Innovation in Colorectal Cancer Treatment with Patient-Derived Tumor Organoids (PDTOs)

Introduction

In the era of personalized oncology, the ability to predict individual responses to cancer treatments is a game-changer. Living Out In Vitro Cellular Testing Laboratory, a recent joint venture with Base Científica, uses Patient-Derived Tumor Organoids (PDTOs) to bridge the gap between laboratory research and clinical outcomes.

These 3D tumor models, grown from patient biopsy samples, accurately replicate the architecture and microenvironment of the original tumor. This case study highlights how PDTOs can be important tools for recapitulating the molecular profile of the original tumor and predicting treatment responses in colorectal cancer patients, demonstrating their potential to revolutionize precision oncology.

The Challenge

Colorectal cancer treatment often involves a trial-and-error approach, with patients undergoing standard therapies without certainty of their effectiveness. This can lead to unnecessary side effects, delays in effective treatment, and reduced quality of life. The challenge was to develop a predictive tool that could guide oncologists in selecting the most effective treatment for each patient.

The Approach

Living Out developed a protocol to grow PDTOs from colorectal cancer biopsy samples. These organoids were exposed to commonly used chemotherapy agents, including cetuximab, irinotecan, 5-FU, oxaliplatin, and the FOLFOX protocol. The organoids' viability after treatment was measured using cell viability assays, and the results were compared to patients' genetic profiles and clinical outcomes.

The main steps included:

• Biopsy Collection and Cultivation: Tumor samples were collected from patients at the Hospital de Amor in Barretos, Brazil, and used to generate PDTO cultures.

• Drug Sensitivity Testing: Organoids were exposed to varying concentrations of chemotherapeutic agents, and their viability was assessed.

• Clinical Correlation: Drug sensitivity results were compared with patients' genetic mutations (e.g., KRAS, BRAF) and their clinical responses to the treatments they underwent (based on Hospital guidelines and protocols).

Main Findings

Patient-Specific Responses: Each PDTO exhibited unique responses to the drugs tested, reflecting the individuality of each patient's tumor biology.

For example:

• CRHA05B: This culture was highly sensitive to Irinotecan, aligning with the positive clinical response the patient obtained when treated with Irinotecan.

• CRHA06B: Demonstrated resistance to 5-FU and irinotecan, consistent with the patient's lack of response to these treatments. Organoid assays suggested oxaliplatin as a potential alternative, which was subsequently adopted by the clinical staff.

• CRHA10B: Showed sensitivity to the FOLFOX protocol, corroborated by the patient's improvement after the clinical team decided to change to this treatment.

Genetic Insights: PDTO cultures that did not show sensitivity to Cetuximab were originated from patients with KRAS mutations (where no tumor regression is expected with this treatment), showing an agreement between the PDTO response and the patient's molecular profile.

Clinical Validation: These preliminary results obtained with PDTO cultures were validated by clinical patient outcomes, demonstrating the potential of this approach to guide treatment planning.

Impact

The use of PDTOs may have the potential to transform colorectal cancer treatment by:

• Reduce Trial and Error: Oncologists can make informed decisions based on predictive data, minimizing ineffective treatments.

• Personalize Therapy: Tailor treatments to each patient's unique tumor biology.

• Improve Outcomes: Increase the likelihood of positive clinical responses and improve patients' quality of life.

Conclusion

This study highlights the transformative potential of PDTOs in personalized oncology. By providing a reliable and specific tool for predicting treatment responses, Living Out is paving the way for a future where cancer treatment is as unique as the patients themselves. Continued development and validation of this technology could redefine the standard of care in oncology.

Robson Amaral, PhD.

CEO, Living Out