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Establishment of Zebrafish Patient-Derived Xenografts from Pancreatic Cancer for Chemosensitivity Testing
Published on: May 12, 2023
Integrated Patient-Derived Models Delineate Individualized Therapeutic Vulnerabilities of Pancreatic Cancer
Agnieszka K Witkiewicz1, Uthra Balaji2, Cody Eslinger2
1McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Simmons Cancer Center, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390, USA; Department of Pathology, University of Arizona, 1501 N. Campbell Street, Tucson, AZ 85724, USA; University of Arizona Cancer Center, University of Arizona, 1515 N. Campbell Street, Tucson, AZ 85724, USA.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC.
Insights
Pancreatic cancer (PDAC) is difficult to treat. Genetic analysis alone cannot predict drug effectiveness, highlighting the need for personalized therapy based on individual tumor sensitivity profiles.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents a poor prognosis and therapeutic resistance.
- Existing clinical trials for PDAC have largely failed, underscoring the need for novel therapeutic strategies.
Purpose of the Study:
- To identify conserved genetic alterations in PDAC.
- To discover effective therapeutic strategies for PDAC by evaluating drug sensitivity.
- To assess the utility of genetic analysis versus sensitivity profiling for predicting treatment response.
Main Methods:
- Exome sequencing of patient tumors to identify genetic alterations.
- High-throughput drug screening using patient-derived cell lines and patient-derived xenograft (PDX) models.
- Testing over 500 single and combination drug regimens.
Main Results:
- Multiple conserved genetic alterations were found, but most tumors lacked clear therapeutic targets.
- Rare cases of monotherapy sensitivity were observed; most models required combination therapy.
- Treatment responses were confirmed in PDX models, with unique sensitivity profiles for each tumor.
- Genetic analyses could not predict drug efficacy.
Conclusions:
- Reliance on genetic analysis alone is insufficient for predicting PDAC treatment efficacy.
- Sensitivity profiling of patient-derived models is crucial for informing personalized PDAC therapy.
- Combination therapies are often necessary for effective PDAC treatment.
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