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Evaluating Potential Drug Therapies

Evaluating Potential Drug Therapies. Mike Shuler Biomedical Engineering. Can we use tissue engineering and related approaches to evaluate potential effectiveness of drugs? Can they be adapted for personalized medicine?. Claudia Fischbach-Teschl Abe Stroock Larry Bonassar Jonathan Butcher.

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Evaluating Potential Drug Therapies

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  1. Evaluating PotentialDrug Therapies Mike Shuler Biomedical Engineering

  2. Can we use tissue engineeringand related approachesto evaluate potentialeffectiveness of drugs?Can they be adapted forpersonalized medicine? Claudia Fischbach-Teschl Abe Stroock Larry Bonassar Jonathan Butcher

  3. Drug responsiveness in 3-D tumor cell culture In vitro In vivo  Tissue engineered tumors recreate conditions in vivo Tumor cells cultured in biomimetic tumor microenvironments are less responsive to cytotoxic therapy

  4. Observations • Individual cancers vary/many possible combination of mechanisms • Metabolizing tissue – significant variation throughout human population – metabolites can vary in amount and kind • Dose-limiting normal tissues; tolerance varies

  5. Premise • Single drugs are unlikely to be broadly effective • Combination therapy should be more effective • How can we predict accurately the best therapy for an individual?

  6. In vitro Replacements for Animals and Humans • Animal studies are expensive, long, and not particularly predictive of human response • Currently only 1 in 10 drugs entering human clinical trials emerge as FDA approved products

  7. lung fat Other Tissues liver “Microscale Cell Culture Analog” 1” 1” CCA: a physical replica of the PBPK model We can model our body as combinations of tissue culture reactors (physiologically based pharmacokinetic model)

  8. Combination Therapies forCancer Treatment • Could exposure to multiple agents more effectively treat cancer? • With multiple agents the potential number of combinations and scenarios to be tested is impracticable for animal studies • Could CCA with PBPK explore a broad experimental range to predict a testable subset for detailed study?

  9. Multidrug Resistant (MDR) Cancer • Tumor responds initially but reoccurs and in non-responsive or MDR • Multiple causes of MDR; may need multiple agents to control • Best studied case is P-glycoprotein (P-gp) overexpression: Pump protein intercepts chemotherapeutic agent before it enters cell

  10. MDR Suppressing Agents Fail • No MDR suppressing agent has passed clinical trials • Toxicity to normal tissue/altered pharmacokinetics for chemotherapeutic • Animal studies not good predictor • - Rat has 3 P-gp isoforms; humans have 2

  11. Human Cell Culture Analog

  12. Model Drugs Used • Doxorubicin as chemotherapeutic agent (naturally fluorescent) • Cyclosporin, Nicardipine as MDR suppressors

  13. Micro Cell Culture Analog Application to Study Multidrug Resistance Suppressors Sensitive Tumor Cells (MES-SA) Other Tissues/ Debubbler Resistant Tumor Cells (MES-SA/DX-5) Liver Cells (Hep-G2/C3-A) Bone Marrow Blood Cells (MEG-01) Device on peristaltic pump in incubator All cells labeled with celltracker green before experiment

  14. Proliferative Toxicity Study We challenged the MDR CCA device to 3 day exposure to mixtures of Doxorubicin and 2 modulators: nicardipine and cyclosporine A in McCoys 5A medium with 10% FBS. The ratio of final cell density to initial cell density for each condition is displayed below. Result: Modulators have strong response on resistant cell line, moderate in others, and a synergistic effect is observed between the two modulators in the resistant cell type.

  15. Can we use biopsy tissue from the cancer target, the liver, and other relevant tissue to test patient specific response using a microCCA?

  16. Relevant Features • Can be made disposable/polystyrene • Requires few cells – multiple tests possible from modest tissue sample • Screen large set of drug combinations • Could also be used to study mechanisms?

  17. Challenges • Maintenance of tissue specific characteristics in vitro • Automated processing and “simple” to use • Validation?

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