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.
|Agaram, Narasimhan P; Chen, Chun-Liang; Zhang, Lei et al. (2014) Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 53:779-87|
|Antonescu, Cristina R; Chen, Hsiao-Wei; Zhang, Lei et al. (2014) ZFP36-FOSB fusion defines a subset of epithelioid hemangioma with atypical features. Genes Chromosomes Cancer 53:951-9|
|Kohsaka, Shinji; Shukla, Neerav; Ameur, Nabahet et al. (2014) A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet 46:595-600|
|Kim, Teresa S; Cavnar, Michael J; Cohen, Noah A et al. (2014) Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. Clin Cancer Res 20:2350-62|
|Qin, Li-Xuan; Breeden, Linda; Self, Steven G (2014) Finding gene clusters for a replicated time course study. BMC Res Notes 7:60|
|Brennan, Murray F; Antonescu, Cristina R; Moraco, Nicole et al. (2014) Lessons learned from the study of 10,000 patients with soft tissue sarcoma. Ann Surg 260:416-21; discussion 421-2|
|Patwardhan, Parag P; Surriga, Oliver; Beckman, Michael J et al. (2014) Sustained inhibition of receptor tyrosine kinases and macrophage depletion by PLX3397 and rapamycin as a potential new approach for the treatment of MPNSTs. Clin Cancer Res 20:3146-58|
|Weinreb, Ilan; Zhang, Lei; Tirunagari, Laxmi M S et al. (2014) Novel PRKD gene rearrangements and variant fusions in cribriform adenocarcinoma of salivary gland origin. Genes Chromosomes Cancer 53:845-56|
|Antonescu, Cristina R; Sung, Yun-Shao; Chen, Chun-Liang et al. (2014) Novel ZC3H7B-BCOR, MEAF6-PHF1, and EPC1-PHF1 fusions in ossifying fibromyxoid tumors--molecular characterization shows genetic overlap with endometrial stromal sarcoma. Genes Chromosomes Cancer 53:183-93|
|Lee, William; Teckie, Sewit; Wiesner, Thomas et al. (2014) PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors. Nat Genet 46:1227-32|
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