Expanding Chemical Space

Expanding the Chemical Space for Osteosarcoma: $782,377 over 2 years

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An outstanding field of basic scientists and clinical investigators have explored the chemical space (druggable space) for osteosarcoma and have pioneered an efficient system of rapidly-completed phase II studies in the Children’s Oncology Group. Drugs have included RANKL inhibitors, anti-disialoganglioside antibodies, irreversible tubulin inhibitors, and anti-glycoprotein NMB conjugates – among others. Thus far, osteosarcoma has proven refractory to most of these agents. A broader chemical space is needed for these qualified scientists and clinical investigators to pursue.

In an academic-pharma partnership project with a Swiss pharmaceutical company, we used our GEM model-derived primary tumor cell cultures of soft tissue sarcomas (ARMS, ERMS and UPS versus nonmalignant cells) to explore a massive chemical space for these cancers. We have already completed this screen of 640,000 compounds — and have in hand results for 446 confirmed, high priority hits. These hits are all unexpected classes of compounds. For example, one hit is an FDA-approved cardiovascular agent that is taken safely for decades in an extended release tablet. The other hits are not FDA approved, but have favorable structural features for clinical use. To extend the impact of these findings to osteosarcoma, we propose to counterscreen & validate these agents against human, mouse and canine osteosarcoma cultures in vitro, prioritize hits via an in ovo CAM assay, then test each agent in vivo using diverse human patient-derived xenografts models.