The Mesothelioma Applied Research Foundation is calling for applications for its 2012 round of mesothelioma research grant funding. Continuing its efforts to stimulate translational research for the treatment of malignant mesothelioma, the Meso Foundation is again soliciting applications for funding of innovative projects that address issues for the treatment of the disease.

A recent publication by Sekido and colleagues has highlighted the connection between two relevant survival/growth pathways in mesothelioma, TGF-beta and NF2/Hippo.

TGF-beta may play important roles in the immune regulation of mesothelioma and in the production of extracellular matrix.
NF2 (neurofibromatosis type 2; Merlin) gene or downstream signaling molecules of the Hippo signaling cascade contain inactivating mutations in nearly 75% of MM cases.

Given the high level of IL-4 receptor alpha (IL-4Ra) in other human cancers and the tumor promoting effects of IL-4, the authors in the present study studied the presence and possible role of IL-4Ra in mesothelioma.
RT-PCR and immunohistochemical analysis confirmed the expression of IL-4Ra in human mesothelioma; strong expression of IL-4Ra correlated with poor survival in patients with epithelial histology following surgery.  Moreover, intracellular cytokine analysis of T cells demonstrated that the T cells are the potential source of IL-4.
Furthermore, IL-4 tested on four different mesothelioma cell lines induced an …

The BRCA1 (breast cancer gene 1) tumour suppressor gene has been reported as a potential predictive biomarker of response to chemotherapy to antimicrotubule agents including vinorelbine, vincristine, paclitaxel and docetaxel. High levels of BRCA1 mRNA expression have been linked to better response rates and improved progression-free survival.

The data presented here highlights that BRCA1-immunonegativity can effectively predict resistance to vinorelbine and microtubule-directed chemotherapy .

Polycomb group proteins (PcG), proteins that act to regulate transcription, have been implicated in numerous aspects of malignancies especially the ones with an aggressive phenotype and in stem cell biology. Misregulation of Polycomb protein levels often leads to either a block or unscheduled activation of developmental pathways, thereby enhancing the proliferation capability of a cell. Polycomb proteins form at least two distinct complexes, the Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2). There is increasing evidence that PRC complexes have a role in tumor progression and development by blocking differentiation …

Many targeted agents, such as anti-VEGF and anti-EGFR blockers, have not shown promise against mesothelioma, at least when used as single agents. However these same targeted agents might be effective when used in combination with chemotherapy or when used in a selected subpopulation. This study tested a variety of targeted agents together with cisplatinum-pemetrexed against 4 mesothelioma lines and found vandetanib, an inhibitor of EGFR/VEGFR2/RET, to be the most effective. Although the agent has multiple effects (see figure), the effect seemed to be explained by the effect on EGFR and …

In this article, transcriptional deregulation, mediated by inactivation of the nuclear deubiquitinase BAP1, is implicated in the pathogenesis of mesothelioma.  The two most common known genetic alterations in mesotheliomas are 9p21 deletions on CDKN2A and 22q deletions causing NF2 loss. The authors show that another gene with a high rate of non-synonymous mutations is BAP1 (encoding BRCA1-associated protein 1).  Somatic mutations were found in 23% of mesotheliomas.  The study also shows that other common tumor suppressors, such as PTEN and p53, showed few or no mutations, confirming data from previous …

In this short communication, the authors focus on the SRC pathway, which is hyperactivated in MM specimens and cell lines compared with normal mesothelial cells (Menges et al., 2010). Inhibition of the SRC pathway with the multi-targeted inhibitor dasatinib has been shown to result in apoptosis, cell cycle arrest and decreased migration and invasion in mesothelioma cell lines (Tsao et al., 2007).
Here the authors test a panel of newly synthesized pyrazolo[3,4-d]pyrimidine derivative SRC kinase inhibitors, that bind the ATP pocket of the SRC kinase, which effectively inhibit SRC activity at nanomolar concentrations.

Here is a paper by Deborah Altomare analyzing Ink4A and Arf role in mesothelioma pathogenesis.
p16(INK4A) and p14(ARF) are frequently co-deleted in human malignant mesothelioma and the authors here find that in vivo both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while the inactivation of Arf appears to be crucial for mesothelioma pathogenesis, the inactivation of both p16(INK4A) and p19(ARF) cooperate to accelerate asbestos-induced tumorigenesis.

Here is a paper analyzing the intriguing possibility that epigenetic drugs may increase the immunogenic profile of mesothelioma, thereby enhancing the ability of an immune response to target the tumor. 
HDAC inhibitors and demethylating agents open the chromatin into a conformation that facilitates transcription not only of tumor suppressors but also of tumor antigens, such as NY-ESO-1, MAGE-A1 and MAGE-A3.