Latest developments in our understanding of the pathogenesis of mesothelioma and the design of targeted therapies

Abstract

Malignant mesothelioma is an aggressive cancer whose pathogenesis is causally linked to occupational exposure to asbestos. Familial clusters of mesotheliomas have been observed in settings of genetic predisposition. Mesothelioma incidence is anticipated to increase worldwide in the next two decades. Novel treatments are needed, as current treatment modalities may improve the quality of life, but have shown modest effects in improving overall survival. Increasing knowledge on the molecular characteristics of mesothelioma has led to the development of novel potential therapeutic strategies, including: molecular targeted approaches, that is the inhibition of vascular endothelial growth factor with bevacizumab; immunotherapy with chimeric monoclonal antibody, immunotoxin, antibody drug conjugate, vaccine and viruses; inhibition of asbestos-induced inflammation, that is aspirin inhibition of HMGB1 activity may decrease or delay mesothelioma onset and/or growth. We elaborate on the rationale behind new therapeutic strategies, and summarize available preclinical and clinical results, as well as efforts still ongoing.

Keywords: BAP1; HMGB1; asbestos; aspirin; carcinogenesis; immunotherapy; mesothelioma; molecular therapy; polyclonal tumors.

Figure 1. Molecular alterations involved in the development of MM and possible strategies for therapeutic intervention

(a) Key genetic alterations. The BAP1 gene encodes BRCA1 associated protein-1 (BAP1), which plays a role in the regulation of gene transcription, chromatin remodeling and DNA repair, by forming multi-protein complexes with several nuclear proteins, including host cell factor-1 (HCF1), Ying Yang 1 (YY1) and histone H2A. The NF2 gene encodes the protein merlin, which acts as an upstream regulator of the mammalian target of rapamycin (mTOR), focal adhesion kinase (FAK) and Hippo pathways. The merlin-Hippo signaling inactivation leads to constitutive Yes-associated protein (YAP) activation. The CDKN2A/ARF gene encodes p16^INK4a and p14^ARF, respectively. The p16^INK4a protein activates the retinoblastoma protein (pRb) pathway by inhibiting the cyclin-dependent kinase (CDK)-mediate hyperphosphorylation of pRb. The p14^ARF protein mediates p53 stabilization by promoting the degradation of the human ortholog of mouse double minute 2 (MDM2). (b) Receptor tyrosine kinases (RTKs) are frequently activated in MM. Inhibition of RTKs or their ligands with specific antibodies or small molecules has been tested as targeted approach in MM. Strategies for therapeutic intervention are summarized in this and in the following figures, accordingly to results obtained in past and ongoing clinical trials, or to possible future directions. The color code defines drugs that have not been tested (blue), drugs that gave positive results and are under further evaluation (green), and drugs that gave negative results (red). For further detail refer to the relative section in the main text.

Figure 2. Anti-tumor immune response and mechanisms of MM immune escape with possible strategies for immunotherapeutic interventions

Malignant mesothelioma (MM) cells express mesothelin and other tumor specific antigens. During the anti-tumor immune response (displayed on the left), antigen-presenting cells (APCs) display tumor antigens represented by major histocompatibility complexes (MHCs) to naïve T cells, inducing T cell activation and subsequent immune destruction of cancer cells via T cell receptor (TCR). However, tumors can activate several immune escape (displayed on the right) mechanisms to evade immune destruction. Molecules like transforming growth factor β (TGF-β) can block T cell function. T cell function can be also abrogated by activation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on activated T cells. CTLA-4 binding to B7, and the interaction of PD-1 ligand 1 (PD-L1) with PD-1, are crucial to inhibit immune response. MM cells can also block immune activation by upregulating PD-L1. Potential targets and strategies for MM immunotherapy are summarized in the figure. Color code: drugs that have not been tested (blue), drugs that gave positive results and are under further evaluation (green), and drugs that gave negative results (red).

Figure 3. Targeting asbestos-induced inflammation to prevent malignant transformation of mesothelial cells

Asbestos is very cytotoxic to human primary mesothelial (HM) cells and causes DNA damage, as well as extensive necrotic cell death leading to the release of high-mobility group box 1 (HMGB1) into the extra cellular space. Secreted HMGB1 stimulates receptor for advanced glycation end products (RAGE), Toll-like receptor 2 (TLR2), and TLR4, expressed on neighboring inflammatory cells, mostly macrophages. HMGB1 release elicits macrophage accumulation and triggers the inflammatory response, with secretion of Interleukin-1β (IL-1β) and especially tumor-necrosis factor-α (TNF-α). HMGB1 and TNF-α cooperate to promote the activation of nuclear factor κB (NF-κB) pathway, which increases HM survival after asbestos exposure. This allows HM with asbestos-induced DNA damage to divide rather than die and, if key genetic alterations accumulate, to eventually develop into malignant mesothelioma (MM). HMGB1 is also highly expressed and secreted by MM cells, establishing an autocrine circuit that further influences their proliferation and survival. Potential targets and strategies for MM therapy that have been proposed based on recent studies are summarized in the figure. Color code: drugs that have not been tested (blue), drugs that gave positive results and are under further evaluation (green), and drugs that gave negative results (red).