Functional Characterization of Neoadjuvant Chemotherapy Resistance in Breast Cancer Using Patient-Derived Organoid Models and Development of Drug Repurposing Strategies With Next-Generation Small Molecules
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Correlation Between PDO-Based Chemotherapy Response Metrics and Pathological Complete Response (pCR)
研究概览
简要总结
This prospective observational study aims to functionally characterize chemotherapy resistance in patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy. Despite standard molecular classification, significant heterogeneity in treatment response exists, and the biological mechanisms underlying chemoresistance remain incompletely understood.
In this study, patient-derived organoid (PDO) models will be established from tumor tissues obtained during routine clinical care. These three-dimensional models preserve the biological characteristics of individual tumors and enable ex vivo functional assessment of drug response. Chemotherapy sensitivity and resistance will be evaluated using quantitative parameters including Half-Maximal Inhibitory Concentration (IC50) values, cell viability, and apoptotic response.
Functional data obtained from PDO models will be correlated with clinical and pathological treatment outcomes, particularly pathological complete response (pCR), to assess the predictive value of PDO-based assays. In addition, apoptotic biomarkers such as Caspase-3/7 will be measured in serum samples collected during routine clinical evaluation and analyzed in relation to treatment response.
Furthermore, selected Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved small molecules will be tested in PDO models to evaluate their potential to reverse chemotherapy resistance, supporting drug repurposing strategies. This study aims to establish a functional, patient-specific platform for assessing chemoresistance and to contribute to the development of personalized therapeutic approaches in breast cancer.
详细描述
Breast cancer is one of the most common malignancies worldwide, and neoadjuvant chemotherapy (NACT) is a standard treatment approach in patients with locally advanced disease. Achieving pathological complete response (pCR) after NACT is strongly associated with improved long-term outcomes. However, significant inter-patient variability in treatment response is observed, even among patients with similar molecular subtypes, highlighting the need for functional approaches to better understand and predict chemotherapy resistance.
Current predictive models based on molecular and genomic profiling are limited in their ability to capture the dynamic and functional behavior of tumors. Patient-derived organoid (PDO) models have emerged as a promising platform that preserves tumor architecture, heterogeneity, and biological characteristics, enabling patient-specific functional drug testing in a controlled ex vivo environment.
In this prospective observational study, 40 adult female patients diagnosed with locally advanced breast cancer and scheduled to receive neoadjuvant chemotherapy will be enrolled. Tumor tissues obtained during routine diagnostic or therapeutic procedures will be used to establish PDO cultures. No additional invasive procedures will be performed for research purposes.
PDO models will be subjected to standardized drug response assays to evaluate chemotherapy sensitivity and resistance. Quantitative endpoints will include dose-response curves (Half-Maximal Inhibitory Concentration (IC50) values), cell viability assays, and apoptotic activity measurements, particularly Caspase-3/7 activation. These functional parameters will be integrated to define resistance phenotypes at the individual patient level.
Clinical and pathological response data, including pCR status, will be collected and correlated with PDO-derived functional results to assess the predictive performance of the PDO platform. In parallel, serum samples obtained during routine clinical care will be analyzed for apoptotic biomarkers, and their association with treatment response will be evaluated.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Female patients aged 18 years or older
- •Histologically confirmed locally advanced breast cancer
- •Planned to receive neoadjuvant chemotherapy
- •Availability of tumor tissue obtained during routine diagnostic or therapeutic procedures
- •Availability of clinical and pathological treatment data
- •Ability to provide written informed consent
排除标准
- •Age under 18 years
- •Metastatic breast cancer
- •Prior systemic chemotherapy or targeted therapy for the current diagnosis
- •Presence of another active malignancy
- •Severe comorbid conditions that may interfere with study participation
- •Insufficient biological sample for organoid generation or analysis
- •Inability or unwillingness to provide informed consent
研究组 & 干预措施
Locally Advanced Breast Cancer Patients Cohort
Adult female patients diagnosed with locally advanced breast cancer and scheduled to receive standard neoadjuvant chemotherapy. Tumor tissue and blood samples obtained during routine clinical care will be used to generate patient-derived organoid models and to perform biomarker analyses. No experimental intervention will be applied to participants.
结局指标
主要结局
Correlation Between PDO-Based Chemotherapy Response Metrics and Pathological Complete Response (pCR)
时间窗: At completion of neoadjuvant chemotherapy (approximately 6 months)
Assessment of the association between functional drug response parameters obtained from patient-derived organoid (PDO) models (including Half-Maximal Inhibitory Concentration (IC50) values, cell viability, and apoptotic response) and pathological complete response (pCR) following neoadjuvant chemotherapy.
次要结局
- Serum Apoptotic Biomarkers and Their Association With Treatment Response(At baseline, during neoadjuvant chemotherapy, and at completion of treatment (approximately 6 months))
- Development of Functional Predictive Models for Chemotherapy Response(Within 12 months after completion of data collection)
- Association Between PDO-Derived Drug Sensitivity Metrics and Clinical Chemotherapy Resistance(At baseline (prior to initiation of neoadjuvant chemotherapy) and at completion of treatment (approximately 6 months))
- Evaluation of Drug Repurposing Strategies in PDO Models(Within 6 months after sample collection)
研究者
Emine YILDIRIM
Associate Professor of General Surgery, Head of the Department of General Surgery
Atlas University