Cancer Communications最新文献

Bladder cancer (BCa) is the most prevalent urological cancer worldwide [1]. A significant proportion of BCa (89%) exhibits molecular alterations in the cell cycle pathway, and targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is deemed as a promising therapeutic strategy [2]. Selective inhibitors of CDK4/6 (CDK4/6is) have been approved by the US Food and Drug Administration (FDA) [3]. They could induce cell cycle arrest in BCa immediately, and after this “sensitive stage”, unknown compensatory mechanism may cause acquired resistance [4, 5]. To address this issue, our study employed multi-omics and identified ribonucleotide reductase regulatory subunit M2 (RRM2), a crucial component of the ribonucleotide reductase (RNR) complex [6], as a key mediator in conferring acquired resistance. We further investigated whether Palbociclib activates proteolysis of RRM2 by the ubiquitin-proteasome system (UPS) and the ubiquitin-like proteins (UBLs) during the sensitive stage. Additionally, we explored whether RRM2 is controlled by E2F transcription factor 3 (E2F3) when acquired resistance is established. Interestingly, upregulation of RRM2 may also cause chemotherapy resistance [7]. Thus, we verified if concurrent inhibition of RNR and CDK4/6 holds promise as a novel therapeutic strategy for BCa patients, especially those exhibit resistance to chemotherapy. All the study designs and methods are described in the Supplementary file.

Retinoblastoma (RB)-positive BCa elicits a sequential progression from sensitivity to resistance to Palbociclib [8]. We utilized multi-omics to identify key regulators of this process (Figure 1A, Supplementary Tables S1-S5). The only candidate matching all three high-throughput screening approaches was RRM2, and pathway analysis further demonstrated related mechanisms (Supplementary Figures S1-S2). To validate this finding, we examined the cell cycle distribution and expression levels of the other RNR subunit RRM1 and RRM2 in a time kinetic (Figure 1B-C, Supplementary Figure S3A-D). Transcript levels were initially downregulated, followed by a partial recovery, while the decline and recovery pattern of proteins mirrored this. We then transduced single-guide RNAs of RRM1 and RRM2 into T24 synergistic activation mediator (SAM) cells and confirmed partial resistance (Figure 1D-E, Supplementary Figure S3E). However, degradation of RRM2 was still observed at early time points (Supplementary Figure S3F), indicating that proteolysis might be essential for therapy response. We then applied the proteasome inhibitors Epoxomicin/MG-132 in combination with Palbociclib. As shown, protein degradation of RRM2 was effectively blocked, but only partially for RRM1 (Figure 1F, Supplementary Figure S4A-B). We next tested the combination of Palbociclib with ubiquitin-like proteins (UBLs) inhibitor MLN4924 and proved that the initial degradation of RRM1/2

The cornerstone of scientifically valid and ethically sound clinical trials is in compliance with established global quality requirements. Although China has made significant progress over the past 20 years in terms of the clinical trial quantity [1], quality and participation in multiregional trials [2], there still remain concerns regarding the trial quality, which could be associated with the self-inspection initiative in 2015 [3].

In fact, the clinical trial quality in China has improved significantly during the past decade, which is reflected in the harmonized development trends of industry quality systems and regulatory quality promotion systems (Figure 1). In 2003, the China Good Clinical Practice (GCP) guidelines have been released, which identified the subject protection and data integrity as two basic principles of clinical trials. Four rigorous management policies started to implement in 2015, which required sponsors to re-evaluate the authenticity, integrity, and compliance of trial data before new drug application [4]. A series of high-profile policies were subsequently announced by the National Medical Products Administration, to improve quality ecosystem [5]. The regulatory supervision of trial quality in China has been significantly strengthened since then. In the meantime, a vital shift occurred since the quality culture in the industry emerged, and the approaches and tools of quality management systems were launched through information exchange and training.

Another milestone of trial quality progress in China was that China officially joined the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and began to integrate into the international drug regulatory system. This alliance initiated a proactive and harmonized process with China pledging to gradually transform its pharmaceutical regulatory authorities, industry and institutions to implement the international coalition's technical standards and guidelines [6]. Universal quality standard GCP guidelines and ideas, such as quality by design (QbD) and risk-based inspection, could be implemented almost simultaneously in China. Gradually, trial quality culture has been embedded in the full life cycle of drug research and development (R&D) in China.

All four regions, including China, the European Union (EU), the United States (US) and Japan, have a common consensus and harmonized standards to ensure the participants’ safety, data integrity and GCP compliance, and all have established similar regulatory frameworks for quality compliance (Supplementary Table S1). For example, local and international GCP standards and principles should be established, then inspection processes and checklists with key points for investigational drugs should be employed. In terms of inspection objects, types, requirements and disclosure, we observed cons

Background: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study.

Methods: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan-Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management.

Results: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks.

Conclusion: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.