Sarcoma treatment in the era of molecular medicine

Abstract

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

Keywords: bone sarcoma; molecular diagnostics; molecular medicine; soft tissue sarcoma; targeted therapy.

Figure 1. Diversity of sarcomas as highlighted by DNA methylation profiling

t‐distributed stochastic neighbor embedding (t‐SNE) plot of n = 18 major sarcoma and soft tissue tumor subtypes based on genome‐wide DNA methylation profiling on Illumina EPIC arrays (Koelsche et al, 2018a,b). Web‐link to classifier: www.molecularsarcomapathology.org.

Figure 2. Biological features of sarcomas and therapeutic approaches

Sarcoma development results from a complex biological process. Their natural history combines the emergence of a first oncogenic hit followed by secondary oncogenic and epigenetic events with a conjuncture of a permissive microenvironment composed by cell types from mesodermal tissues, immune infiltrate, vascular, and extracellular matrix components. Sarcoma cells interact with their close environment through direct contact, enhanced cytokine/growth factors/miRNA signaling under a soluble form or encapsulated in extracellular vesicles. Sarcoma cells are characterized by a phenotypic and genetic heterogeneity coming from the successive oncogenic/epigenetic events occurring during tumor development and by cancer cells acquiring stemness properties that become progressively quiescent. Sarcomas are prone to induce distant metastatic foci spread by circulating tumor cells and invading after extravasation appropriate metastatic niches. Cancer cells installed in distant organs can spread again and enrich other metastatic sites increasing the tumor heterogeneity and potentially drug resistances. Persisting cells after resection of the primary tumor or dormant cancer cells located in distant organs characterize the minimal residual disease and are responsible of tumor recurrences. A selection of approved and experimental treatments aimed to prevent tumor growth and/or dissemination is shown.

Figure 3. Sarcomas are characterized by an immune oasis

Sarcomas are infiltrated by numerous immune cells, which are in some sarcoma subtypes deleterious by establishing an immune tolerant microenvironment that can be at the origin of innovative therapeutic approaches. In physiological condition, the adaptive immune system is activated by exogenous antigens leading to initiation of an effective immune response against the host at the origin of these antigens. Unfortunately, in most cases immune activation by tumor‐associated antigen is counterbalanced by inhibitory signals transmitted after the binding of immune checkpoint molecules (e.g., PD‐1) expressed by immune effectors to their ligands expressed by cancer cells such as PD‐L1. Macrophages also contribute to the immune surveillance in sarcomas with two main distinct subsets: M1 macrophages with pro‐tumor activities and M2 macrophages with anti‐tumor and immunosuppressive functions. This immune landscape has led to the development of immunotherapies including immune checkpoint inhibitors, activated NK cells, or genetically modified T lymphocytes (CAR T cells) in order to reactivate the tumor immune surveillance.

Figure 4. Main features and functional aspects of oncolytic virus

(A) Characteristics of oncolytic Adenoviruses Delta‐24-RGD and VCN‐01. These two Adenoviruses harbor different modifications (black for Delta‐24-RG (D24‐RGD) and dashed blue for VCN‐01) that render them with tumor specificity and enhanced infectivity. (B) Schematic representation of the virus’ mechanism of action. (1) The viruses are able to infect both normal and tumor cells. (2) However, due to their tumor specificity they only replicate and lyse the tumor cells. (3) They exert a potent cytolytic effect, and they are able to trigger an anti‐tumor immune response, which is crucial to successfully eliminate the tumors.