Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions

Abstract

Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in sarcoma could represent the premise for targeted treatments. Summarizing, soft-tissue sarcomas can be differentiated into histotypes with reciprocal chromosomal translocations, with defined oncogenic mutations and complex karyotypes. If the latter are improbably approached with targeted treatments, many suggest that innovative therapies interfering with the identified fusion oncoproteins and altered pathways could be potentially resolutive. In most cases, the characteristic genetic signature is discouragingly defined as "undruggable", which poses a challenge for the development of novel pharmacological approaches. In this review, a summary of genomic alterations recognized in most common soft-tissue sarcoma is reported together with current and future therapeutic opportunities.

Keywords: genome; personalized medicine; precision medicine; sarcoma; translocation.

Figure 1

(A) Chromosome 12 represents the hallmark of WDLPS and DDLPS. Amplified relevant genes are depicted in red. (B) Relationship between Mdm2 and p53: Mdm2 induces degradation of p53 through polyubiquitylation; (C) the translocation t(12;16)(q13;p11) induces the expression of FUS DDIT 3 fusion protein in MLPS.

Figure 2

A schematic view of genetic alterations in LPS.

Figure 3

SMARCB1 /PRC2 balance. The SWI/SNF-SMARCB1 binding induces the activation of the epigenetic enzyme such as the histone acetyltransferase inducing a chromatin open-frame mediated by the acetylation of lysine 27 on histone 3 (H3K27Ac) and consequential target genes expression. The PRC2 complex acts as antagonist inducing a gene silencing by an increase in the methylation status of H3K27me3. This defined equilibrium is modified by the selective EZH2 inhibitor tazemetostat which inhibiting the enzyme activity, blocks the PRC2 complex silencing effect.

Figure 4

SS 18 SSX fusion oncoproteins in SS. The common translocation in SS, t(X;18)(p 11.2; q11.2), leads to the expression of SS 18 SSX fusion proteins. In normal mesenchymal cells, BAF(mSWI /complex induces a cell quiescence by an increase in “repressive” epimarks (H3K27me3) and Sox 2 inhibition. In SS, the SS 18 SSX fusion proteins replace the wild type SS 18 in the BAF complex and form an altered complex lacking the tumor suppressor BAF 47 (hSNF 5). The altered complex binds Sox 2 causing its activation and cell proliferation.