Molecular Approaches to Sarcoma Therapy

[摘要] Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Althoughconventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve acurative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminatingthe clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of genealterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a singlechromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML,these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric proteinthat displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additionalgrowth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinaseinhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cellsmay be effective. This review summarizes published approaches targeting a specific molecular mechanism associated withsarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. Theseinclude: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translationalmodifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptoticpathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and theconceptual obstacles to be overcome are discussed.

[学科分类] 肿瘤学