Signaling Drivers of Sarcoma Drug Resistance

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PROJECT SUMMARY Sarcomas are a heterogenous group of rare cancers affecting about 16,000 people each year in the US. Bone sarcomas are particularly rare, with 3,500 diagnoses a year. Resistance to therapy is a critical clinical challenge in bone sarcoma management, limiting the utility of systemic treatment in the management of relapsing and metastatic disease. There is limited data on drivers of bone sarcoma innate and acquired drug resistance. As part of the parent grant, we have established a pipeline to develop personalized bone sarcoma organoids to screen hundreds of drugs and determine a drug resistance and sensitivity profile for each tumor. We pair this with whole-genome sequencing to identify mutational correlates of drug sensitivity. Here, we will complement this work by interrogating disruptions in signaling pathways at the RNA and protein level to identify correlates of drug resistance in pre- and post-neoadjuvant samples (Aim 1) as well as in different metastatic lesions from the same patient (Aim 2). The combination of spatial and temporal genomic, transcriptomic and proteomic analyses with functional drug testing will allow us to determine the factors impacting drug resistance and develop biomarkers of response.