Patient-derived ovarian cancer organoids as platforms for predicting platinum resistance and screening tumor stem cell inhibitors.

BACKGROUND

Ovarian cancer is the deadliest gynecological malignancy, with platinum-based chemotherapy being the standard treatment. However, most patients develop resistance to platinum treatment, making it essential to evaluate chemotherapy sensitivity.

METHODS

Patient-derived ovarian cancer organoids (OCOs) from primary or metastatic tumor tissues and malignant effusions were validated by histopathological and molecular profiling. The correlation between organoid drug sensitivity test results and clinical outcomes was evaluated based on longitudinal follow-up data. An AI model integrating multimodal omics data and treatment trajectories was developed to predict platinum-sensitive versus resistant recurrence following therapy. Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) -related analysis identified genes associated with chemotherapy prognosis, and these findings informed AI-assisted high-throughput screening of candidate inhibitors, which were subsequently validated in cell lines and OCOs.

RESULTS

A total of 191 patient-derived organoid models were generated from 123 ovarian cancer patients, including those from primary tumors, metastatic lesions, and malignant effusion. In vitro sensitivity testing with platinum-based chemotherapy agents was conducted with follow-ups. Organoids derived from primary tumors showed the highest predictive accuracy, followed by metastatic lesions, while ascites-derived organoids demonstrated lower predictive ability. Additionally, long-term organoid culture and chemotherapy resistance were strongly associated with tumor stem cell ALDH1A1 expression, then inhibitors against ALDH1A1 were screened and validated in ovarian cancer cells and organoids.

CONCLUSIONS

Ovarian cancer organoid drug sensitivity testing represents a potential precision medicine tool for predicting platinum response in patients, which could serve as a preclinical model for drug screening and validation. ALDH1A1, a key molecular marker of cancer stem cells, presents a viable therapeutic target; its inhibitors demonstrate potential efficacy against platinum-resistant ovarian tumors.