Patient-Derived Breast Cancer Organoids Validate I-SPY2 Biomarkers and Predict Treatment Response

Researchers at the University of California, San Francisco查看公司主页 have demonstrated that patient-derived breast cancer (搜索)搜索该疾病 organoids can successfully model how corresponding patient tumors respond to therapies, providing a powerful new tool for validating clinical biomarkers and identifying alternative treatment strategies for resistant cancers. The study, published August 6 in Cell Reports Medicine, leverages data from the I-SPY2 (搜索)搜索该靶点 breast cancer trial to bridge the gap between molecular biomarkers and precision medicine.

"The breast tumor organoids modeled how corresponding patient tumors responded to therapies and identified candidate combination therapies for cancers that don't respond to standard treatment," said senior author Jennifer M. Rosenbluth, MD, PhD, a medical oncologist and the Sulochana Pradhan, MD, Endowed Professor in Breast Cancer (搜索)搜索该疾病 at UCSF. "These findings support organoid modeling as a bridge between clinical biomarkers and precision treatment strategies in breast cancer."

Building a Biobank of Living Tumor Models

The research team created breast cancer (搜索)搜索该疾病 organoids by placing patient-derived tumor cells into a gel designed to support the original tumor's biology. Over several weeks, the cells clustered into tiny spheres that reflected the structure and biology of the original tumor. Each cluster contained up to thousands of cells — too small to see clearly without a microscope — with the largest appearing as translucent clusters in the gel.

The investigators evaluated this biobank of early-stage invasive breast cancer (搜索)搜索该疾病 organoids to study mechanisms of therapy resistance. Response predictive subtypes — molecular subtypes developed during the course of the I-SPY2 (搜索)搜索该靶点 trial — provided a framework of anticipated tumor responses to current therapies, including immunotherapy, PARP-inhibitors, platinum chemotherapy drugs, and dual-HER2 targeted therapies. With access to clinical patient data, the team used these response predictive subtypes and biomarker data from I-SPY2 trial patients to predict treatment responses in the organoids.

Validating Resistance and Finding Alternatives

Since many of the organoids were derived from triple-negative breast cancer (搜索)搜索该疾病 (TNBC) tumors, those organoids were selected to validate a model predicting response to veliparib查看药品详情-platinum chemotherapy (VP). Platinum chemotherapies and combination therapies like VP are often prescribed to patients with TNBC, even though this subtype can be highly treatment resistant.

With the aim of finding alternative treatment strategies to overcome tumors' resistance to platinum chemotherapy, the researchers selected tumor organoid TORG40, which had the highest predicted and subsequently validated resistance to VP. The team performed a drug screen of 386 small-molecule inhibitors on this organoid, including ABT-263查看药品详情, a drug that helps eliminate damaged cells. They then compared ABT-263 alone with ABT-263 in combination with the chemotherapy drug cisplatin查看药品详情. This drug combination enhanced activity against resistant tumor cells, producing a uniquely potent effect on TORG40.

The organoid drug screen also revealed other promising hits, including a class of drugs called HSP90 inhibitors, and the researchers were able to link what they observed in the lab to a subset of I-SPY patients who had responded better to these types of drugs.

"The breast cancer (搜索)搜索该疾病 organoids were found to express important cancer biomarkers — many of which can be targeted with drugs," said Tam Binh V. Bui, MD, MSc, the study's first author and a PhD candidate at UCSF. "These organoids allowed us to study the effects of drugs directly in human tissue and prioritize the most promising therapies for this subtype."

Limitations and Future Directions

The study did not test how organoid-guided treatment decisions would perform over time. Additionally, the organoids could not reflect the complexity of a whole organ and could not mimic the environment inside the body, which includes blood vessels, immune cells, and other processes that influence the signals tumor cells receive.

Nevertheless, the researchers are optimistic about the translational potential. "By combining computational analyses of large molecular and clinical datasets with organoid model systems, this proof-of-principle study demonstrated the utility of matching I-SPY2 (搜索)搜索该靶点 resistance biomarkers and signatures to residual disease tumor organoid cultures," Rosenbluth said. "Our findings highlight the value of a reverse translational approach that integrates patient-level clinical trial data and testing in organoid models to inform drug discovery and future personalized treatment strategies for patients."

The I-SPY trial consortium, led by UCSF, has worked for more than a decade to accelerate the development of new therapeutics for early-stage, high-risk breast cancer (搜索)搜索该疾病. The current I-SPY 2.2 trial tests multiple cancer therapies simultaneously among different breast cancer subtypes, using clinical biomarkers of response and resistance to optimize treatment based on individual patient responses.

The study was supported by funding from the DF/HCC Breast SPORE (NCI 1P50CA168504), the National Institutes of Health (R01CA281361), the Susan G. Komen Foundation, METAvivor, and the Breast Cancer (搜索)搜索该疾病 Foundation.