Phase II Study of TAS-109 to Treat Advanced Colorectal Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Colorectal Neoplasms,Advanced Colorectal Cancer
PROVIDER: 2066461 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Background: The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumor efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. Methods: Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). Results: We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p=0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven percent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhea, nausea, and vomiting). Conclusions: Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard of care therapy is warranted.
2024-08-26 | GSE275628 | GEO
Project description:Metastatic pancreatic cancer (mPC) has a dismal prognosis, with first line systemic therapy relying primarily on FOLFIRINOX (5FU/irinotecan/oxaliplatin) or AG (Gemcitabine/Nab-Paclitaxel). Therapeutic options for mPC refractory to these regimens remain poorly-defined, and data on later lines options are scare. This prospective, single-arm study (NCT05481463) evaluated the safety and preliminary efficacy of combining the anti-angiogenic agent surufatinib with the cytotoxic drug TAS-102 (Trifluridine/Tipiracil) in mPC patients who had progressed on ≥ 2 prior lines of therapy. Primary and secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Among 20 patients analyzed for efficacy, median PFS was 2.35 months (95% CI: 1.91-3.94) and median OS was 6.34 months (95% CI: 3.81-10.09). The ORR and DCR were 20% (4/20; all partial response) and 30% (6/20), respectively. All patients experienced treatment emergent adverse events (TEAEs), with anemia (59.1%), neutropenia (54.6%), leukopenia (50.0%), and lymphopenia (45.5%) as the most common any-grade events. Grade ≥3 TEAEs including neutropenia (31.8%), lymphopenia (13.6%), and anemia (9.1%), were observed in 50.0% (11/22) of patients. Subgroup analysis identified metastases involving > 2 organs or hepatic sites as potential predicative biomarkers for inferior efficacy. Proteomic screening revealed that overexpressed OCIAD2 correlated with poor prognosis, a finding validated in two publicly available external cohorts (CPTAC database and RuiJin cohort). In conclusion, combination of TAS-102 and surufatinib demonstrates clinically meaningful efficacy and manageable toxicity as a later line therapeutic option for refractory mPC. The biomarkers identified in this study may hold the potential to guide patient stratification and warrant further investigation to optimize precision application of this regimen.
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Project description:Small RNAs, including ta-siRNAs, play crucial roles in various processes in plants. Efforts have been made for decades to elucidate the biogenesis and function of ta-siRNAs. Though the key proteins involved in ta-siRNA biogenesis have been identified, the subcellular localization where ta-siRNAs are processed remains largely unexplored. Remarkably, non-coding TAS transcripts were reported to be bound by ribosomes, the machinery responsible for protein translation. Utilizing edited TAS genes in Arabidopsis, a combination of sRNA-seq, mRNA-seq, RIP-seq, and degradome-seq was employed to investigate the role of ribosomes in ta-siRNA biogenesis in this study. In the two-hit model, deletion of ribosome-binding regions resulted in a decrease in the abundance of intact TAS3 transcripts but did not significantly affect ta-siRNAs production or the efficiency of miRNA-guided cleavage. Conversely, the deletion of ribosome-binding regions led to a significant reduction in ta-siRNA abundance without affecting mRNA levels in the one-hit model. These findings indicate that in the two-hit model, ribosomes primarily stabilize TAS transcripts, while in the one-hit model, they suppress miRNA cleavage but facilitate subsequent processing. Collectively, this study proposes a model that ribosomes play distinct roles in the one-hit and two-hit models of ta-siRNA biogenesis, and provides a new angle to investigate the tangled connection between small RNAs, including miRNA and ta-siRNA, and translation.
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Project description:Small RNAs, including ta-siRNAs, play crucial roles in various processes in plants. Efforts have been made for decades to elucidate the biogenesis and function of ta-siRNAs. Though the key proteins involved in ta-siRNA biogenesis have been identified, the subcellular localization where ta-siRNAs are processed remains largely unexplored. Remarkably, non-coding TAS transcripts were reported to be bound by ribosomes, the machinery responsible for protein translation. Utilizing edited TAS genes in Arabidopsis, a combination of sRNA-seq, mRNA-seq, RIP-seq, and degradome-seq was employed to investigate the role of ribosomes in ta-siRNA biogenesis in this study. In the two-hit model, deletion of ribosome-binding regions resulted in a decrease in the abundance of intact TAS3 transcripts but did not significantly affect ta-siRNAs production or the efficiency of miRNA-guided cleavage. Conversely, the deletion of ribosome-binding regions led to a significant reduction in ta-siRNA abundance without affecting mRNA levels in the one-hit model. These findings indicate that in the two-hit model, ribosomes primarily stabilize TAS transcripts, while in the one-hit model, they suppress miRNA cleavage but facilitate subsequent processing. Collectively, this study proposes a model that ribosomes play distinct roles in the one-hit and two-hit models of ta-siRNA biogenesis, and provides a new angle to investigate the tangled connection between small RNAs, including miRNA and ta-siRNA, and translation.
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