% of pembrolizumab induced AIHA. Peripheral blood smear examination showed spherocytes (20.7%), red cell agglutination (10.3%). After discontinuation of pembrolizumab and treatment with glucocorticoids (100%) and red blood cell infusion (69.0%), 96.5% of the patients achieved a treatment response. AIHA is a rare and serious complication of pembrolizumab. Clinicians should be aware of the possibility of AIHA occurrence during the treatment process. DAT negativity does not rule out pembrolizumab -induced AIHA. Glucocorticoids may be an important option for the treatment of AIHA. For refractory AIHA, second-line treatment needs to be initiated.

The adenosinergic pathway represents a critical immunometabolic checkpoint within the tumor microenvironment of non-small cell lung cancer (NSCLC), contributing to immune suppression and therapeutic resistance. PBF-1129, an oral, selective A2B adenosine receptor (A2BAR) antagonist, was evaluated in a phase 1, open-label, dose-escalation trial (NCT03274479) in patients with advanced/metastatic NSCLC who had progressed on standard therapies. All patients had previously received chemotherapy and immune checkpoint blockade. Twenty-one patients received escalating doses (40-320 mg once daily), with no dose-limiting toxicities observed. The most frequently reported treatment related adverse events of any grade were lymphocytopenia (n = 8, 38.1%), vomiting (n = 8, 38.1%), anorexia (n = 6, 28.5%), and fatigue (n = 6, 28.5%). PBF-1129 showed dose-proportional pharmacokinetics and maintained plasma concentrations above the 90% maximal inhibitory concentration (IC₉₀) of A2BAR at 320 mg for 24 h, which was determined to be the recommended phase 2 dose (RP2D). Best response was stable disease in 3 out of 21 patients including 2 of 6 treated at RP2D. Immunophenotyping revealed post-treatment reductions in programmed cell death protein 1 (PD-1) expression on CD8⁺ T cells, which correlated with improved survival. The reduction of PD-1 expression on CD4⁺ T cells and decreased myeloid-derived suppressor cells were also associated with better outcomes. These findings suggest PBF-1129 is safe and modulates the systemic immune parameters, warranting further evaluation in combination with immune checkpoint blockade.

Patients with metastatic non-small cell lung cancer (NSCLC) harbouring targetable genomic alterations who progressed on standard tyrosine kinase inhibitors (TKIs) have limited treatment options, with platinum-based chemotherapy offering modest efficacy. We evaluated the efficacy and safety of a novel combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed in this population. This phase 2, open-label, single-arm study enrolled patients with metastatic NSCLC with sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) or c-ROS oncogene 1 (ROS1) alteration who progressed on standard TKIs. Patients received a combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety. Of the 24 patients screened, 19 were enrolled and included in the intention-to-treat population. Median follow-up time was 10.7 months (95% CI 4.4-11.9). ORR was 31.6% (6/19, 95% CI 12.6%-56.6%; all partial responses). Median PFS was 11.9 months (95% CI 4.3-not reached). Median OS was not reached. Most of the treatment-related adverse events (TRAEs) were grade 1-2, which occurred in 63% (12/19) of the patients. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%) and anorexia (21.1%). The combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed showed modest efficacy and manageable toxicity in metastatic NSCLC patients with targetable genomic alterations who progressed on standard TKIs. NCT04989322.

Background: Ceralasertib is an oral, selective, and potent inhibitor of ATR serine/threonine kinase, a key protein involved in cell cycle checkpoint regulation and DNA damage response. We report preliminary safety, tolerability, and pharmacokinetic data of ceralasertib monotherapy in Japanese patients with advanced solid tumors.

Methods: In this phase 1, open-label study, patients orally received ceralasertib twice daily 240 mg on days 1-7 (Cohort 1) or 160 mg on days 1-14 (Cohort 2) of a 28-day cycle, respectively; both cohorts also received a single ceralasertib dose 4 days before Cycle 1. Patients were aged ≥ 18 years with solid malignancies refractory to standard therapies or for which no standard therapy exists. The primary objective was to determine ceralasertib safety; secondary objectives included assessing antitumor activity and pharmacokinetics. Exploratory objectives included biomarker analysis.

Results: Twelve of 14 patients screened received ceralasertib. At data cutoff (August 17, 2023), all 12 patients had experienced at least one treatment-emergent adverse event (AE; grade ≥ 3, n = 3). One patient in each cohort had a dose-limiting toxicity; no AE-related deaths were reported. In total, 6 patients had a best objective response of stable disease (Cohort 1, n = 2; Cohort 2, n = 4). A trend suggesting dose-proportional increases in exposure following single and multiple administration of ceralasertib was observed.

Conclusion: Ceralasertib monotherapy was generally well tolerated in Japanese patients with advanced solid tumors. The small number of patients enrolled prevents definitive conclusions on the efficacy of ceralasertib monotherapy to be made.

Trial registration: ClinicalTrials.gov, NCT05469919. Registration date: May 18, 2022.

Background: Selpercatinib is the current standard of care for patients with recurrent or advanced RET fusion-positive non-small cell lung cancer (RET-NSCLC). However, real-world data on selpercatinib for RET-NSCLC are extremely limited, particularly in the Japanese population.

Methods: This retrospective multicenter study enrolled 27 patients who were pathologically diagnosed with RET-NSCLC and started selpercatinib treatment between September 2021 and June 2024. Patients who had previously received other molecular-targeted drugs were excluded. Of the patients, 10 had received prior treatment and 17 had not.

Results: As of August 31, 2024, the median follow-up period was 12.0 months (range 0.5-31.5 months). The objective response rate (ORR) was 100% (8/8 cases) in the previously treated group and 81% (13/16 cases) in the treatment-naïve group. The median progression-free survival (PFS) was 13.3 months (95% confidence interval [CI] 0.5-not evaluable [NE]) in the previously treated group and 23.5 months (95% CI 5.7-NE) in the treatment-naïve group. The median overall survival was 25.4 months (95% CI 0.5-NE) in the previously treated group and not reached (95% CI NE-NE) in the treatment-naïve group. No significant differences were observed in any of these comparisons. The most frequent grade 3 adverse event (AE) was increased ALT (n = 11, 41%), followed by increased AST (n = 7, 26%).

Conclusions: In Japanese patients treated with selpercatinib, efficacy in whole patients was similar to the worldwide population, whereas AEs (especially liver dysfunction) was more severe than worldwide population. This result highlights the need for careful dose management strategies for Japanese patients.

This study investigated the association between ATP-binding cassette (ABC) transporter gene polymorphisms and Epidermal Growth Factor Receptor (EGFR)- Tyrosine kinase inhibitor (TKI) sensitivity in non-small cell lung cancer (NSCLC). Our goal was to determine if these genetic variations could serve as valuable biomarkers for predicting treatment efficacy. We examined the associations between ABC transporter mRNA expression and EGFR-TKI sensitivity in 16 NSCLC cell lines. Expression of ABCB1, ABCG2, ABCC10, and ABCC11 was quantified by real-time PCR and correlated with IC₅₀ values of gefitinib and osimertinib. Additionally, associations between transporter gene single nucleotide polymorphisms (SNPs) (ABCB1 C1236T, ABCB1 C3435T, ABCG2 C421A, ABCC10 T2843C, ABCC11 G538A) and EGFR-TKI sensitivity were evaluated. To assess clinical relevance, blood samples from 109 gefitinib/erlotinib- and 54 osimertinib-treated patients were analyzed for these SNPs. While no significant correlation was found between mRNA expression and IC₅₀ values in cell lines, we did find that specific SNPs significantly correlated with drug cytotoxicity in vitro. Clinically, the ABCB1 C1236T T/T genotype was associated with prolonged PFS in patients on first-generation EGFR-TKIs, while the ABCC10 T2843C T/T genotype was linked to longer PFS with third-generation EGFR-TKIs. These findings suggest that ABC transporter SNPs could be valuable biomarkers for personalized medicine in NSCLC. These findings suggest that ABC transporter SNPs may serve as valuable biomarkers for predicting EGFR-TKI efficacy in NSCLC patients with EGFR mutations, which will contribute to personalized medicine.