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.
|Prieto-Granada, Carlos N; Zhang, Lei; Antonescu, Cristina R et al. (2017) Primary cutaneous adenoid cystic carcinoma with MYB aberrations: report of three cases and comprehensive review of the literature. J Cutan Pathol 44:201-209|
|Antonescu, Cristina R; Sung, Yun-Shao; Zhang, Lei et al. (2017) Recurrent SRF-RELA Fusions Define a Novel Subset of Cellular Myofibroma/Myopericytoma: A Potential Diagnostic Pitfall With Sarcomas With Myogenic Differentiation. Am J Surg Pathol 41:677-684|
|Zeng, Shan; Seifert, Adrian M; Zhang, Jennifer Q et al. (2017) Wnt/?-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor. Mol Cancer Ther 16:1954-1966|
|Kao, Yu-Chien; Sung, Yun-Shao; Zhang, Lei et al. (2017) EWSR1 Fusions With CREB Family Transcription Factors Define a Novel Myxoid Mesenchymal Tumor With Predilection for Intracranial Location. Am J Surg Pathol 41:482-490|
|Kao, Yu-Chien; Sung, Yun-Shao; Zhang, Lei et al. (2017) BCOR upregulation in a poorly differentiated synovial sarcoma with SS18L1-SSX1 fusion-A pathologic and molecular pitfall. Genes Chromosomes Cancer 56:296-302|
|Owosho, Adepitan A; Estilo, Cherry L; Huryn, Joseph M et al. (2017) A Clinicopathologic Study of Head and Neck Malignant Peripheral Nerve Sheath Tumors. Head Neck Pathol :|
|Flucke, Uta; van Noesel, Max M; Wijnen, Marc et al. (2017) TFG-MET fusion in an infantile spindle cell sarcoma with neural features. Genes Chromosomes Cancer 56:663-667|
|Henssen, Anton G; Koche, Richard; Zhuang, Jiali et al. (2017) PGBD5 promotes site-specific oncogenic mutations in human tumors. Nat Genet 49:1005-1014|
|Desmeules, Patrice; Joubert, Philippe; Zhang, Lei et al. (2017) A Subset of Malignant Mesotheliomas in Young Adults Are Associated With Recurrent EWSR1/FUS-ATF1 Fusions. Am J Surg Pathol 41:980-988|
|Ran, Leili; Chen, Yuedan; Sher, Jessica et al. (2017) FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor. Cancer Discov :|
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