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Differential drug responses of circulating tumor cells within patient blood.

ABSTRACT: Personalized medicine holds great promise for cancer treatment, with the potential to address challenges associated with drug sensitivity and interpatient variability. Circulating tumor cells (CTC) can be useful for screening cancer drugs as they may reflect the severity and heterogeneity of primary tumors. Here we present a platform for rapidly evaluating individualized drug susceptibility. Treatment efficacy is evaluated directly in blood, employing a relevant environment for drug administration, and assessed by comparison of CTC counts in treated and control samples. Multiple drugs at varying concentrations are evaluated simultaneously to predict an appropriate therapy for individual patients.

SUBMITTER: Hughes AD

PROVIDER: S-EPMC3997656 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Differential drug responses of circulating tumor cells within patient blood.

Hughes Andrew D AD Marshall Jocelyn R JR Keller Eric E Powderly John D JD Greene Bryan T BT King Michael R MR

Cancer letters 20130821 1

Personalized medicine holds great promise for cancer treatment, with the potential to address challenges associated with drug sensitivity and interpatient variability. Circulating tumor cells (CTC) can be useful for screening cancer drugs as they may reflect the severity and heterogeneity of primary tumors. Here we present a platform for rapidly evaluating individualized drug susceptibility. Treatment efficacy is evaluated directly in blood, employing a relevant environment for drug administrati ...[more]

PMID: 23973263

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Project description:BackgroundCirculating tumor cells (CTCs) are liquid biopsies that represent micrometastatic disease and may offer unique insights into future recurrences in non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no stable CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs and means of potential future metastases in this potentially curable patient group.MethodsSurgically resected NSCLC primary tumor tissues from non-metastatic patients were implanted subcutaneously in immunodeficient mice to establish primary tumor patient-derived xenograft (ptPDX) models. CTCs were isolated as liquid biopsies from the blood of ptPDX mice and re-implanted subcutaneously into naïve immunodeficient mice to generate liquid biopsy CTC-derived xenograft (CDX) tumor models. Single cell RNA sequencing was performed and validated in an external dataset of non-xenografted human NSCLC primary tumor and metastases tissues. Drug response testing in CDX models was performed with standard of care chemotherapy (carboplatin/paclitaxel). Blockade of MYC, which has a known role in drug resistance, was performed with a MYC/MAX dimerization inhibitor (10058-F4).ResultsOut of ten ptPDX, two (20%) stable liquid biopsy CDX mouse models were generated. Single cell RNA sequencing analysis revealed an additional regenerative alveolar epithelial type II (AT2)-like cell population in CDX tumors that was also identified in non-xenografted NSCLC patients' metastases tissues. Drug testing using these CDX models revealed different treatment responses to carboplatin/paclitaxel. MYC target genes and c-MYC protein were upregulated in the chemoresistant CDX model, while MYC/MAX dimerization blocking could overcome chemoresistance to carboplatin/paclitaxel.ConclusionsTo overcome the lack of liquid biopsy CDX models from non-metastatic NSCLC patients, CDX models can be generated with CTCs from ptPDX models that were originally established from patients' primary tumors. Single cell analyses can identify distinct drug responses and cell heterogeneities in CDX tumors that can be validated in NSCLC metastases tissues. CDX models deserve further development and study to discover personalized strategies against micrometastases in non-metastatic NSCLC patients.

Dataset Information

Differential drug responses of circulating tumor cells within patient blood.

Publications

Differential drug responses of circulating tumor cells within patient blood.

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