Sarcoma is a heterogeneous disease with at least 50 different subtypes. Given this genetic diversity, the developnnent of new targeted therapies is particularly challenging. However, one consistent theme now emerging is that receptor tyrosine kinase (RTK) activation of PI3K/Akt and mTOR pathways are critical for sarcoma tumor oncogenesis, proliferation, and survival across histologic subtypes. Despite the compelling rationale to target RTKs and mTOR in sarcomas, results from clinical studies have been disappointing. Hence, a new direction in drug development is needed to optimize therapeutic approaches directed at these rational targets. We hypothesize that PDGFRA represents a critical therapeutic target in a subset of sarcomas that can be effectively targeted in combination with mTOR inhibitors and chemotherapy.
Our specific aims are to 1) conduct a phase Ib/ll clinical trial of imatinib and everolimus in PDGFRA expressing synovial sarcomas;2) conduct a phase Ib/ll randomized clinical trial of doxorubicin with or without IMC-3G3, a human monoclonal antibody specific for PDGFRA;and 3) investigate anti-tumor mechanisms of PDGFRA inhibition in sarcoma tumors. Public Health Statement: Given the lack of effective chemotherapy, patients with advanced and metastatic sarcoma are in great need of new therapies. Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (PDGFRA and mTOR) should result in major advances in the treatment and cure of this disease. Sloan-
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