Novel Therapeutic Targets in Soft Tissue Sarcomas

IntroductionApproximately 1% of all malignancies or 10,000 cases diagnosed in North American are sarcomas.Amongst which, soft tissue sarcoma comprises of the majority.Local disease is managed with the use of pre-operative or post-operative radiation and surgery, yielding over 90% local control rate. 1 In the meta-analysis reported by Figueredo et al., 2 adjuvant chemotherapy yielded an absolute overall survival benefit of 4% and the benefit was mainly observed in tumours in the extremity, at a deep location, larger than 5 cm or high histological grade.Unfortunately, a recently reported adjuvant trial comparing doxorubicin/ifosfamide combination with observation enrolling patients with such features failed to demonstrate any overall survival benefit. 3Upon follow-up, 50% of localized soft tissue sarcomas will recur either locally, or systemically or both.The benefit of systemic therapy in the recurrent and/or metastatic setting, including doxorubicin, ifsofamide and DTIC, has been shown to be modest with an overall response rate of 10-15%, as single agent, and of 30% in combination at the expense of toxicity without any improvement to the median overall survival rate of 12 months. 4n the past 10 years, the most significant advancement has been observed in gastrointestinal stromal sarcoma (GIST), a rare form of gastrointestinal (GI) tract sarcoma.GIST originates from the interstitial cell of Cajal, a pacemaker cell in the muscularis mucosa of the GI tract. 5,6t is characterized by the expression of CD117 or c-KIT.Eighty-five to 90% of GIST harbour activating mutation in c-KIT, predominantly at exon 11 (70-75%), followed by exon 9 (10%) and rarely exons 13 and 17 (1-2%).About 5-10% of GISTs have platelet derived growth factor receptor-mutation, predominantly in exons 12 and 18. [7][8][9][10][11] The rest harbour mutation in neither tyrosine kinase receptors are considered as wild type. 7,11,12][15][16] More recently, imatinib has been licensed as adjuvant therapy for resected GIST more than 3 cm for 1 year with an improvement in progression-free survival. 17In the annual meeting of the American Society of Clinical Oncology Meeting in 2011, GISTs with c-KIT expression www.intechopen.com

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