Tailored chemotherapy for colorectal cancer peritoneal metastases based on a drug-screening platform in patient-derived organoids: a case report

Abstract

Background: Peritoneal metastasis from colorectal cancer (CRC) has limited therapeutic options and poor prognosis. Systemic chemotherapy combined with cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC) have yielded initial promising results. However, standard local therapies with oxaliplatin and mitomycin are not optimal and a better individualized management of these patients remains as an unmet clinical need. Patientderived organoid (PDO) technology allows to culture in three dimensions normal and cancer stem cells (CSC) that self-organize in multicellular structures that recapitulates some of the features of the particular organ or tumor of origin, emerging as a promising tool for drug-testing and precision medicine. This technology could improve the efficacy of systemic and intraperitoneal chemotherapy and avoid unnecessary treatments and side effects to the patient.Case Description: Here we report a case of a 45-year-old man with a rectal adenocarcinoma with liver, lymph node and peritoneal metastases. The patient was treated with systemic chemotherapy (FOLFOXIRI plus Bevacizumab) and was subjected to mitomycin-based PIPAC. We generated patient-derived peritoneal carcinomatosis organoids in order to screen the activity of drugs for a personalized treatment. Both 5-FU and SN-38, the active irinotecan derivative, displayed strong cytotoxicity, while the response to oxaliplatin was much lower. Although the development of a colo-cutaneous fistulae prevented from further PIPAC, the patient continued with fluoropirimidine maintenance treatment based on standard clinical practice and the drug-screening test performed on organoids.Conclusions: Our results suggest that the peritoneal implant shows chemoresistance to oxaliplatin, while it might still be sensitive to irinotecan and 5-FU, which supports a potential benefit of these two drugs in the local and/or systemic treatment of our patient. This study shows the strength of the utility of the establishment of organoids for drug response assays and thus, for the personalized treatment of colorectal carcinomatosis patients.

Advances in Precision Medicine Approaches for Colorectal Cancer: From Molecular Profiling to Targeted Therapies

“…Combination therapies take this personalization to the next level. In colorectal cancer, a combination of targeted therapies may be used to simultaneously block multiple signaling pathways that drive the disease . For instance, dual inhibition of the EGFR and HER2 pathways has shown promise in preclinical studies.…”

“…In colorectal cancer, a combination of targeted therapies may be used to simultaneously block multiple signaling pathways that drive the disease. 222 For instance, dual inhibition of the EGFR and HER2 pathways has shown promise in preclinical studies. Additionally, combining targeted therapies with immunotherapy can enhance the body's immune response against the tumor, improving treatment outcomes.…”

Progress in the Treatment of Peritoneal Metastatic Cancer and the Application of Therapeutic Nanoagents

“…In a recent case report, Prieto et al reported that they performed a low-throughput drug screen (treatment of organs with 5-FU, SN-38 (7-ethyl-10-hydroxycamptothecin, the active metabolite of the DNA topoisomerase I inhibitor irinotecan), or oxaliplatin), using patient-derived organoids prior to the patient undergoing a second, personalized, intraperitoneal chemotherapy session, and found that 5-FU and SN-38 showed strong cytotoxicity, while oxaliplatin was less cytotoxic. They also found that 5-FU and SN-38 showed strong cytotoxicity, whereas oxaliplatin had much lower cytotoxicity, suggesting that the best therapeutic results could be achieved by using these two drugs in this intraperitoneal chemotherapy . In addition, they showed that the chances of obtaining a beneficial outcome for the patient are significantly greater if the organoid is modeled at an early stage of carcinogenesis.…”

“…They also found that 5-FU and SN-38 showed strong cytotoxicity, whereas oxaliplatin had much lower cytotoxicity, suggesting that the best therapeutic results could be achieved by using these two drugs in this intraperitoneal chemotherapy. 81 In addition, they showed that the chances of obtaining a beneficial outcome for the patient are significantly greater if the organoid is modeled at an early stage of carcinogenesis.…”