Preliminary experience of ex-vivo high-throughput drug screening in muscle invasive bladder cancer: moving towards improved patient selection and treatment personalisation
BAUS ePoster online library. Conroy S. 06/22/21; 319005; p10-16
Disclosure(s): The Urology Foundation Research Scholarship Award 2020-21
Ms. Samantha Conroy
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Abstract
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Introduction: Despite increased understanding of complex tumour biology and advances in drug discovery, outcomes in muscle-invasive bladder cancer (MIBC) have not significantly improved in 30 years. Ex-vivo high-throughput drug screening – a novel pre-clinical model – may improve patient selection, treatment personalisation, and expedite novel drug discovery.
Patients and Methods: 15 patients with MIBC provided informed consent (09/2020-01/2021)(Ethics:10/H1310/73). Each tumour sample was dissociated into a composite cellular suspension (tumour/stromal/immune) and seeded onto drug plates containing standard-of-care, novel and repurposed agents. Two plates were ran for each sample to generate enzymatic and immunofluorescence end-point data. Drug responses were determined by comparing drug wells with vehicle controls; responses were categorised as partial response (PR:51-75% growth), good response (GR:26-50% growth), and complete response (CR:0-25% growth) at highest drug concentrations.
Results: 10 patients had end-point enzymatic data available for inclusion. Table 1 describes clinical features and ex-vivo seeding densities. Figure 1 depicts an example of end-point results. All tumours had CR to Cisplatin, but only 40% had GR/PR to Gemcitabine. Ex-vivo screening identified additional effective (at least GR) standard-of-care treatments (could be added immediately) for all tumours eg. Vinblastine; and identified effective (at least GR) novel agents in all tumours eg. mTOR, PI3K, EGFR, and FRFR inhibitors.
Conclusions: Preliminary experiences using ex-vivo screening to determine patient-specific drug sensitivities in MIBC is promising. Future work includes: immunofluorescence-based cell-type specific sensitivities and cell-on-cell interaction analysis; genetic analysis to explore implicated molecular pathways; clinical follow-up correlation; and expansion of plates to include combination treatments.
Patients and Methods: 15 patients with MIBC provided informed consent (09/2020-01/2021)(Ethics:10/H1310/73). Each tumour sample was dissociated into a composite cellular suspension (tumour/stromal/immune) and seeded onto drug plates containing standard-of-care, novel and repurposed agents. Two plates were ran for each sample to generate enzymatic and immunofluorescence end-point data. Drug responses were determined by comparing drug wells with vehicle controls; responses were categorised as partial response (PR:51-75% growth), good response (GR:26-50% growth), and complete response (CR:0-25% growth) at highest drug concentrations.
Results: 10 patients had end-point enzymatic data available for inclusion. Table 1 describes clinical features and ex-vivo seeding densities. Figure 1 depicts an example of end-point results. All tumours had CR to Cisplatin, but only 40% had GR/PR to Gemcitabine. Ex-vivo screening identified additional effective (at least GR) standard-of-care treatments (could be added immediately) for all tumours eg. Vinblastine; and identified effective (at least GR) novel agents in all tumours eg. mTOR, PI3K, EGFR, and FRFR inhibitors.
Conclusions: Preliminary experiences using ex-vivo screening to determine patient-specific drug sensitivities in MIBC is promising. Future work includes: immunofluorescence-based cell-type specific sensitivities and cell-on-cell interaction analysis; genetic analysis to explore implicated molecular pathways; clinical follow-up correlation; and expansion of plates to include combination treatments.
Introduction: Despite increased understanding of complex tumour biology and advances in drug discovery, outcomes in muscle-invasive bladder cancer (MIBC) have not significantly improved in 30 years. Ex-vivo high-throughput drug screening – a novel pre-clinical model – may improve patient selection, treatment personalisation, and expedite novel drug discovery.
Patients and Methods: 15 patients with MIBC provided informed consent (09/2020-01/2021)(Ethics:10/H1310/73). Each tumour sample was dissociated into a composite cellular suspension (tumour/stromal/immune) and seeded onto drug plates containing standard-of-care, novel and repurposed agents. Two plates were ran for each sample to generate enzymatic and immunofluorescence end-point data. Drug responses were determined by comparing drug wells with vehicle controls; responses were categorised as partial response (PR:51-75% growth), good response (GR:26-50% growth), and complete response (CR:0-25% growth) at highest drug concentrations.
Results: 10 patients had end-point enzymatic data available for inclusion. Table 1 describes clinical features and ex-vivo seeding densities. Figure 1 depicts an example of end-point results. All tumours had CR to Cisplatin, but only 40% had GR/PR to Gemcitabine. Ex-vivo screening identified additional effective (at least GR) standard-of-care treatments (could be added immediately) for all tumours eg. Vinblastine; and identified effective (at least GR) novel agents in all tumours eg. mTOR, PI3K, EGFR, and FRFR inhibitors.
Conclusions: Preliminary experiences using ex-vivo screening to determine patient-specific drug sensitivities in MIBC is promising. Future work includes: immunofluorescence-based cell-type specific sensitivities and cell-on-cell interaction analysis; genetic analysis to explore implicated molecular pathways; clinical follow-up correlation; and expansion of plates to include combination treatments.
Patients and Methods: 15 patients with MIBC provided informed consent (09/2020-01/2021)(Ethics:10/H1310/73). Each tumour sample was dissociated into a composite cellular suspension (tumour/stromal/immune) and seeded onto drug plates containing standard-of-care, novel and repurposed agents. Two plates were ran for each sample to generate enzymatic and immunofluorescence end-point data. Drug responses were determined by comparing drug wells with vehicle controls; responses were categorised as partial response (PR:51-75% growth), good response (GR:26-50% growth), and complete response (CR:0-25% growth) at highest drug concentrations.
Results: 10 patients had end-point enzymatic data available for inclusion. Table 1 describes clinical features and ex-vivo seeding densities. Figure 1 depicts an example of end-point results. All tumours had CR to Cisplatin, but only 40% had GR/PR to Gemcitabine. Ex-vivo screening identified additional effective (at least GR) standard-of-care treatments (could be added immediately) for all tumours eg. Vinblastine; and identified effective (at least GR) novel agents in all tumours eg. mTOR, PI3K, EGFR, and FRFR inhibitors.
Conclusions: Preliminary experiences using ex-vivo screening to determine patient-specific drug sensitivities in MIBC is promising. Future work includes: immunofluorescence-based cell-type specific sensitivities and cell-on-cell interaction analysis; genetic analysis to explore implicated molecular pathways; clinical follow-up correlation; and expansion of plates to include combination treatments.
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