In the era of precision medicine, it has been increasingly recognized that individuals with a certain disease are complex and different from each other. Due to the underestimation of the significant heterogeneity across participants in traditional “one-size-fits-all” trials, patient-centered trials that could provide optimal therapy customization to individuals with specific biomarkers were developed including the basket, umbrella, and platform trial designs under the master protocol framework. In recent years, the successive FDA approval of indications based on biomarker-guided master protocol designs has demonstrated that these new clinical trials are ushering in tremendous opportunities. Despite the rapid increase in the number of basket, umbrella, and platform trials, the current clinical and research understanding of these new trial designs, as compared with traditional trial designs, remains limited. The majority of the research focuses on methodologies, and there is a lack of in-depth insight concerning the underlying biological logic of these new clinical trial designs. Therefore, we provide this comprehensive review of the discovery and development of basket, umbrella, and platform trials and their underlying logic from the perspective of precision medicine. Meanwhile, we discuss future directions on the potential development of these new clinical design in view of the “Precision Pro”, “Dynamic Precision”, and “Intelligent Precision”. This review would assist trial-related researchers to enhance the innovation and feasibility of clinical trial designs by expounding the underlying logic, which be essential to accelerate the progression of precision medicine.

Background: Foxp3⁺ regulatory T (T_reg) cells facilitate tumor immune evasion by forming a suppressive tumor microenvironment. Therefore, immune therapies promoting T_reg fragility may greatly enhance immune checkpoint blockade (ICB) efficacy in cancers. Methods: We have screened 2640 compounds and identified the gut microbial metabolite gallic acid, which promotes Foxp3 degradation and T_reg instability by repressing Usp21 gene transcription. In vivo and in vitro experiments have been performed to explore the roles of Usp21 in T_reg cells. Importantly, we treated tumor-bearing mice with gallic acid and anti-PD-1 antibody to explore the potential therapeutic value of gallic acid in clinical cancer immunotherapy. Results: Mechanistically, gallic acid prevents STAT3 phosphorylation and the binding of phosphorylated STAT3 to Usp21 gene promoter. The deubiquitinated Usp21 and stabilized PD-L1 proteins boost the function of T_reg cells. Combination of gallic acid and anti-PD-1 antibody, in colorectal cancer (CRC) treatment, not only significantly dampen T_reg cell function by impairing PD-L1/PD-1 signaling and downregulating Foxp3 stability, but also promote CD8⁺ T cells’ production of IFN-γ and limited tumor growth. Conclusion: Our findings have implications for improving the efficacy of ICB therapy in CRC by inducing T-helper-1-like Foxp3^lo T_reg cells.

Central precocious puberty (CPP), largely caused by germline mutations in the MKRN3 gene, has been epidemiologically linked to cancers. MKRN3 is frequently mutated in non–small cell lung cancers (NSCLCs) with five cohorts. Genomic MKRN3 aberrations are significantly enriched in NSCLC samples harboring oncogenic KRAS mutations. Low MKRN3 expression levels correlate with poor patient survival. Reconstitution of MKRN3 in MKRN3-inactivated NSCLC cells directly abrogates in vitro and in vivo tumor growth and proliferation. MKRN3 knockout mice are susceptible to urethane-induced lung cancer, and lung cell–specific knockout of endogenous MKRN3 accelerates NSCLC tumorigenesis in vivo. A mass spectrometry–based proteomics screen identified PABPC1 as a major substrate for MKRN3. The tumor suppressor function of MKRN3 is dependent on its E3 ligase activity, and MKRN3 missense mutations identified in patients substantially compromise MKRN3-mediated PABPC1 ubiquitination. Furthermore, MKRN3 modulates cell proliferation through PABPC1 nonproteolytic ubiquitination and subsequently, PABPC1-mediated global protein synthesis. Our integrated approaches demonstrate that the CPP-associated gene MKRN3 is a tumor suppressor.

The present study aimed to evaluate the effects of concomitant proton pump inhibitor (PPI) use on immune checkpoint inhibitor (ICI) efficacy among advanced cancer patients.A systematic literature s...