University of Texas M.D. Anderson Cancer Center Archives

2018

Young Investigator

Branko Cuglievan

Houston, TX

Pre-clinical high-throughput drug testing using implantable microdevices in Ewing sarcoma patient-derived xenografts

Though most patients diagnosed with localized Ewing sarcoma (ES) can be cured using modern-day chemotherapy regimens, <30% of those with metastatic/recurrent disease achieve this outcome. Within this application, our team addresses two critical challenges, that if overcome, promise to revolutionize the drug discovery process for ES and other pediatric tumor types.

First, preclinical drug discovery reliant upon cell cultures and animal models, poorly predicts clinical activity; less than one-tenth of ‘active’ agents succeed when advanced to the clinic. Misleading drug-testing results complicate our ability to prioritize which drug(s) should be evaluated in the 2-3 ES-specific clinical trials conducted yearly.

Second, favorable tumor response through imaging studies for example, provides only a superficial interpretation of drug activity that fails to measure intratumoral and inter-patient cell heterogeneity, factors that account for drug resistance and tumor growth. Curative therapy for metastatic ES requires rational drug combinations capable of eradicating each and every tumor cell.

As recognized by the NIH Cancer Moonshot’s Blue-Ribbon Panel, both problems can potentially be solved using novel microdevices (rice-sized drug-delivery devices developed at MIT) that facilitate direct intratumoral assessments of >18 drugs and/or drug combinations in <24 hours. The microdevice delivery of drug micro-doses directly into human tumors or patient-derived explants (PDXs) bypasses lower-fidelity preclinical models and preliminarily, appears to better correlate with systemic drug response. Additionally, the technology allows for single-cell analyses to determine intratumoral heterogeneity within the actual tumor architecture and microenvironment. Once validated, this technology will pave the way for precision-based therapies, permitting a rapid and accurate evaluation of novel drug combinations that may save the lives of those patients afflicted with this malignancy.