Targeted therapies in sarcomas: challenging the challenge

Abstract

Sarcomas are a heterogeneous group of mesenchymal malignancies that very often lead to death. Nowadays, chemotherapy is the only available treatment for most sarcomas but there are few active drugs and clinical results still remain very poor. Thus, there is an imperious need to find new therapeutic alternatives in order to improve sarcoma patient's outcome. During the last years, there have been described a number of new molecular pathways that have allowed us to know more about cancer biology and tumorigenesis. Sarcomas are one of the tumors in which more advances have been made. Identification of specific chromosomal translocations, some important pathways characterization such as mTOR pathway or the insulin-like growth factor pathway, the stunning development in angiogenesis knowledge, and brand new agents like viruses have lead to the development of new therapeutic options with promising results. This paper makes an exhaustive review of preclinical and clinical evidence of the most recent targeted therapies in sarcomas and provides a future view of treatments that may lead to improve prognosis of patients affected with this disease.

Figure 1

Inhibition of angiogenesis by blocking different tumorigenic signaling pathways.

Figure 2

The activation of IGFR by ligand binding triggers a signal transduction pathway that causes the activation of mTOR pathway and inhibition of apoptosis, thus promoting cell survival. Anti-IGFR antibodies prevent this effect.

Figure 3

AKT activation, among other stimulus, can activate mTOR complexes, mTORC1 and mTORC2, promoting protein synthesis and cell proliferation. Rapamycin and rapalogs are specific inhibitors of mTORC1 but an escape route remains through mTORC2 activity.