Survival of children with cancers has dramatically improved over the past several decades. This success has been achieved through improvement of combined modalities in treatment approaches, intensification of cytotoxic chemotherapy for those with high-risk disease and refinement of risk stratification incorporating novel biologic markers in addition to traditional clinical and histologic features. Advances in cancer genomics have shed important mechanistic insights on disease biology and have identified "driver" genomic alterations, aberrant activation of signaling pathways, and epigenetic modifiers that can be targeted by novel agents. Thus, the recently described genomic and epigenetic landscapes of many childhood cancers have expanded the paradigm of precision medicine in the hopes of improving outcomes while minimizing toxicities. In this review, we will discuss the biologic rationale for molecularly targeted therapies in genomically-defined subsets of pediatric leukemias, solid tumors, and brain tumors.
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