HiTS Seminar: Juliet Williams and Hui Gao, 10:00 am, November 16, 2017
Juliet Williams, Ph.D. and Hui Gao, Ph.D.
Novartis Institutes of Biomedical Research
10:00 am – 11:00 am
Thursday, November 16, 2017
Harvard Medical School
200 Longwood Avenue
Warren Alpert Bldg, Room 563
Human Clinical Trials in Mice: Modeling Inter-patient Response Heterogeneity in PDXs
Less than 10% of molecules which enter oncology trials become approved drugs. One factor attributing to our inability to predict which molecules may be successful in humans is the poor translatability of our preclinical models. Assessing drug candidates across panels of PDX models which capture inter-tumor heterogeneity could help us understand what therapeutics will work across cancer patient populations and aid identification of factors for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a PDX clinical trial format to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. This experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.