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Modeling rectal cancer to advance neoadjuvant precision therapy
Harinarayanan Janakiraman1,2, Yun Zhu1,2, Scott A Becker1,2
1Department of Surgery, Medical University of South Carolina, Charleston, SC.
International Journal of Cancer
|January 29, 2020
Summary
New rectal cancer models (patient-derived xenografts and organoids) accurately mimic patient tumors and treatment responses, aiding personalized therapy and biomarker discovery for better rectal cancer outcomes.
Area of Science:
- Oncology
- Translational Research
- Cancer Biology
Background:
- Effective preclinical models are crucial for advancing rectal cancer therapy.
- Existing models often fail to capture the unique molecular and biological characteristics of rectal cancer.
- Lack of suitable models hinders personalized treatment strategies.
Purpose of the Study:
- To develop and validate patient-derived xenograft (PDX) and patient-derived tumor organoid (PDTO) platforms for rectal cancer.
- To assess the fidelity of these models in replicating human rectal cancer histology, mutational profiles, and treatment responses.
- To evaluate the potential of these platforms for personalized medicine, biomarker discovery, and experimental therapy testing.
Main Methods:
- Established subcutaneous PDX models from 26 Stage 2/3 rectal cancer patients' pre-neoadjuvant therapy samples.
- Developed PDTOs from rectal cancer specimens, preserving cellular heterogeneity.
- Validated PDX and PDTO models by comparing histology, mutational profiles, and 5-fluorouracil/radiation therapy (5FU/RT) response with patient clinical outcomes.
Main Results:
- 15 subcutaneous PDX models were generated, showing 100% histological correlation and maintained mutational profiles.
- PDX models accurately reproduced patient responses to 5FU/RT.
- PDTOs exhibited significant heterogeneity and replicated patient responses to 5FU/RT (p < 0.05).
- Cetuximab combined with 5FU/RT showed increased sensitivity in PDX/PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05).
Conclusions:
- Rectal cancer PDX and PDTO platforms serve as powerful translational research tools.
- These models facilitate biomarker discovery and experimental therapy testing for personalized rectal cancer care.
- Findings suggest cetuximab could enhance radiation therapy effectiveness, potentially guided by KRAS mutational status for patient selection.
