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Circulating Tumor DNA Analysis to Optimize the Operative and Postoperative Treatment for Patients With Colorectal Cancer - Intervention Trial 2

ABSTRACT: IMPROVE-IT2 is a randomized multicenter trial comparing the outcomes of ctDNA guided post-operative surveillance and standard-of-care CT-scan surveillance. The hypothesis of this study is that ctDNA guided post-operative surveillance combining ctDNA and radiological assessments could result in earlier detection of recurrent disease and identify more patients eligible for curative treatment.

DISEASE(S): Ctdna,Gastrointestinal Neoplasms,Intestinal Diseases,Colorectal Cancer,Gastrointestinal Cancer,Digestive System Diseases,Colo-rectal Cancer,Rectal Cancer,Gastro-intestinal Disorder,Neoplasms,Gastrointestinal Diseases,Rectal Neoplasms,Rectal Diseases,Colonic Cancer,Colorectal Neoplasms,Digestive System Disease,Colonic Diseases,Colonic Neoplasms,Digestive System Neoplasms,Digestive System Neoplasm

PROVIDER: 2315870 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Post-operative abdominal adhesions are the leading cause of bowel obstruction and a major cause of chronic pain and infertility. Further, adhesion formation complicates any re-operative strategy, increasing the length of surgery and rendering a safe minimally invasive approach impossible. Despite the prevalence of abdominal adhesions, which form following 50-90% of abdominal operations, no proven preventative or treatment strategy has been developed. Our group previously established a mouse model to study adhesive disease in vivo and explored adhesion biology across mouse and human tissues. We established that adhesions derive primarily from the visceral peritoneum, are composed of poly-clonally proliferating tissue-resident fibroblasts, and identified that modulation of JUN signaling regulates abdominal adhesiogenesis following surgery. We identified a small molecule JUN inhibitor (T-5224) that decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with anti-adhesion properties for intra-peritoneal delivery and sustained-release for post-operative adhesion prevention. We extensively characterized this novel therapeutic system, and found it to be safe, systemically well-tolerated, and efficacious in reducing adhesions in our mouse model. Furthermore, this therapeutic system minimizes not only the quantity of adhesions that form, but also limits the maturation of adhesion fibrosis at an ultrastructural level. Critical towards clinical translation, we developed a large mammal (porcine) preclinical model of adhesions with bowel resection and showed that the T-5224-hydrogel therapeutic provides robust adhesion prevention without deleterious effects on bowel anastomosis or abdominal wall (laparotomy) wound healing. At a single-cell transcriptomic level, treated fibroblasts in our pig model show decreased JUN and associated pathway signaling. Adhesion biology shares close similarities across surgical sites (e.g. thoracic, joint space, neurological); as such, this formulation has significant potential for applicability across the body. Material properties of the T-5224-hydrogel formulation, such as shear-thinning and self-healing, also facilitate ease of open or minimally invasive application. Therefore, these results are promising for immediate and high-impact translation to patient care to address a common, unmet clinical need.

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Circulating Tumor DNA Analysis to Optimize the Operative and Postoperative Treatment for Patients With Colorectal Cancer - Intervention Trial 2

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