Abstract
Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. We leverage matched PDXs and PDX-derived organoids (PDxO) for drug screening that is feasible and cost-effective with in vivo validation. Moreover, we demonstrate the feasibility of using these models for precision oncology in real time with clinical care in a case of triple-negative breast cancer (TNBC) with early metastatic recurrence. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models. Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. This work provides valuable methods and resources for functional precision medicine and drug development for human breast cancer.
Highlights
Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies
We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers
We previously reported that breast PDXs recapitulated key tumor characteristics, including metastasis and clinical outcomes[13]
Summary
Models that recapitulate the complexity of human tumors are urgently needed to develop more effective cancer therapies. We report a bank of human patient-derived xenografts (PDXs) and matched organoid cultures from tumors that represent the greatest unmet need: endocrine-resistant, treatment-refractory and metastatic breast cancers. Our results uncovered a Food and Drug Administration (FDA)-approved drug with high efficacy against the models Treatment with this therapy resulted in a complete response for the individual and a progression-free survival (PFS) period more than three times longer than their previous therapies. PDX models recapitulate human tumors with high fidelity[1] and exhibit treatment responses that are concordant with human responses[2]. Human patient-derived organoids (PDOs) show strong biological fidelity with their parental tumors, including concordant drug responses, and have been developed for many cancer types[4]. Drug responses could often be related to genomic findings, in half of the cases, functional screening identified different drug responses despite similar driver mutations[6]
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