Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for peritoneal metastasis from colorectal or appendiceal cancer: a feasibility study
Ontology highlight
ABSTRACT:
DISEASE(S): Peritoneal Metastasis From Colorectal Or Appendiceal Cancer
PROVIDER: 2636593 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Peritoneal metastases (PM) in colorectal cancer (CRC) present a significant challenge due to limited treatment options and poor patient prognosis. While cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) offers curative potential for selected patients, its overall benefit remains limited compared to surgery alone. In this study we show that the majority of CRC-PM represent the CMS4-subtype. Despite CRS-HIPEC treatment, CMS4 patients had high rates of recurrent disease and mortality, indicating limited effectiveness of the treatment. To explore alternative treatment approaches, we queried large-scale compound screens and discovered the copper (Cu)-ionophore elesclomol (ES) as a highly effective agent against CMS4-specific disease models. ES exhibited rapid and selective cytotoxicity against CMS4 cells by targeting the oxidative phosphorylation machinery. CMS4 cells had reduced absolute mitochondrial content and lower expression of genes involved in oxidative phosphorylation, making them vulnerable to ES-induced cytotoxicity. Short exposures to ES combined with Cu (ES-Cu) resulted in near-complete growth inhibition of cancer cells, suggesting its potential for HIPEC-like intra-abdominal treatment procedures. Furthermore, ES-Cu demonstrated efficacy in preclinical models of PM, including CRC-PM and ovarian cancer organoids, and a HIPEC rat model of PM. These findings highlight ES-Cu as promising candidate for the local treatment of CRC-PM, with broader implications for other cancer types characterized by high incidence of PM.
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Project description:Peritoneal carcinomatosis is a common event in the natural history of colorectal and other digestive tract cancers. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provides a promising therapeutic option for highly selected patients with peritoneal carcinomatosis arising from different malignancies such as colorectal cancer, gastric cancer, ovarian cancer, or peritoneal mesothelioma with improvement of both patient survival and quality of life. CRS, i.e., removal of all visible metastatic abdominal and pelvic disease with peritonectomy along with HIPEC (for 90 min at a temperature of 42º C) and/or early postoperative intraperitoneal chemotherapy (EPIC) in order to eradicate all microscopic metastasis.
CRS with HIPEC is a long and complex procedure with significant blood and fluid loss during debulking, hemodynamic, hematological, and metabolic alterations before and during the HIPEC phase, and even in the early postoperative period, with resultant significant morbidity and mortality. Despite that most of the reported patients are in American Society of Anesthesiologist class I and II, without significant comorbidities or systemic disorder; the morbidity and mortality ranges from 12 to 65% in these procedures, so a well coordinated team of anesthesiologist, surgeons and intensivist and other ancillary services can result in good outcome. This study will see the challenges faced by the team regarding the pathophysiological alterations during the CRS with HIPEC in the perioperative period.
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Project description:Patients with peritoneal metastasis of colorectal or high grade appendiceal origin who are candidates for cytoreductive surgery with HIPEC (hyperthermic intraperitoneal chemotherapy) will be enrolled in this study. Blood collection for measurements of plasma cell-free DNA hydroxymethylation signatures will be performed at different time points, before and after surgery, in order to determine if plasma hydroxymethylation signatures are more sensitive than conventional tumor markers in identifying clinically detectable recurrence at 1 year after surgery.
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Project description:Pseudomyxoma peritonei (PMP) is a rare, malignant tumour with unknown underlying molecular mechanisms characterised by a progressive accumulation of mucin and secreting tumour cells within the abdomen and pelvis. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the only therapeutic option currently available for its treatment and recurrence with a fatal outcome is common despite its use. The lack of information available about the molecular mechanisms underlying this condition is mainly due to the physicochemical characteristics of mucin, whose main purpose is to protect epithelial cells, which makes it inaccessible to a proteomic analysis. In this paper we describe the first protocol available to break this barrier and offer a chance to isolate proteins from soft and hard mucinous tumour tissues. This approach is based on the depletion of glycoproteins, immunoglobins, and albumins by affinity liquid chromatography, which makes the mucin available for label free quantification by mass spectrometry. As in the case of non mucinous tissues, our protocol yields a mix of total proteins and has allowed us to establish the first protein profile in mucinous tumours. In addition, our protein-protein interaction networks and pathway enrichment analyses revealed MUC13 and TFF1 as potential therapeutic targets in this disease.
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