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1.
Cancer Sci ; 112(7): 2915-2920, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1294969

ABSTRACT

Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.


Subject(s)
Circulating Tumor DNA/blood , Colorectal Neoplasms/blood , Neoplasm Recurrence, Local/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Capecitabine/administration & dosage , Chemotherapy, Adjuvant , Colonic Neoplasms/blood , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Colonic Neoplasms/therapy , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Colorectal Neoplasms/therapy , Double-Blind Method , Humans , Japan , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Oxaliplatin/administration & dosage , Prospective Studies , Pyrrolidines/administration & dosage , Thymine/administration & dosage , Trifluridine/administration & dosage
2.
Cell Rep ; 33(3): 108286, 2020 10 20.
Article in English | MEDLINE | ID: covidwho-880155

ABSTRACT

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.


Subject(s)
Aging/genetics , Diffuse Intrinsic Pontine Glioma/genetics , Polycomb Repressive Complex 1/metabolism , Astrocytoma/genetics , Brain Stem Neoplasms/drug therapy , Brain Stem Neoplasms/genetics , Cell Differentiation/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Child , Child, Preschool , Chromatin/genetics , Diffuse Intrinsic Pontine Glioma/drug therapy , Diffuse Intrinsic Pontine Glioma/metabolism , Epigenomics , Female , Glioma/drug therapy , Glioma/genetics , Glioma/pathology , Histones/metabolism , Humans , Lysine/metabolism , Male , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Polycomb Repressive Complex 1/antagonists & inhibitors , Polycomb Repressive Complex 1/genetics
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