NKD2 is frequently methylated in human esophageal cancer, and the expression of NKD2 is regulated by promoter region methylation. NKD2 suppresses esophageal cancer progression by inhibiting Wnt signaling both in vitro and in vivo.

Key Points Question What is the safety and antitumor activity of MRG003 in patients with advanced solid tumors? Findings In this phase 1 clinical trial of 61 patients with advanced or metastatic solid tumors, treatment with MRG003 exhibited manageable safety and showed encouraging antitumor activity in squamous cell carcinomas of the head and neck and nasopharyngeal carcinoma, with a confirmed objective response rates of 40% and 44%, respectively. Meaning The study findings suggest the safety of treatment with MRG003 and an acceptable tolerance in most patients with epidermal growth factor receptor–expressing solid tumors, as well as encouraging antitumor activity in patients with squamous cell carcinomas of the head and neck and nasopharyngeal carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignances and the second leading cause of cancer related death worldwide. RASSF10 is located on chromosome 11p15.2, a region that shows frequent loss of heterozygosity (LOH) in several cancer types. Our previous study found that RASSF10 suppresses colorectal cancer growth by activating P53 signaling. To explore the epigenetic changes and the mechanism of RASSF10 in human HCC, 69 cases of primary HCC, twenty cases of normal liver tissue samples and 17 HCC cell lines were involved in this study. We found that RASSF10 was methylated in 82.6% (57/69) of human primary HCC and methylation of RASSF10 was significantly associated with tumor size (P < 0.05) and TNM stage (P < 0.05). The expression of RASSF10 was regulated by promoter region methylation. Restoration of RASSF10 expression suppressed cell proliferation, induced apoptosis and G2/M phase arrest, as well as sensitized cells to docetaxel and activated P53 signaling in HepG2 and QGY7703 cells. In conclusion, we demonstrated that RASSF10 is frequently methylated in human HCC and its methylation is a potential docetaxel resistant marker. Our data also indicate that RASSF10 suppresses human HCC growth by activating P53 signaling.

Background: Gastric cancer is one of the most common malignant tumors worldwide, and the 2nd most common in China. The development of new agents for the treatment of advanced gastric cancer is stagnant. Immunotherapy which inhibits the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) interaction is becoming a new option for treatment of late-stage gastric cancer (GC). Several trials suggest patients with PD-L1 positive expression (Combined Positive Score: CPS ≥ 1) population, especially CPS ≥ 10 population, are most likely to benefit from anti-PD-1 antibody treatment. Emerging data show encouraging efficacy signals of anti-PD-1 antibody in combination with chemotherapy in GC. Sintilimab, a highly selective, fully human, anti-PD-1 monoclonal antibody, was approved for relapsed or refractory Hodgkin Lymphoma in China in 2008. Based on the efficacy signals and the safety profile from a phase 1b trial of sintilimab plus XELOX regimen (oxaliplatin and capecitabine) as first line treatment for unresectable advanced gastric and GEJ adenocarcinoma, we aim to verify the therapeutic potential of sintilimab in combination with chemotherapy in patients with advanced GC/gastroesophageal junction (GEJ) cancer . Methods: The ORIENT-16 study (NCT: 03745170) is a randomized, double-blind, multi-center, phase III trial conducted in China to evaluate the efficacy and safety of sintilimab or placebo in combination with XELOX as first-line treatment in subjects with recurrent unresectable locally advanced or metastatic GC or GEJ adenocarcinoma. The study will enroll 650 patients. Patients will be randomly assigned in a 1:1 ratio to receive sintilimab every 3 weeks plus XELOX (capecitabine, 1000mg/m2 orally twice daily for 14 days followed by 7 days off; oxaliplatin, 130mg/m2 intravenously on day1 every 3 weeks) or placebo plus XELOX for up to six cycles. Thereafter, the patients will receive maintenance therapy with sintilimab every 3 weeks plus capecitabine (1000mg/m2 orally twice daily for 14 days followed by 7 days off) or placebo plus capecitabine every 3 weeks. Sintilimab will be dosed according to the subject’s bodyweight ( &lt; 60kg, 3mg/kg; ≥ 60kg, 200mg). Stratification factors are ECOG Performance status (0 or 1), liver metastasis (yes or no) and PD-L1 expression score in tumor cells and immune cells (DAKO 22C3: CPS &lt; 10 or ≥ 10). Major eligibility criteria include age between 18 and 75 years; newly diagnosed, recurrent unresectable locally advanced or metastatic G or GEJ adenocarcinoma; at least one evaluable tumor lesion according to RECIST v1.1 criteria; and patients must have fresh tumor tissue or archival tumor tissue for PD-L1 assessment from within 6 months of entrance. Patients with known HER2 positive G or GEJ cancer are excluded. Treatment will be discontinued for disease progression, unacceptable toxicity, patient / physician decision to withdraw or after 24-months of treatment. The primary endpoint is median overall survival assessed in both entire population and in PD-L1 positive (CPS ≥ 10) population of patients. Secondary endpoints include progression free survival, objective response rate, disease control rate,duration of response and safety. Recruitment is currently ongoing in multiple sites in China. Citation Format: Jianming Xu, Yongshuai Jin, Ying Liu, Hui Zhou, Yan Wang. ORIENT-16: Sintilimab plus XELOX vs placebo plus XELOX as 1st line treatment for unresectable advanced gastric and GEJ adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT213.