Investigational New Drugs最新文献

Over the past decade, Bruton's tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström's macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors.

De novo or acquired resistance to chemotherapy is ubiquitous in pancreatic ductal adenocarcinoma (PDAC). SCO-101 is an oral compound that may counteract chemo-resistance by interacting with SRPK1, ABCG2 drug transporter, and liver enzyme UGT1A1. We first conducted preclinical experiments in paclitaxel-resistant PDAC cells to access the tumoricidal effects of SCO-101 or SRPK1-inhibitor alone or in combination with paclitaxel. Second, we enrolled 22 patients with non-resectable PDAC in a phase Ib trial to investigate safety and pharmaco-kinetics, and to establish maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) during the first cycle of 80% dose gemcitabine (Gem) and nab-paclitaxel (Nab) together with increasing doses of SCO-101. In paclitaxel-resistant PDAC cells in vitro, a synergistic effect between SCO-101 and paclitaxel was demonstrated. In patients, daily doses for 6 days of SCO-101 resulted in a two- to threefold drug accumulation, and drug exposure was dose proportional. Treatment was well tolerated. Transiently increased blood bilirubin attributable to SCO-101 was observed in 12 cases (55%) and associated with jaundice in three patients. One and two DLTs, respectively, were observed at 150 and 250mg dosing-levels of SCO-101, and the MTD was determined to be 200 mg of SCO-101 daily for 6 days on a bi-weekly schedule together with 80% dose of Gem and Nab. Median progression-free and overall survival was 3.3 and 9.5 months, respectively. In PDAC, SCO-101 can be added to Gem and Nab with little and manageable toxicity. However, no clear added efficacy signal was observed of the combination. Trial registration number: NCT04652205 (Nov 29, 2020).

This study investigates the function of Ubiquitin-specific protease 46 (USP46), a deubiquitinase, in the context of lung cancer, particularly its role in regulating cell proliferation via the ubiquitination of TRAF6. In A549 lung cancer cells, analysis revealed a significant downregulation of USP46 expression, while TRAF6 levels were notably elevated. These findings were corroborated by Western blotting, which confirmed the altered expression patterns. To further assess the implications of these changes, several experimental assays, including the Cell Counting Kit-8, transwell migration assays, and flow cytometry, were conducted to evaluate cell viability and apoptosis rates. Co-immunoprecipitation experiments demonstrated a direct interaction between USP46 and TRAF6, implicating USP46 in the modulation of TRAF6 ubiquitination, a process that is fundamental to tumor physiology. The results indicated that decreased USP46 expression led to an increase in the levels of the anti-apoptotic protein Bcl-2, while there was a corresponding decrease in key pro-apoptotic proteins such as caspase-3, caspase-9, and Bax. Additionally, the study found elevated levels of phosphorylated AKT and mTOR, which suggest the activation of survival signaling pathways in the cancer cells. These findings collectively suggest that the up-regulated USP46 promotes apoptosis in lung cancer cells through the regulation of TRAF6. Therefore, targeting the USP46/TRAF6 signaling pathway presents a promising therapeutic strategy for lung cancer treatment, potentially offering new avenues for intervention in cancer progression and cell survival mechanisms.

EGFR exon 19 deletions and exon 21 point mutations are the most common mutations in lung adenocarcinoma, with patients deriving significant clinical benefits from EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs in rare compound EGFR mutations remains uncertain. We report a case of lung adenocarcinoma with concurrent EGFR exon 18 G719A and exon 21 L833V mutations, showing a favorable response to third-generation TKI treatment. We reported a case of a 63-year-old female patient with brain, bone, and adrenal metastases from lung adenocarcinoma. Next-generation sequencing analysis identified a rare EGFR exon 18 G719A mutation in combination with an EGFR exon 21 L833V mutation. The patient received furmonertinib as first-line treatment and achieved a sustained response lasting over 12 months. This is the first reported case highlighting the efficacy of a third-generation TKI in treating lung adenocarcinoma with this rare compound mutation. Our findings suggest that third-generation TKIs may be a viable therapeutic option for prolonging progression-free survival in this patient subset.

Fruquintinib has been recommended for treating refractory metastatic colorectal cancer. This single-arm, phase II study explored for the first time whether fruquintinib combined with capecitabine could be used as a first-line treatment for patients with metastatic colorectal cancer who are intolerant to intravenous chemotherapy. From December 8, 2021, to December 31, 2024, 17 patients were included in the effect analysis who respectively received capecitabine and fruquintinib at a starting dose of 825 mg/m² twice a day and 4 mg every day (2 weeks followed by 1-week rest) and recorded changes in safety and quality of life; the dosage can be appropriately adjusted according to the protocol to make it tolerable for the patients. The median age was 76 years old; the study achieved a disease control rate of 88.2%, an overall response rate of 17.6%, and a median progression-free survival of 16.3 months (95% CI 9.7-22.9); the overall survival had not been reached. The median quality of life scores and self-assessment of health scores change, respectively, from 42 (IQR 34, 47) to 45 (IQR 41, 57) and from 5 (IQR 4.25, 6.75) to 4 (IQR 3.00, 6.00). There were only 3 events of grade ≥ 3 TRAEs, including one rare case of aortic dissection. Fruquintinib combined with capecitabine has initially shown ideal disease control, safety, and convenience, especially as a first-line treatment for elderly frail patients with metastatic colorectal cancer. Further phase III study is planned to refine this combination. Clinical Trial Number: NCT04866108.

Glioblastoma multiforme (GBM) accounts for 70% of all primary malignancies of the central nervous system. Current treatment strategies involve surgery followed by chemotherapy with temozolomide (TMZ); however, the median survival after treatment is approximately 15 months. Many GBM cases develop resistance to TMZ, resulting in a poor prognosis for patients, which underscores the urgent need for novel therapeutic approaches. One promising avenue is the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates α-tubulin and is increasingly recognized as a potential pharmacological target in cancer. In GBM specifically, HDAC6 overexpression has been linked to poor prognosis and chemoresistance. In this study, we demonstrate that HDAC6 protein levels are elevated in GBM and evaluate the effects of the novel selective HDAC6 inhibitor, WT161, on U251, U87, and T98G cells to assess its potential to revert the malignant phenotype. Our results show a significant increase in acetylated α-tubulin levels, suppression of cell growth, cell cycle arrest at the G2/M phase, and decreased clonogenicity of 2D-cultured GBM cells. Additionally, WT161 acted synergistically with TMZ, induced apoptosis and enhanced TMZ-induced apoptosis. Notably, HDAC6 inhibition resulted in reduced cell migration and invasion, associated with decreased β-catenin levels. When cultured in 3D conditions, WT161-treated T98G spheroids were sensitized to TMZ and exhibited reduced migration. Finally, HDAC6 inhibition altered the metabolome, particularly affecting metabolites associated with lipid peroxidation. In conclusion, our data reveal, for the first time, the efficacy of the selective HDAC6 inhibitor WT161 in a preclinical GBM setting.

Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) is reported to play a potential role in cancer immunotherapy. However, the association between DYNC2H1 mutation and the clinical benefit of immunotherapy in non-small cell lung cancer (NSCLC) and melanoma remains to be elucidated. We collected data from three public immune checkpoint inhibitor (ICI)-treated NSCLC cohorts (n = 137 in total) and seven ICI-treated melanoma cohorts (n = 418 in total) to explore the potential of DYNC2H1 mutation as a predictive biomarker. The clinical outcomes, including the objective response rate (ORR) and progression-free survival (PFS), of patients with DYNC2H1 mutations are significantly better than those of patients with wild-type DYNC2H1. Multivariate Cox regression analysis confirmed that DYNC2H1 mutation was an independent predictive factor for ICI efficacy in NSCLC and melanoma. In addition, DYNC2H1 mutation exhibited no prognostic value for NSCLC or melanoma. Tumour mutational burden (TMB) and tumour neoantigen burden (TNB) were significantly higher in patients with DYNC2H1 mutation than in those with wild-type DYNC2H1 in both NSCLC and melanoma cohort. The analysis of immune-related genes and immune cell enrichment revealed an association between DYNC2H1 mutation and increased immune infiltration, revealing a potential mechanism underlying the predictive role of DYNC2H1 mutation in immunotherapy efficacy. In conclusion, DYNC2H1 mutation serves as a predictive biomarker of ICI efficacy in NSCLC and melanoma.

Colorectal cancer is the third most prevalent cancer in the world. Early screening and detection of tumours, active surgical radical treatment, postoperative adjuvant chemotherapy, targeted therapy, and immunotherapy are performed based on pathological staging and immunohistochemistry. Even with these measures, the 5-year survival rate of colorectal cancer is only 65%, and a considerable number of patients still experience tumour recurrence or even metastasis. The KRAS G12C mutation accounts for 3 to 4% of refractory colorectal cancer (advanced or metastatic colorectal cancer), and it was once believed that KRAS did not have a drug target until the emergence of KRAS G12C inhibitors provided targeted treatment for KRAS-mutated colorectal cancer. However, KRAS G12C inhibitors only produce moderate efficacy, and resistance occurs after a short remission. The mechanism of drug resistance in tumour cells is complex and diverse, and existing research has limited understanding of it. This review aims to elucidate the clinical trial progress of KRAS G12C inhibitors in refractory colorectal cancer, the research progress of drug resistance mechanisms, and the combined treatment strategies for drug resistance.

Research on prodrug technology has opened new avenues for site-directed chemotherapy rather than systemic chemotherapy. This distinctive strategy allows drug delivery to be activated by light-, irradiation-, or ultrasound (US)-tunable chemistries, which have been termed photopharmacology, radiopharmacology, and sonopharmacology, respectively. Prodrugs have emerged as a main strategy for improving pharmacokinetics, reducing side effects, and thus enhancing the therapeutic efficacy of drugs. This review summarizes stimuli-responsive drug release systems and the latest progress in exogenous stimuli-responsive prodrug activation, e.g., light, irradiation, and US, with a focus on the activation of small molecule prodrugs, antibody‒drug conjugates, and prodrug nanosystems. In addition, challenges encountered by Pt drugs and Pt(IV) prodrug nanotherapeutics are summarized and discussed. Moreover, this review presents the current state of precise treatment and discusses the opportunities and challenges for the clinical translation of these strategies.