Haiying Ding

Antibody-drug conjugates (ADCs) are a class of innovative biopharmaceutical drugs, which, via their antibody (mAb) component, deliver and release their potent warhead (a.k.a. payload) at the disease site, thereby simultaneously improving the efficacy of delivered therapy and reducing its off-target toxicity. To design ADCs of promising efficacy, it is crucial to have the critical data of pharma-information and biological activities for each ADC. However, no such database has been constructed yet. In this study, a database named ADCdb focusing on providing ADC information (especially its pharma-information and biological activities) from multiple perspectives was thus developed. Particularly, a total of 6572 ADCs (359 approved by FDA or in clinical trial pipeline, 501 in preclinical test, 819 with in-vivo testing data, 1868 with cell line/target testing data, 3025 without in-vivo/cell line/target testing data) together with their explicit pharma-information was collected and provided. Moreover, a total of 9171 literature-reported activities were discovered, which were identified from diverse clinical trial pipelines, model organisms, patient/cell-derived xenograft models, etc. Due to the significance of ADCs and their relevant data, this new database was expected to attract broad interests from diverse research fields of current biopharmaceutical drug discovery. The ADCdb is now publicly accessible at: https://idrblab.org/adcdb/.

BACKGROUND: Immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC) have been rapidly evolving. ICIs are likely to be more effective but also lead to escalating healthcare costs. OBJECTIVES: The aim of this study was to evaluate the cost effectiveness of immune checkpoint inhibitors (ICIs) for treatment of non-small cell lung cancer (NSCLC). METHODS: We searched the PubMed, Web of Science, and Cochrane Library for studies comparing the cost effectiveness of ICIs for NSCLC. Potential studies identified were independently checked for eligibility by two authors, with disagreement resolved by a third reviewer. Quality of the included studies was evaluated using Consolidated Health Economic Evaluation Reporting Standards checklists. RESULTS: A total of 22 economic studies were included. Overall reporting of the identified studies largely met CHEERS recommendations. In the first-line setting, for advanced or metastatic NSCLC patients with PD-L1 ≥ 50%, pembrolizumab appeared cost-effective compared with platinum-based chemotherapy in the US and Hong Kong (China), but not in the UK and China. The cost-effectiveness of pembrolizumab versus chemotherapy for first-line treatment of NSCLC in PD-L1 ≥ 1% patients remained obscure. Regardless of PD-L1 expression status, pembrolizumab in combination with chemotherapy could be a cost-effective first-line therapy in the US. On the contrary, addition of atezolizumab to the combination of bevacizumab and chemotherapy was not cost-effective for patients with metastatic non-squamous NSCLC from the US payer perspective. In the second-line setting compared with docetaxel, pembrolizumab was cost-effective; though nivolumab was not cost-effective in the base case, it could be by increased PD-L1 threshold. Results of the cost-effectiveness of atezolizumab second-line treatment remained inconsistent. In addition, the adoption of durvalumab consolidation therapy after chemoradiotherapy could be cost-effective versus no consolidation therapy for patients with stage III NSCLC. CONCLUSIONS: Immunotherapy can be a cost-effective option for treatment of NSCLC in several scenarios. A discount of the agents or the use of PD-L1 expression as a biomarker improves the cost-effectiveness of immunotherapy.

BACKGROUND Ovarian cancer is the most common gynecological malignancies in women, with high mortality rates worldwide. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily which preferentially induces apoptosis of cancer cells. However, acquired resistance to TRAIL hampers its therapeutic application. Identification of compounds that sensitize cancer cells to TRAIL is vital in combating resistance to TRAIL. The effect of kaempferol, a flavonoid enhancing TRAIL-induced apoptosis in ovarian cancer cells, was investigated in this study. MATERIAL AND METHODS The cytotoxic effects of TRAIL (25 ng/mL) and kaempferol (20-100 µM) on human ovarian cancer cells OVCAR-3 and SKOV-3 were assessed. Effect of kaempferol on the expression patterns of cell survival proteins (Bcl-xL, Bcl-2, survivin, XIAP, c-FLIP) and apoptotic proteins (caspase-3, caspase-8, caspase-9, Bax) were studied. The influence of kaempferol on expression of DR4 and DR5 death receptors on the cell surface and protein and mRNA levels was also analyzed. Apoptosis following silencing of DR5 and CHOP by small interfering RNA (siRNA), and activation of MAP kinases were analyzed as well. RESULTS Kaempferol enhanced apoptosis and drastically up-regulated DR4, DR5, CHOP, JNK, ERK1/2, p38 and apoptotic protein expression with decline in the expression of anti-apoptotic proteins. Further transfection with siRNA specific to CHOP and DR5 indicated the involvement of CHOP in DR5 up-regulation and also the contribution of DR5 in kaempferol-enhanced TRAIL-induced apoptosis. CONCLUSIONS Kaempferol sensitized ovarian cancer cells to TRAIL-induced apoptosis via up-regulation of DR4 and DR5 through ERK/JNK/CHOP pathways.

Abstract As a critical component of the tumour immune microenvironment (TIME), the resident microbiota promotes tumorigenesis across a variety of cancer types. Here, we integrated multiple types of omics data, including microbiome, transcriptome, and metabolome data, to investigate the functional role of intratumoral bacteria in gastric cancer (GC). The microbiome was used to categorize GC samples into six subtypes, and patients with a high abundance of Streptococcus or Pseudomonas had a markedly worse prognosis. Further assays revealed that Streptococcus anginosus (SA) promoted tumour cell proliferation and metastasis while suppressing the differentiation and infiltration of CD8 + T cells. However, antibiotic treatment significantly suppressed tumorigenesis in SA + mice in vivo. We further demonstrated that the SA arginine pathway increased the abundance of ornithine, which may be a major contributor to reshaping of the TIME. Our findings demonstrated that SA, a novel risk factor, plays significant roles in the initiation and progression of GC, suggesting that SA might be a promising target for the diagnosis and treatment of GC.