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Medium-throughput Drug Screening of Patient-derived Organoids from Colorectal Peritoneal Metastases to Direct
Vignesh Narasimhan1, Josephine A Wright2, Michael Churchill3
1Peter Mac Callum Cancer Centre, Melbourne, Victoria, Australia and Sir Peter Mac Callum Department of Oncology, University of Melbourne, Victoria, Australia.
Purpose:
Patients with colorectal cancer with peritoneal metastases (CRPMs) have limited treatment options and the lowest colorectal cancer survival rates. We aimed to determine whether organoid testing could help guide precision treatment for patients with CRPMs, as the clinical utility of prospective, functional drug screening including nonstandard agents is unknown.
Experimental Design:
CRPM organoids (peritonoids) isolated from patients underwent parallel next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing.
Results:
Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for two patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications.
Conclusions:
Our approach is feasible, reproducible, and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.
Insights
Organoid testing (peritonoids) can guide precision medicine for colorectal cancer with peritoneal metastases (CRPMs). This functional drug screening showed feasibility and guided treatment changes in patients with poor prognoses.
Area of Science:
- Oncology
- Translational Medicine
- Genomics
Background:
- Colorectal cancer with peritoneal metastases (CRPMs) presents limited therapeutic options and poor survival rates.
- Novel strategies are crucial for improving outcomes in this patient cohort.
Purpose of the Study:
- To evaluate the utility of organoid testing for guiding precision treatment in patients with CRPMs.
- To assess the feasibility and reproducibility of ex vivo drug screening using patient-derived organoids.
Main Methods:
- Patient-derived colorectal cancer with peritoneal metastases organoids (peritonoids) were established.
- Organoids underwent parallel next-generation sequencing and medium-throughput drug panel testing.
- Key metrics included organoid generation success, culture time, drug testing reproducibility, and clinical therapy changes.
Main Results:
- Peritonoids were successfully generated from 68% of patients.
- Genomic and drug profiling was completed within 8 weeks, guiding therapy post-standard care failure.
- Treatment was altered for two patients, with one achieving a partial response after progressing on prior chemotherapy.
Conclusions:
- Organoid testing is a feasible and reproducible approach to guide novel therapeutics in CRPM patients.
- This platform offers a promising avenue for precision medicine in a poor-prognosis group.
- The approach has potential applicability to other solid organ malignancies.
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