Background:The most effective treatment with immune checkpoint inhibitors (ICIs) is limited to the microsatellite instability high (MSI-H) subgroup of advanced colorectal cancer. ICIs are completely ineffective in microsatellite stabilized (MSS) patients with advanced colorectal cancer. Fruquintinib, a tyrosine kinase inhibitor (TKI) domestically made in China that specifically inhibits vascular endothelial growth factor receptors, is used to treat refractory metastatic colorectal cancer (mCRC). Researches showed that anti-angiogenic therapy combined with immunotherapy induces a long-lasting antitumor immune response. Here, we aimed to evaluate antitumor efficacy and safety of fruquintinib with anti-programmed death-1 (PD-1) antibody toripalimab in Chinese patients with non-MSI-H/mismatch repair proficient (pMMR) mCRC.Methods: This was a single-arm, single-center, prospective, phase II clinical trial. A total of 19 MSS patients with refractory or advanced mCRC were enrolled They received fruquintinib (5 mg, orally, once daily for 3 weeks followed by 1 week off in 4-week cycles) and toripalimab (240 mg, intravenously administered on day 1 once every 3 weeks) until disease progression or unacceptable toxicity. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), 1-year PFS rate, disease control rate (DCR), and toxicity were reviewed and evaluated. The Cox regression model was used to analyze the influence on OS and PFS.Results: Among the 19 patients, the median age was 52 years (range, 30-71 years); 4 patients (21.05%) achieved partial response, 10 patients (52.63%) experienced stable disease, and 4 patients (21.05%) experienced progressive disease. The ORR was 21.05%. The median PFS and OS were 5.98 months and 11.10 months, respectively. Patients with peritoneal metastasis received greater benefit from combination therapy, with a longer PFS (P=0.043) in the univariate analysis. The most common treatment-related adverse reactions were fatigue (57.89%), hepatic dysfunction (42.11%) and hypertension (36.84%). No serious adverse effects or adverse effect-related deaths were reported. Conclusions:Our study provides evidence supporting fruquintinib combined with an anti-PD-1 monoclonal antibody have the better effect than fruquintinib alone in the third-line setting for Chinese patients with MSS advanced colorectal cancer. Primary lesion excision and peritoneal metastasis were independent prognostic factors of PFS. Further well-designed, prospective, large-scale studies are needed to validate this outcome.

BackgroundLung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. The role of the long non-coding RNA (lncRNA) LINC00958, which regulates the malignant behavior of multiple tumors, in LUAD has not been elucidated.MethodsTissue microarray, FISH, and qRT-PCR were used to detect the expression of LINC00958. Plasmid and viral infections were used to manipulate gene expression. The role of LINC00958 in LUAD was studied by cell proliferation analysis, cell apoptosis analysis, cell migration and invasion analysis, and subcutaneous inoculation of animal models. At the same time, RNA-Seq, RNA pull-down, ChIRP, ChIP, and luciferase reporter gene assays were performed to clarify the mechanism.ResultsThe expression of LINC00958 in LUAD tissues was significantly upregulated when compared with that in adjacent tissues and could independently predict poor survival of patients with LUAD. LINC00958 knockdown significantly inhibited the growth and metastasis of lung cancer cells in vitro and in vivo. LINC00958 localized to the nucleus, regulated oncogenes and metabolism-related and immune response-related genes, and interacted with histones. The targets of LINC00958 were TRPV3, STAP2, and EDN2 promoters with motifs of HOXA1, NANOG, FOSL2, JUN, and ATF4. Moreover, HOXA1 overexpression mitigated the LINC00958 knockdown-induced oncogenic phenotype. MYC/MAX motif, which was detected at the cis-element of LINC00958, trans-activated the LINC00958 promoter.ConclusionsMYC/MAX-trans-activated LINC00958 promotes the malignant behavior of LUAD by recruiting HOXA1 and inducing oncogenic reprogramming.

BackgroundThe involvement of microRNA-338-5p in modulating NPC pathogenesis is still largely unknown, and this study aimed to investigate this issue.MethodsThe expressions of cancer associated genes were determined by Real-Time qPCR and Western Blot, and cell apoptosis was determined by flow cytometer (FCM). CCK-8 assay and colony formation assay were respectively used to determine cell proliferation and colony formation abilities. Transwell assay was used to evaluate cell migration. The expression levels of Ki67 protein in mice tissues were measured by Immunohistochemistry (IHC) assay.ResultsThe present study found that microRNA-338-5p suppressed NPC progression by degrading its downstream target, Wnt family member 2B (WNT2B). Specifically, microRNA-338-5p tended to be low-expressed in NPC tissues and cell lines, compared to the non-tumor nasopharyngeal mucosa tissues and normal nasopharyngeal cell line (NP69). Upregulation of microRNA-338-5p inhibited proliferation, mobility, and epithelial-mesenchymal transition (EMT) in NPC cells in vitro, while silencing of microRNA-338-5p had opposite effects. Consistently, microRNA-338-5p suppressed tumorigenesis of NPC cells in vivo. In addition, microRNA-338-5p targeted WNT2B for degradation and inhibition, and the inhibiting effects of microRNA-338-5p overexpression on NPC development were reversed by upregulating WNT2B.ConclusionsTaken together, we concluded that microRNA-338-5p targeted WNT2B to hinder NPC development.

e15573 Background: The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. Currently, Fruquintinib/ Regorafenib is the standard third-line treatment for metastatic colorectal cancer (mCRC) with microsatellite stable (MSS), which efficacy remains limited in pre-clinical trials. According to the published literature, ICIs has little efficacy in the treatment of refractory advanced mCRC patients with MSS. However, there may be a good synergistic mechanism in the combination of ICIs and anti-VEGFR drugs, which can improve the tumor microenvironment (TME). Our study aimed to evaluate the efficacy and safety of Fruquintinib plus Toripalimab as third-line treatment for refractory advanced mCRC. Methods: This was a single-arm, single-center, phase II clinical trial with 30 patients. Pts received toripalimab (240mg, i.v., Q3W), combined with Fruquintinib (5mg, p.o., 3 weeks on/ 1 week off) until the disease progresses/unacceptable toxicity or receiving the above two drugs as maintenance treatment. The primary endpoint was objective response rate (ORR); the secondary endpoints were disease control rate (DCR), 1-year progression-free survival (PFS) rate, overall survival (OS) and safety. Results: As of Feb 5, 2022, 24 mCRC pts (female: 29.2%, median age: 52.1 years) with ECOG PS ≤ 2 who failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan combined with Bevacizumab or Cetuximab were enrolled. The ORR was 16.7% (95% CI：59.7%-94.8%). The DCR was 54.1%, including 4 patients with PR and 9 patients with SD, respectively. 16 patients were alive and the study treatments for 6 patients were still ongoing. Median PFS was 6.0 months (95% CI：3.511-12.489), the 1-year PFS rate was 18%; median OS was 8.0 months (95% CI：1.452-10.548). Overall, 24 pts were enrolled for safety analysis, The most frequent treatment related adverse events were fatigue (50%), hepatocyte dysfunction (36.3%), hypertension (29.1%) and abdominal pain (27.0%). 6 patients (25%) experienced grade 3/4 TRAE (including hypertension, liver enzyme elevation, and immune-associated pneumonia). No treatment-related death was reported. TRAEs leading to either Fruquintinib or Toripalimab discontinuation occurred in 3 (12.5%) pts each. Conclusions: Fruquintinib plus Toripalimab showed certain efficacy and favorable safety profile in refractory advanced mCRC with MSS. It may provide a new choice for mCRC patients who are receiving third-line treatment. The results supported ongoing combined treatment in mCRC patients with MSS and more data will being updated subsequently. Clinical trial information: ChiCTR2000028965.