Investigational New Drugs最新文献

Ovarian cancer remains one of the most lethal gynecologic malignancies, largely due to high recurrence rates and treatment-related toxicities. Although PARP inhibitors like Olaparib have shown efficacy in BRCA-mutated cancers, their benefit is limited in broader patient populations. TP53 mutations, highly prevalent in ovarian cancer, promote tumor progression and resistance, making p53 a key therapeutic target. This study evaluated the anticancer potential of HO-3867, a curcumin analog known to restore mutant p53 function, alone and in combination with Olaparib. We used fallopian tube-derived ovarian cancer models harboring mutant or null TP53 and analyzed TP53 expression and mutation profiles using TCGA datasets. Molecular docking simulations and cellular thermal shift assays (CETSA) confirmed HO-3867 binding to the p53^Y220C mutant core domain. Cytotoxicity was assessed via SRB assays; flow cytometry and Western blotting were used to examine cell cycle progression, apoptosis, and DNA damage. HO-3867 treatment increased phospho-p53 (Ser15) and p21 expression, induced G1 phase arrest, and suppressed cell viability. Notably, co-treatment with Olaparib synergistically enhanced apoptosis, as indicated by increased caspase-3 and PARP1 cleavage and elevated γH2AX levels. These findings suggest that HO-3867 reactivates mutant p53 and potentiates Olaparib efficacy by promoting apoptosis and amplifying DNA damage, offering a promising therapeutic strategy for TP53-mutant ovarian cancer.

Histone deacetylases (HDACs) serve a crucial function in transcription regulation, and their dysregulation is linked to numerous diseases, including cancer. Among them, HDAC1 and HDAC2 are particularly significant in neural progenitors and are frequently overexpressed in neural-derived cancers. HDAC inhibitors (HDACis) have shown promise in overcoming chemoresistance by restoring tumor suppressor function in neuroblastoma cells. However, the lack of selectivity in existing HDACis presents challenges, highlighting the need for isoform-selective inhibitors to reduce side effects. This research investigated the anticancer properties of a newly synthesized hydroxamic acid derivative, emphasizing its selective HDAC1 and HDAC2 inhibition and strong antitumor activity. Our findings demonstrated that the newly developed hydroxamic acid analogues, 3A and 3B, effectively inhibited neuroblastoma cells (SH-SY5Y) proliferation, with IC₅₀ values of 8.49 µM and 4.44 µM, respectively, comparable to suberoylanilide hydroxamic acid (SAHA) with IC₅₀ of 0.91 µM. Additionally, compounds 3A and 3B exhibited potent HDAC inhibition. Compound 3A selectively inhibited HDAC2 with an IC₅₀ value of 0.89 μM, while compound 3B showed dual inhibition of HDAC1 and HDAC2, with IC₅₀ values of 0.44 μM and 1.94 μM, respectively. Compound 3B triggered cell cycle arrest in the G2/M phase, reduced colony formation efficiency, and altered cellular architecture upon treatment, further highlighting its anticancer potential. In an in vivo xenograft model, compound 3B significantly decreased tumor growth and tumor weight, highlighting its potential as an effective anticancer agent for neuroblastoma, offering both isoform-selective HDAC inhibition and potent anticancer effects.

Background: To explore the clinical characteristics of dabrafenib-associated uveitis and provide a basis for diagnosis and treatment.

Methods: The database was retrieved to collect reports of dabrafenib-associated uveitis and clinical data were collected for retrospective analysis.

Results: Twenty-six patients were included in the study, with a median age of 56 years (range 30, 75). The onset time of uveitis was 3 months (range 0.75, 96) after administration. The types of uveitis were pan-uveitis (38.5%), anterior uveitis (34.6%), posterior uveitis (15.4%), and intermediate uveitis (3.8%). Fifty percent of the patients were Vogt-Koyanagi-Harada disease-like uveitis. After discontinuation of dabrafenib and treatment with topical and systemic steroids, the symptoms of uveitis improved in all patients.

Conclusion: Patients are advised to have regular ophthalmology examinations during the use of dabrafenib. Timely administration of systemic or local corticosteroid treatment can significantly improve the symptoms of patients.

Trastuzumab is currently a key targeted drug for HER2-positive gastric cancer (GC), but there are common problems of drug resistance and cardiotoxicity in clinical treatment, resulting in poor therapeutic effects. Exosomes are natural nanocarriers for drug delivery and engineered exosomes have been widely used in translational medicine research. This study is designed to compare the anti-tumor effects and adverse effects between engineered exosomes carrying HER2 siRNA and trastuzumab. The stable cell line of iRGD-293T was constructed by using lentiviruses, and iRGD-293T and 293T cells were transfected with si-HER2 and exosomes were isolated by ultra-centrifugation. Functional experiments were performed to examine the inhibitory effects of iRGD-exo-si-HER2 and trastuzumab on both HER2-positive GC cells and mouse xenograft models. Blood biochemical indexes were used to test the adverse effects, especially cardiotoxicity. The engineered exosomes modified by iRGD peptide showed higher tumor affinity compared to control exosomes in vitro and in vivo. si-HER2 delivered by iRGD-exosomes significantly inhibited the proliferation and promoted apoptosis of HER2-positive GC cells, and iRGD-exo-si-HER2 significantly reduced the expression of HER2 in GC cells in vitro and in vivo, showing similar efficacy as trastuzumab but with lower cardiac side effects. Our data indicated that iRGD-exo-si-HER2 shows good anti-tumor effect both in vivo and in vitro, and has fewer side effects compared with trastuzumab. And this study suggested that engineering exosomes with si-HER2 can serve as novel strategy for the treatment of HER2-positive GC.

Serine metabolism plays a pivotal role in supporting the rapid proliferation of tumor cells, with PHGDH recognized as a key rate-limiting enzyme and therapeutic target. However, whether its antitumor effects rely exclusively on serine metabolism remains controversial. In this study, we compared the effects of PHGDH and PSPH inhibitors on serine metabolism and cell proliferation in the breast cancer cell lines HCC-70 and BT-20. While two PSPH inhibitors markedly reduced cellular serine M + 3 levels, they failed to effectively inhibit cell proliferation. In contrast, PHGDH inhibitors exhibited robust antiproliferative activity under both serine-deprived and serine-supplemented conditions. Furthermore, supplementation with α-ketoglutarate, a downstream metabolite of PHGDH, partially reversed this inhibitory effect. These findings indicate that the antitumor activity of PHGDH inhibition cannot be solely attributed to blockade of serine biosynthesis, but rather arises from the coordinated disruption of multiple metabolic pathways. This provides new insights into the potential of metabolic targeting strategies for cancer therapy.

Epidermal Growth Factor Receptor (EGFR), a transmembrane receptor tyrosine kinase (RTK) belonging to the ErbB family, initiates cancer-promoting pathways upon binding with epidermal growth factor (EGF). This activation leads to increased cellular proliferation, inhibition of apoptosis, invasion, and neovascularization. EGFR plays a critical role in non-small cell lung cancer (NSCLC) and is targeted by EGFR tyrosine kinase inhibitors (TKIs). However, resistance to these inhibitors often develops over time, complicating treatment strategies. Proteolysis-targeting chimeras (PROTACs) represent a novel class of drugs that induce targeted protein degradation by promoting ubiquitination upon binding, resulting in degradation via the 26S proteasome. This innovative strategy potentially addresses the drug resistance associated with small molecule inhibitors and holds promise for the treatment of NSCLC. In this paper, we designed and synthesized a series of small molecule PROTACs targeting EGFR utilizing WZ4002, known for its mutation selectivity, as the warhead. These compounds were evaluated for their antiproliferative activity against A549 and NCl-H1975 cell lines, with WZ4002 serving as a control drug. Most compounds exhibited moderate to strong activity against NCl-H1975 cells, with comparatively weaker effects on A549 cells. Among the tested compounds, HJM- 17 and HJM- 19 emerged as the most potent against NCl-H1975 cells. Further analysis through protein immunoblotting revealed that HJM- 17 effectively reduced the expression of EGFR^L858R/T790M. These active compounds lay the groundwork for future studies focused on EGFR-targeting PROTACs.

Background: This study focuses on rare immune-mediated psoriasis induced by anti-PD-L1 drugs. Given that its clinical features have not been fully defined, the aim is to clarify the clinical manifestations, treatment, and outcomes of anti-PD-L1-induced psoriasis.

Methods: We performed a retrospective analysis of psoriasis cases induced by anti-PD-L1 agents. The study involved systematically retrieving case reports from relevant databases up to April 23, 2025, for comprehensive evaluation.

Results: This study included 31 patients, with 90.2% being male and a median age of 65 years (40-81 years). The anti-PD-L1 agents administered to patients included atezolizumab, durvalumab, and avelumab. Notably, 16 patients (51.6%) developed de novo psoriasis. The median time to psoriasis onset after drug initiation was 54.5 days (7-690 days), with plaque psoriasis being the most common clinical type (54.8%). In terms of treatment strategies, 19 patients (61.3%) discontinued anti-PD-L1 therapy, while 8 patients (25.8%) continued treatment. Following clinical interventions, including primarily the administration of topical steroids, symptomatic improvement or complete remission was reported in 25 patients (80.6%).

Conclusion: When administering anti-PD-L1 agents, close monitoring for the onset of psoriatic symptoms in patients is essential to ensure timely detection and diagnosis. For patients who have been diagnosed with psoriasis, appropriate measures should be taken based on their specific clinical conditions, such as discontinuing anti-PD-L1 therapy or administering psoriasis treatment medications.

Early access to promising new drugs with superior efficacy compared to existing treatments is globally sought after. To facilitate such access, regulatory authorities in each country have implemented special regulatory measures that expedite drug approval. This study examined the approval lag of anticancer drugs granted accelerated approval (AA) by the U.S. Food and Drug Administration (FDA) and their corresponding approval timelines in Japan. Additionally, we assessed the use of expedited regulatory pathways in Japan. Our analysis included 55 anticancer drugs that received AA from the FDA between 2012 and 2021 and evaluated their approval in Japan through 2022. The median approval lag was 649 days, primarily attributable to submission delays. Drugs for which Japan participated in the pivotal FDA study and the use of expedited regulatory pathways in Japan had significantly shorter approval lags (P < 0.001 and P = 0.0172, respectively). However, the utilization of the recently implemented conditional early approval system was limited. Although AA anticancer drugs are often approved based on early clinical trial data, our findings highlight that participation in pivotal studies is crucial for minimizing approval delays in Japan. Despite improvements in drug approval timelines, substantial delays persist, underscoring the need for more effective utilization of expedited regulatory pathways. Enhancing collaboration in early-stage clinical trials and optimizing regulatory processes may facilitate faster access to high-benefit anticancer therapies in Japan.

We are currently living in the era of precision medicine, and antibody‒drug conjugates (ADCs) represent promising advancements in targeted cancer therapy. While several ADCs have been investigated over the years, only three have gained FDA approval for breast cancer (BC): ado-trastuzumab emtansine (T-DM1/Kadcyla), trastuzumab deruxtecan (T-DXd/Enhertu), and sacituzumab govitecan (SG/Trodelvy). This review focuses on the three approved ADCs for BC, reviewing the trials that led to their approval and detailing the ongoing trials testing their clinical efficacy and safety profiles. We examine ongoing trials targeting both metastatic and early-stage patients. Notably, we explore trials incorporating investigational ADCs into early management strategies, addressing the unique challenges of biomarker identification, target toxicity, and cost-effectiveness. By summarizing the current landscape of FDA-approved and investigational ADCs, this study highlights the evolving nature of BC treatment. Preliminary findings from ongoing trials suggest that early integration of ADCs can lead to significant improvements in disease-free survival, reinforcing their role in personalized medicine. As research advances, ADCs are likely to become a cornerstone of breast cancer treatment, providing new hope for better patient outcomes.

To explore the clinical features of pembrolizumab induced psoriasis to provide reference for the optimal treatment of immune checkpoint inhibitor-induced psoriasis. Clinical reports of pembrolizumab induced psoriasis were collected by searching the database until January 31, 2025. The clinical data extracted from the collected articles were retrospectively analyzed. A total of 42 patients were included, 76.2% male, with a median age of 69 years (range 28, 83). These patients included 21 (50.0%) patients with new-onset psoriasis and 21 (50.0%) patients with pre-existing psoriasis. The duration of onset of psoriasis was 8 weeks (range 0.4, 108), and the duration of onset of new psoriasis was longer than that of preexisting psoriasis (9 weeks vs. 7.2 weeks). Plaque psoriasis (38.1%) and psoriatis vulgaris (33.3%) were the most commonly reported phenotypes. After discontinuation or continuation of medication, 90.5% of patients experienced partial or complete improvement of skin symptoms after receiving topical, biologics, and oral systemic treatments. Pembrolizumab induced psoriasis can lead to various types of psoriasis, mainly in elderly and male patients. The pathogenesis and optimal treatment of Pembrolizumab in psoriasis require further investigation.