Investigational New Drugs最新文献

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.

Lung cancer continues to be a significant health burden in the United States, with 2025 estimates indicating approximately 226,650 new cases and 124,730 deaths. NSCLC is the predominant histological subtype of lung cancer, representing approximately 80% to 85% of all diagnosed cases. Within the NSCLC cohort, the EGFR represents the most commonly altered tumor-initiating mutation, exhibiting the highest prevalence among actionable molecular aberrations. Ex20ins in the EGFR gene represent the third most common type of EGFR mutation, observed in approximately 0.3% to 2.9% of all NSCLC cases and 2% to 5% of EGFR-mutant NSCLC subtypes. In July 2025, the US FDA granted accelerated approval for sunvozertinib, an oral and irreversible EGFR tyrosine kinase inhibitor, for the treatment of NSCLC patients who have mutations in the EGFR Ex20ins. Sunvozertinib received conditional approval in China for the second-line NSCLC with mutations in the EGFR Ex20ins, based on safety and efficacy data derived from a Phase II clinical study. Before the approval of sunvozertinib, treatment approaches for EGFR Ex20ins-mutant patients with NSCLC were limited and largely suboptimal. Conventional EGFR-TKIs exhibited minimal clinical efficacy, primarily due to intrinsic structural resistance mechanisms conferred by these specific mutations. This manuscript focuses on the clinical studies that supported the USFDA accelerated approval of sunvozertinib, along with its ongoing and upcoming clinical trials, preclinical research, and other pharmacological aspects.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, and current therapies offer limited efficacy for many patients. GSK6853, a selective inhibitor of the BRPF1, has shown promising anticancer activity in preclinical studies. However, its therapeutic potential and underlying molecular mechanisms in NSCLC remain uncharacterized. We evaluated the antiproliferative effects of GSK6853 on A549 and H1975 using CCK-8 and colony formation assays. Cell cycle distribution was analyzed by flow cytometry. Annexin V/PI method was performed to detect the rate of apoptosis. Transcriptomic changes induced by GSK6853 were assessed via RNA sequencing, followed by functional enrichment analysis and protein-protein interaction (PPI) network construction. Hub gene identification and pathway predictions were performed using bioinformatics tools. Western blotting was used to validate key protein expression changes. GSK6853 significantly inhibited the proliferation of A549 and H1975 cells in a dose-dependent manner and induced G0/G1 cell cycle arrest and apoptosis. RNA-seq analysis revealed that GSK6853 downregulated genes involved in DNA replication, homologous recombination, and base excision repair pathways. CCNA2 (Cyclin A2) emerged as a central hub gene among the downregulated targets. Western blotting confirmed that GSK6853 suppressed CCNA2 expression via inhibition of the JAK2/STAT3 signaling pathway. Clinical database analysis further showed that CCNA2 is highly expressed in LUAD tissues and its overexpression correlates with poor overall and disease-free survival. Our findings demonstrate that GSK6853 exerts potent antiproliferative effects in NSCLC by disrupting JAK2/STAT3 signaling pathway and suppressing CCNA2-mediated cell cycle progression, and further stimulates apoptosis. These results highlight GSK6853 as a promising therapeutic candidate for lung adenocarcinoma and support further preclinical and clinical evaluation.

β3-adrenergic receptors (β3-ARs) are increasingly recognized as modulators of tumor progression and treatment resistance across multiple cancer types. SR59230A, a β3-AR antagonist, has shown preclinical antitumor activity through mechanisms involving mitochondrial reactivation, reactive oxygen species (ROS) production, and antiangiogenic effects. Based on this premise, this study aimed to investigate the in vitro synergistic effects of SR59230A combined with standard chemotherapeutics or targeted therapies in various human cancer cell lines (glioblastoma, melanoma, triple-negative breast cancer, and anaplastic thyroid carcinoma) and endothelial cells (HUVECs). Cells were treated with SR59230A alone or in fixed-ratio combinations with temozolomide, paclitaxel, vemurafenib, lenvatinib, or sorafenib. Drug interactions were quantified using the Chou-Talalay method and validated with the Loewe additivity model. SR59230A exhibited dose-dependent antiproliferative activity, particularly in HUVECs and thyroid carcinoma cells. Synergistic effects were observed in all models, with the strongest synergy in A-2058 melanoma cells (SR59230A + vemurafenib), MDA-MB-231 breast cancer and 8505C thyroid carcinoma cells (SR59230A + paclitaxel), U-87 glioblastoma cells (SR59230A + temozolomide), and HUVECs (SR59230A + lenvatinib or sorafenib). Dose reduction index (DRI) values confirmed the potential to lower cytotoxic drug doses while preserving efficacy. These findings suggest that SR59230A may enhance the efficacy of conventional and targeted anticancer agents through multimodal mechanisms. The consistent synergistic effects across diverse tumor types support further investigation into the role of SR59230A, including its effects on β3-AR, as a promising strategy to overcome resistance and optimize cancer therapy.

The aim of this study was to investigate gene expressions related to beta cell function, and the altered protein profiles in insulinoma INS-1 cells following DB application, under both cytotoxic and non-cytotoxic conditions, with a focus on cell death and proliferation. Caspase 3 activity, LDH level, Bax, Bcl-2, PCNA, MafA, Nkx6.1, Pdx1, NeuroD1, and Pax6 gene expressions, TOS, TAS, and OSI were demonstrated. Protein profiles were analyzed using LC-MS/MS. The upstream and downstream proteins using the IPA database were determined. ERP29, UBE2V2, UBE2L6, PSMA4, TSMB10, ARF1, NUDCD2, ARF3, IRS1, PTEN, AKT, HSPA8, and Fibronectin levels were shown. The changes were observed in genes depending on pancreatic beta cell function and apoptosis. Bcl2, MafA, Nkx6.1, Pdx1, and NeuroD1 gene levels decreased, while Bax and Pax6 gene levels and TAS and TOS levels increased in the group given STZ + DB. PCNA, Bcl-2, Nkx6.1, Pdx1, and Pax6 gene levels increased, while MafA gene levels decreased in the group given DB. The protein ubiquitination pathway more predominates than the other many signaling pathways. Several proteins not previously associated, or only indirectly linked, with beta cell function, apoptosis, or proliferation were identified and characterized for the first time in insulinoma. These findings provide new insights and potential targets for the treatment of pancreatic cancer.

To explore the regularity and clinical characteristics of pembrolizumab induced myocarditis, and to provide a reference for the diagnosis and treatment of myocarditis. Clinical reports of pembrolizumab induced myocarditis were collected by searching the database as of May 31, 2025. Clinical data were extracted and analyzed statistically. A total of 97 patients were enrolled in the study, with a median age of 70 years (range 25, 89), of which 53(54.6%) were male. The median time for diagnosis of myocarditis was 25 days (range 3, 4050). The common clinical symptoms were dyspnoea (23.7%), shortness of breath (16.5%), and thoracic pain (13.4%). Myositis and/or myasthenia gravis occurred in 43.3% of the patients. These patients with myocarditis may be accompanied by abnormalities in myocardial biomarkers, electrocardiograms, cardiac magnetic resonance and echocardiograms. After the patients discontinued pembrolizumab and received steroid-based immunotherapy, 72.2% of the patients recovered and 26.8% of the patients died. Myocarditis is a rare and fatal immune-related adverse event of pembrolizumab. Cardiac biomarkers, electrocardiograms and echocardiograms should be monitored during the use of Pembrolizumab. Cardiac magnetic resonance or myocardial biopsy can be used to further confirm myocarditis.

The solute carrier (SLC) superfamily comprises a broad array of membrane-bound transport proteins that are integral to the intracellular uptake of various substrates, including nutrients, endogenous metabolites, and an expanding repertoire of anticancer drugs. Although they play a pivotal role in drug disposition and pharmacokinetics, SLC-mediated influx mechanisms have historically garnered less research attention compared to the extensively studied ATP-binding cassette (ABC) efflux transporters. Increasing evidence now indicates that the expression profiles, functional activity, and regulatory pathways of SLC transporters critically influence intracellular drug accumulation, therapeutic outcomes, and the emergence of resistance in cancer. This review presents an in-depth analysis of key SLC transporters, such as organic cation transporters (OCTs), organic anion transporting polypeptides (OATPs), L-type amino acid transporter 1 (LAT1), and the cystine/glutamate exchanger(xCT), which have demonstrated relevance in mediating the uptake of anticancer agents. We explore their structural features, cancer-specific expression dynamics, and known interactions with chemotherapeutic and molecularly targeted therapies. Additionally, unconventional drug transport routes, including lipid raft-assisted endocytosis, exosome-mediated cargo transfer, and ion channel-facilitated uptake, are discussed as potential contributors to drug delivery in tumor cells. The review further explores innovative therapeutic strategies that aim to harness SLC transporters for clinical benefit, including prodrug designs, nanoparticle-based delivery systems, and transporter-directed drug development. Clinical progress in targeting LAT1, xCT, and OATP family members is also reviewed, with a focus on ongoing trials. Finally, we address the current limitations in targeting SLCs, such as overlapping substrate specificity, tumor-specific heterogeneity, and interindividual genetic variations affecting transporter function. By framing SLCs as viable and strategic targets within the oncology drug development landscape, this review highlights their emerging potential in shaping future precision oncology initiatives.

The oncogenic transcription factor MYC drives proliferation, metabolism, and therapy resistance in the majority of human cancers, yet its large, nuclear protein-protein interface has long frustrated direct drug discovery. A pivotal breakthrough was the identification of Tribbles pseudokinase 3 (TRIB3) as a high-affinity scaffold that binds the helix-loop-helix/leucine zipper region of MYC, blocks the E3-ubiquitin-ligase, UBE3B, from tagging critical lysines, and thereby prolongs MYC protein half-life while enhancing MYC-MAX transcriptional output. This review integrates structural, biochemical, and in vivo data to show how genetic deletion or pharmacological eviction of TRIB3 collapses MYC levels, silences its gene program, and suppresses tumor growth in B-cell lymphomas and selected solid tumors. We detail two distinct solid-tumor circuits: (i) inducible TRIB3 overload in KRAS- or EGFR-mutant lung adenocarcinoma that triggers lethal paraptosis when mTOR is inhibited by everolimus plus ginsenoside Rh2; (ii) VHL-controlled UBE3B abundance in breast carcinoma, where loss of VHL renders tumors dependent on TRIB3 shielding for sustained MYC signaling. Emerging therapeutics include helix-mimetic and stapled peptides such as PCM4, fragment-derived small molecules that target a unique Glu344-centered pocket on TRIB3, and PROTAC degraders that either eliminate TRIB3 or hijack it to destroy MYC. When combined with DNA-damaging agents, BET or CDK7 inhibitors, or ligase-restoring strategies, these disruptors produce marked synergy in preclinical models. Remaining translational challenges-efficient intracellular delivery, biomarker-guided patient selection, and off-target surveillance-are increasingly tractable thanks to advances in peptide formulation, AI-accelerated screening, and established regulatory paths for targeted degraders. Collectively, current evidence positions the TRIB3-MYC interface as a druggable Achilles' heel and a realistic gateway to long-sought direct MYC blockade in the clinic.

Acute myeloid leukemia (AML) carries a poor prognosis in elderly or medically unfit patients, with median overall survival (OS) of only 7-8 months for those ineligible for intensive chemotherapy. While venetoclax (VEN) combined with azacitidine (AZA) has become a standard therapy, real-world evidence indicates that Asian patients experience higher VEN exposure and toxicity with the standard 400 mg/day dose. This retrospective study aimed to evaluate the efficacy and safety of a reduced-dose regimen (VEN 200 mg/day + AZA) in frail/elderly Chinese AML patients deemed unfit for intensive therapy. We analyzed 14 patients (13 newly diagnosed, 1 relapsed; median age 71.5 years) treated at Zhejiang University Hospital (May 2020-May 2024). All had ECOG status ≥ 3 (64.3%) or comorbidities (71.4%), and 57.1% were classified as adverse-risk by ELN 2022 criteria. Treatment comprised AZA (75 mg/m², days 1-7) and VEN (200 mg/day, days 1-28, in absence of CYP3A4 inducer). Response to treatment was evaluated by bone marrow biopsy for minimal residual disease (MRD). Toxicity was graded per CTCAE v5.0. Survival and trough VEN concentrations were analyzed using Kaplan-Meier and descriptive statistics. All patients (100%) achieved CR/CRi, with a median time to MRD negativity of 1.45 months. Median OS was not reached (> 24.6 months), with 2-year OS and EFS rates of 61.5% and 53.8%, respectively. Adverse-risk patients (42.9%) showed 50.0% survival beyond 21.8 months. Trough VEN concentrations (median 487.7 ng/mL) exceeded therapeutic thresholds (~ 500 ng/mL), confirming adequate exposure. Hematologic toxicity was reduced versus historical full-dose data: grade ≥ 3 thrombocytopenia (21.4% vs. 24-89.5%), febrile neutropenia (35.7% vs. 42.9-78.9%), and anemia (50.0% vs. 70-100%). No VEN dose modifications, tumor lysis syndrome, or 60-day mortality occurred. The semi-dosed VEN-AZA regimen (200 mg/day) demonstrated unprecedented efficacy (100% CR/CRi, median OS > 24.6 months) and a favorable safety profile in frail Chinese AML patients. Reduced toxicity without compromised efficacy supports its use in this population, likely due to optimized pharmacokinetics in Asian patients. These findings challenge the necessity of standard VEN dosing and highlight 200 mg/day as a viable, potentially superior strategy for this demographic.