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Colorectal Cancer Develops Inherent Radiosensitivity That Can Be Predicted Using Patient-Derived Organoids
Kuo-Shun Hsu1,2, Mohammad Adileh1,2, Maria Laura Martin1,2
1Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Abstract:
Identifying colorectal cancer patient populations responsive to chemotherapy or chemoradiation therapy before surgery remains a challenge. Recently validated mouse protocols for organoid irradiation employ the single hit multi-target (SHMT) algorithm, which yields a single value, the D0, as a measure of inherent tissue radiosensitivity. Here, we translate these protocols to human tissue to evaluate radioresponsiveness of patient-derived organoids (PDO) generated from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy. While PDOs from adenomas with a logarithmically expanded Lgr5+ intestinal stem cell population retain the radioresistant phenotype of normal colorectal PDOs, malignant transformation yields PDOs from a large patient subpopulation displaying marked radiosensitivity due to reduced homologous recombination-mediated DNA repair. A proof-of-principle pilot clinical trial demonstrated that rectal cancer patient responses to neoadjuvant chemoradiation, including complete response, correlate closely with their PDO D0 values. Overall, upon transformation to colorectal adenocarcinoma, broad radiation sensitivity occurs in a large subset of patients that can be identified using SHMT analysis of PDO radiation responses.
Significance:
Analysis of inherent tissue radiosensitivity of patient-derived organoids may provide a readout predictive of neoadjuvant therapy response to radiation in rectal cancer, potentially allowing pretreatment stratification of patients likely to benefit from this approach.
Insights
Patient-derived organoids can predict response to rectal cancer radiation therapy. This method identifies patients likely to benefit from chemoradiation, improving treatment strategies.
Area of Science:
- Oncology
- Radiation Oncology
- Genetics and Genomics
Background:
- Predicting patient response to neoadjuvant chemoradiation for colorectal cancer is difficult.
- The single hit multi-target (SHMT) algorithm measures tissue radiosensitivity using the D0 value.
- Previous studies validated SHMT in mouse organoid irradiation models.
Purpose of the Study:
- To translate mouse organoid irradiation protocols to human tissues.
- To evaluate radioresponsiveness of patient-derived organoids (PDOs) from normal and cancerous colorectal tissues.
- To correlate PDO radiosensitivity with clinical outcomes in rectal cancer patients undergoing neoadjuvant therapy.
Main Methods:
- Generated PDOs from normal human intestines and rectal tumors of patients undergoing neoadjuvant therapy.
- Applied SHMT algorithm to determine D0 values, a measure of inherent radiosensitivity.
- Conducted a pilot clinical trial correlating PDO D0 values with patient response to neoadjuvant chemoradiation.
Main Results:
- Colorectal adenocarcinoma PDOs from a significant patient subpopulation showed marked radiosensitivity.
- This radiosensitivity was linked to reduced homologous recombination-mediated DNA repair.
- PDO D0 values closely correlated with clinical responses to neoadjuvant chemoradiation, including complete response.
Conclusions:
- Analysis of inherent tissue radiosensitivity in PDOs can predict neoadjuvant therapy response in rectal cancer.
- SHMT analysis of PDO radiation responses can identify patients with broad radiation sensitivity.
- This approach allows for pretreatment stratification of patients likely to benefit from radiation therapy.
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