Gastric cancer (GC) is the fifth most frequently diagnosed malignant tumor and the third highest cause of cancer mortality worldwide. For advanced GC, many novel drugs and combinations have been tested, but results are still disappointing, and the disease is incurable in the majority of cases. In this regard, it is critical to investigate the molecular mechanisms underlying GC development. Angiogenesis is one of the hallmarks of cancer with a fundamental role in GC growth and progression. Ramucirumab, a monoclonal antibody that binds to vascular endothelial growth factor-2 (VEGFR-2), is approved in the treatment of advanced and pretreated GC. However, no predictive biomarkers for ramucirumab have been identified so far. Micro RNAs (miRNAs) are a class of evolutionarily-conserved single-stranded non-coding RNAs that play an important role (via post-transcriptional regulation) in essentially all biologic processes, such as cell proliferation, differentiation, apoptosis, survival, invasion, and migration. In our review, we aimed to analyze the available data on the role of angiogenesis-related miRNAs in GC.
11534 Background: KIT or PDGFRA oncogenic activation drives GIST progression throughout the disease course. Accordingly, currently approved agents in metastatic GIST focus on the therapeutic suppression of these receptors. However, the clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models. Methods: The phase Ib portion studied IM 400 mg daily plus weekly selinexor in patients (pts) with IM-resistant, advanced GIST. Prior intolerance to IM was not allowed. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D) of this combination. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1. Results: At data cutoff of Sep 25, 2020, 12 pts were enrolled and received treatment with IM 400 mg and selinexor once weekly at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg). Median age 57 (range 46-77), 42% female, median prior therapies 4 (range 2-7). Although only 1/6 pts developed a dose limiting toxicity (DLT) at DL3, the RP2D was defined at DL2 (IM 400 mg daily and selinexor 80 mg once weekly) based on activity data in the DL2 and the need for dose reductions in 5/6 pts at DL3 after the DLT window. All pts were evaluable for toxicity and response. One DLT occurred at DL3 (G3 nausea). Non-DLT G3/4 toxicities were anemia (1/12 pts), neutropenia (1/12 pts), vomiting (1/12 pts) and fatigue (2/12 pts). Common G1/2 toxicities were nausea (11/12 pts), vomiting (10/12 pts), neutropenia (5/12 pts) and anemia, fatigue, diarrhea, and periorbital edema (4/12 pts each). No unexpected toxicities were observed. Overall response rate in the 12 pts evaluable for response was 67% (95% CI 0.349-0.901), with 2 pts achieving PR (17%) and 6 pts SD (50%) as the best response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.157-0.723). Median progression free survival was 3.5 months (95% CI 1.7-7.3). Four pts remain on trial at data cutoff. Conclusions: IM and selinexor combination is well-tolerated and has clinical activity in heavily pretreated GIST pts. The trial is currently exploring selinexor as single agent in the IM-resistant GIST population. Clinical trial information: NCT04138381.
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