A pan-KRAS degrader for the treatment of KRAS-mutant cancers.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

mRNA-based Vaccines Targeting the T-cell Epitope-rich Domain of Epstein Barr Virus Latent Proteins Elicit Robust Anti-Tumor Immunity in Mice.

Epstein-Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV-associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA-based therapeutic vaccines that express the T-cell-epitope-rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc-LMP2A), truncated EBV nuclear antigen 1 (Trunc-EBNA1), and Trunc-EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor-bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc-LMP2A, Trunc-EBNA1, and Trunc-EBNA3A, are more effective than full-length antigens in activating antigen-specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA-based therapeutic vaccines targeting the T-cell-epitope-rich domain of EBV latent proteins and providing new treatment options for EBV-associated cancers.

Development of a web-based prognostic model to quantify the survival benefit of cumulative cisplatin dose during concurrent chemoradiotherapy in childhood nasopharyngeal carcinoma.

PURPOSE: To quantify and predict the survival benefits of cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC). MATERIALS AND METHODS: Patients with CA-LANPC who received first-line neoadjuvant chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) between September 2007 and April 2018 were evaluated. Recursive partitioning analyses (RPAs) helped identify the ideal thresholds of CC-CCD on disease-free survival (DFS). We then developed a web-based predictive model to quantify the survival benefit of CC-CCD for CA-LANPC. RESULTS: In total, 139 patients were eligible for the analysis. The median CC-CCD was 162 mg/m2 (IQR, 138-192 mg/m2). The optimum cut-off point of CC-CCD was 160 mg/m2 for DFS. Hence, we selected 160 mg/m2 as the cut-off to classify CA-LANPC into either high or low CC-CCD groups for survival analysis. The 5-year DFS rates were 91.6% in the high (≥160 mg/m2) CC-CCD group and 77.8% in the low (<160 mg/m2) CC-CCD group (P = 0.011). Multivariate analysis indicated CC-CCD (HR, 0.34; 95%CI, 0.13-0.87; P = 0.024), T stage (HR, 3.72; 95%CI, 1.35-10.22; P = 0.011), and EBV DNA (HR, 3.00; 95%CI, 1.00-8.97; P = 0.049) were independent prognostic factors and were incorporated into the prognostic model. N stage was also included due to its clinical importance. The predictive model was demonstrably accurate (C-index, 0.741) when predicting 5-year DFS rates. CONCLUSIONS: We built a predictive model to quantify the survival benefit of CC-CCD for CA-LANPC treated with NAC plus CCRT. This tool may improve individual treatment consultations and facilitate evidence-based decision-making.

Critical properties of the two-dimensional q-state clock model.

We perform the state-of-the-art tensor network simulations directly in the thermodynamic limit to clarify the critical properties of the q-state clock model on the square lattice. We determine accurately the two phase transition temperatures through the singularity of the classical analog of the entanglement entropy, and provide extensive numerical evidences to show that both transitions are of the Berezinskii-Kosterlitz-Thouless (BKT) type for q≥5 and that the low-energy physics of this model is well described by the Z_{q}-deformed sine-Gordon theory. We also determine the characteristic conformal parameters, especially the compactification radius, that govern the critical properties of the intermediate BKT phase.

Metformin attenuates PD-L1 expression through activating Hippo signaling pathway in colorectal cancer cells.

Programmed cell death ligand 1 (PD-L1) is a key suppressor of the cytotoxic immune response. In colorectal carcinoma (CRC), PD-L1 expression results in immune escape and poor prognosis. Extensive researches suggested that metformin had a potential efficacy of enhancing anti-tumor immune response in different types of cancer. However, the detail mechanisms underlying the efficacy in CRC are unclear. Here, we showed that metformin decreases PD-L1 and YAP1 expression in vitro and in vivo. After silencing or inhibiting YAP1 expression by Verteporfin (VP), the inhibitor of YAP1, the expression of PD-L1 were decreased in protein level in CRC cells. Furthermore, metformin directly phosphorylated YAP1 and restricted YAP1 to entry in the nucleus, so that PD-L1 was reduced via western blot and immunofluorescence assays in SW480 and HCT116 cells. Finally, subcutaneous xenotransplanted tumor models of HCT116 cells were established in BALB/c nude mice. Compared with the control group, PD-L1 and YAP1 expressions in tumor tissues, detected by immunohistochemistry, were reduced in the group of metformin treatment. These findings illuminate a new regulatory mechanism, metformin activates Hippo signaling pathway to regulate PD-L1 expression and suggests that metformin has the possibility to increase the efficacy of immunotherapy in human CRC.

[Research Advances on Programmed Cell Death Receptor-1 Antibody in the Treatment of Lymphoma--Review].

Abstract　　Tumor cells avoid immune surveillance by overexpressing ligands of checkpoint receptors on tumor cells or adjacent cells, resulting in inability or exhaustion of T cells. Numerous studies have shown that lymphoma cells highly expressed programmed cell death ligand-1 (PD-L1), suggesting that PD-1 may become an important target for lymphoma treatment. By targeting the PD-1 protein, the cellular activity of T cells will be significantly enhanced, and the tumor growth will be inhibited. Recently, antibodies against PD-1 have shown high efficacy and safety in the clinical studies of lymphoma, which are expected to become the targeted therapeutic drugs for lymphoma. In order to deeply understand the application of PD-1 antibody in treatment of lymphoma, this review briefly summaries the present state of lymphoma studies, the action mechanism and preparation method of PD-1 antibody in clinical treatment of lymphoma.

AP-1 confers resistance to anti-cancer therapy by activating XIAP.

The underlying cause of treatment failure in many cancer patients is intrinsic and acquired resistance to chemotherapy. Recently, histone deacetylase (HDAC) inhibitors have developed into a promising cancer treatment. However, resistance mechanism induced by HDAC inhibitors remains largely unknown. Here we report that a HDAC inhibitor, JNJ-2648158 induced transcription of XIAP by activating AP-1 expression, which conferring resistance to chemotherapeutics. Our results showed that high expression of c-Fos caused by HDAC inhibitor promoted AP-1 formation during acquired resistance towards chemo-drugs, indicating an extremely poor clinical outcome in breast cancers and liver cancers. Our study reveals a novel regulatory mechanism towards chemo-drug resistance, and suggests that XIAP may serve as a potential therapeutic target in those chemo-resistant cancer cells.

Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro.

Myeloid-derived suppressor cells (MDSC) have been identified as a population of immature myeloid cells that suppress anti-tumor immunity. MDSC are increased in tumor-bearing hosts; thus, depletion of MDSC may enhance anti-tumor immunity. Histone deacetylase inhibitors (HDACi) are chemical agents that are primarily used against hematologic malignancies. The ability of these agents to modulate anticancer immunity has recently been extensively studied. However, the effect of HDACi on MDSC has remained largely unexplored. In the present study, we provide the first demonstration that HDACi treatment decreases MDSC accumulation in the spleen, blood and tumor bed but increases the proportion of T cells (particularly the frequency of IFN-γ- or perforin-producing CD8+ T cells) in BALB/C mice with 4T1 mammary tumors. In addition, HDACi exposure of bone marrow (BM) cells significantly eliminated the MDSC population induced by GM-CSF or the tumor burden in vitro, which was further demonstrated as functionally important to relieve the inhibitory effect of MDSC-enriched BM cells on T cell proliferation. Mechanistically, HDACi increased the apoptosis of Gr-1+ cells (almost MDSC) compared with that of Gr-1- cells, which was abrogated by the ROS scavenger N-acetylcysteine, suggesting that the HDACi-induced increase in MDSC apoptosis due to increased intracellular ROS might partially account for the observed depletion of MDSC. These findings suggest that the elimination of MDSC using an HDACi may contribute to the overall anti-tumor properties of these agents, highlighting a novel property of HDACi as potent MDSC-targeting agents, which may be used to enhance the efficacy of immunotherapeutic regimens.

Nodal signaling modulates the expression of Oct-4 via nuclear translocation of ß-catenin in lung and prostate cancer cells.

Nodal is a member of transforming growth factor beta (TGF-ß) superfamily. Nodal promotes the self-renewal of human cancer stem cells (CSCs) and triggers carcinogenesis of human cancers via an autocrine manner through Smad2/3 pathway. In our study, generation of Nodal-overexpressed cancer cells was constructed, and the effect of Nodal on the stem cell marker Oct-4 was evaluated by overexpression or blocked Nodal/ALKs signaling pathway in non-small cell lung cancer cells A549 and prostate cancer cells PC3. Functionally, Nodal also increased the proliferation via the ß-catenin nuclear translocation. This increase was attributed to GSK-3ß dephosphorylating, and activin receptor-like kinase 4/7 (ALK4/7) played a major role in human cancer cells. Our study provides a positive understanding of Nodal function in cancer cells and suggests a potential novel target for clinical therapeutic research.

Expression and significance of Nodal in human cancers: a meta-analysis.

Cancer is a global and growing problem. Nodal, which has been showed to be involved in occurrence and development of cancers, is an important embryonic morphogen. The aim of this study was to evaluate the significance of Nodal expression in human cancers based on the published related articles. Online databases were searched to retrieve relevant articles published between 2000 and 2015. The odds ratio (OR) with its 95% confident intervals (CI) were employed to calculate the strength of significance. Finally, a total of 11 articles were screened out, including 801 cancer patients and 372 healthy controls. Nine kinds of cancers were contained, and Nodal was detected in 56.7% of all participants (665/1173). Overall, our result found that Nodal was highly expressed in cancer patients than that in healthy controls, indicating that Nodal expression was significantly associated with cancers progression (OR=21.72, 95% CI=9.94-47.46, P<0.00001). Subgroup analysis showed that Nodal expression was significantly corrected with high WHO grade of human cancers (III+IV versus I+II: OR=2.46, 95% CI=1.63-3.71, P<0.00001). This significant relationship was also found in tumor size, differentiation degree, not observed in gender, age and lymphatic metastasis status of patients with all studied cancers in this meta-analysis. In conclusion, our results demonstrated that Nodal might be implicated in cancer progression, suggesting that it was a potential biomarker and therapeutic target for cancers.