A Translational Study to Explore and Overcome Metabolic-driven Resistance Mechanisms to Standard Chemotherapy in High-grade Ovarian Cancer

Overview

This translational study, titled "A translational study to explore and overcome metabolic-driven resistance mechanisms to standard chemotherapy in high-grade ovarian cancer," is designed as a prospective, monocentric, observational cohort study utilizing biological material. The primary objective of this research is to evaluate the functional capacity of the U-Cup bioreactor to predict the clinical response to standard chemotherapy in patient-derived high-grade ovarian cancer tissues maintained in perfusion culture. As a secondary objective, the study seeks to develop a high-throughput platform for the personalized assessment of therapeutic responses. This platform will specifically focus on ovarian cancer cases that demonstrate resistance to standard chemotherapy, exploring their sensitivity to alternative metabolic-driven therapies. The study population consists of women diagnosed with high-grade serous ovarian carcinoma who have not previously undergone chemotherapy. These patients are candidates for surgical intervention at the UOC Ginecologia Oncologica De Iaco - IRCCS AOUBO. Eligibility for the study is strictly defined by specific inclusion and exclusion criteria to ensure a homogeneous and clinically relevant cohort. Inclusion requires patients to be 25 years of age or older, provide informed consent, and have a confirmed histological or surgical diagnosis of high-grade serous ovarian cancer. Furthermore, eligible participants must not have undergone prior surgical treatment for this malignancy and must have sufficient primary or metastatic tumor tissue available for sampling. Conversely, the study excludes patients presenting with significant comorbidities or those affected by other concurrent malignancies. Over a planned duration of 36 months, the study aims to enroll a total of 120 patients. For all parameters measured, including drug response tests related to the secondary objective, data will first undergo the Shapiro-Wilk test to assess the normality of distribution. Continuous variables following a normal distribution will be analyzed using the Student's T-test, while non-normally distributed variables will be evaluated using the Mann-Whitney U test. Categorical variables will be assessed using the Chi-square test or Fisher's exact test, depending on the distribution characteristics. Specifically, for the primary objective, clinical data will be utilized to group patients based on their Chemotherapy Response Score (CRS), comparing those with a high response (CRS3) against those with partial or no response (CRS1/2). The analysis will focus on identifying significant differences in proliferation variation (measured via Ki67-positive nuclei), apoptosis (cleaved Caspase-3 positivity), and necrosis (as evaluated by pathological assessment of HE staining) between SCT-treated and untreated samples. This comparative analysis aims to determine if one or more of these biological parameters can reliably predict a patient's clinical response to standard treatment. To further refine these findings, Area Under the ROC Curve (AUROC) analysis and logistic regression will be employed to define optimal threshold values. These thresholds will be used to discriminate between CRS3 and CRS1/2 patients with high sensitivity and specificity, ultimately validating the bioreactor platform as a predictive tool for personalized oncology.

Detailed description

The study, titled "A Translational Study to Explore and Overcome Metabolic-Driven Resistance Mechanisms to Standard Chemotherapy in High-Grade Ovarian Carcinoma," is designed as a prospective, monocentric, observational cohort study involving the collection and utilization of biological material. The primary scientific objective of this research is to evaluate the predictive capacity of the U-Cup bioreactor system in determining the response to standard chemotherapy (SCT) in patient-derived high-grade ovarian cancer (HGOC) tissues maintained in perfusion culture. By utilizing this advanced bioreactor technology, the study aims to establish whether the ex vivo response of the tumor tissue accurately reflects the clinical outcomes observed in the patients. Complementing this, the secondary objective focuses on the development of a high-throughput platform for the personalized assessment of therapeutic responses in ovarian cancer cases that exhibit resistance to standard chemotherapy, specifically exploring alternative metabolic therapies. The study population consists of women diagnosed with high-grade serous ovarian carcinoma who have not previously undergone chemotherapy and are candidates for surgical intervention at the UOC Ginecologia Oncologica De Iaco - IRCCS AOUBO. To be eligible for enrollment, patients must be at least 25 years of age, provide informed consent, and have a confirmed histological or surgical diagnosis of high-grade serous ovarian carcinoma. Furthermore, inclusion requires that patients have not yet undergone surgical treatment and that there is sufficient primary or metastatic tumor tissue available for sampling. Conversely, patients will be excluded from the study if they present with significant comorbidities or are affected by other concurrent malignancies. The study is projected to span a duration of 36 months, with an anticipated enrollment of 120 patients to ensure a robust dataset. The statistical methodology for this study is rigorous and multifaceted. For all experimental procedures, including the drug response assays outlined in the secondary objective, the values for each measured parameter will initially undergo the Shapiro-Wilk test to assess the normality of their distribution. Continuous variables that follow a normal distribution will be analyzed using the Student's T-test, while those with a non-normal distribution will be evaluated using the Mann-Whitney U test. For categorical variables, the Chi-square test will be applied to normally distributed data, whereas Fisher's exact test will be used for data that does not meet normality assumptions. Regarding the primary objective, clinical data collected from the participants will be used to categorize patients into those with a Chemotherapy Response Score of 3 (CRS3), indicating a good response, versus those with CRS1 or CRS2, indicating a poor or partial response. The T-test or Mann-Whitney test will be employed to identify significant differences in terms of variations in cell proliferation, measured via Ki67-positive nuclei, apoptosis, indicated by cleaved Caspase-3 positivity, and necrosis, as assessed by a pathologist using hematoxylin and eosin (HE) staining. These comparisons will be made between samples treated with SCT in the bioreactor and untreated controls to determine if one or more of these biological parameters can reliably predict the patient's actual clinical response to treatment. Finally, the study will utilize Area Under the Receiver Operating Characteristic (AUROC) curve analysis and logistic regression to define the optimal threshold values for these parameters, aiming to discriminate between CRS3 and CRS1/2 patients with the highest possible levels of specificity and sensitivity, thereby validating the bioreactor as a precision medicine tool.

Primary outcome measures

• To the capacity of the U-Cup bioreactor to predict the response to standard chemotherapy in patient-derived ovarian cancer tumors maintained in perfusion culture [Time frame: 5-6 months after sample collection]

Secondary outcome measures (1)

• To develop a high-throughput platform for the personalized assessment of OC response (resistant to standard chemotherapy) to alternative metabolic therapies. [Time frame: 12 months after sample collection]

Eligibility criteria

Inclusion criteria

• Age>= 25 years
• Obtained informed consent
• Histological and/or surgical diagnosis of high-grade serous ovarian carcinoma
• Patients who have not undergone surgical treatment
• Availability of primary/metastatic tumor tissue for sampling

Exclusion criteria

• Patients with comorbidities
• Patients with other malignancies

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Italy · 1 center

• IRCCS Azienda Ospedaliero-Universitaria di Bologna — Bologna

Identifiers

NCT: NCT07461207 · TEX-MECS · Targeted Research 2024

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗