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.

Eligible projects may relate to benchwork, translational or clinical research, must not be presently funded or pending review, and may be conducted through any not-for-profit academic, medical or research institution, in the U.S. or abroad.

The award for any project will be for two years up to $50,000 per year. Applications are due no later than July 6th, 2012. Notifications will be made at the beginning of January 2013 and awards will be retro-activated to January 1, 2013.

This year all applications will be submitted through Proposal Central.

More info here.

NF2 (neurofibromatosis type 2; Merlin) gene or downstream signaling molecules of the Hippo signaling cascade contain inactivating mutations in nearly 75% of MM cases.  NF2 and downstream signaling molecules negatively regulate the transcription factor Yes-associated protein (YAP).

In the absence of NF2 and in the presence of TGF beta, elevated YAP levels and TGF-beta-induced Smad3 and p300 collaborate to activate a YAP-TEAD4-Smad3-p300 complex. This active complex underlies the activation of connective tissue growth factor (CTGF) which is responsible for cell survival and extracellular matrix deposition and possible oncogenic properties such as vascularization, migration and EMT.

The authors confirmed that CTGF may influence the malignancy of mesothelioma by showing that ablation of CTGF with siRNA  prolonged survival of xenografted mice.  Moreover, CTGF expression and ECM deposition correlated significantly in both mouse xenografts and patient tissue specimens.

Sekido and colleagues provide evidence here for the first time that CTGF could be a strong therapeutic candidate, affecting both cell growth/proliferation and the tumor microenvironment that supports mesothelioma aggressiveness.

Read the full paper here.

Transcriptional regulation of TH1 and TH2 cells. From Nature Reviews Immunology 2, 55-60 (January 2002)

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 increase in STAT-6 phosphorylation and elevated expression of cytokines such as IL-6, IL-8 and VEGF.

The authors conclude that IL-4Ra expression correlates with poor survival of patients undergoing surgical resection for epithelial mesothelioma and they speculate that the IL-4/ IL-4R axis could be a potential therapeutic target in human mesothelioma.

Read the full paper here.

The BRAC1 network (from Nature Reviews, http://goo.gl/Nz1Dy)

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 authors here correlated the BRCA1 levels and the apoptotic response to vinorelbine and found:

1. a strong correlation between vinorelbine sensitivity and BRCA1 expression levels
2. emergence of resistance to vinorelbine by ablating BRCA1 using siRNA
3. a dramatic downregulation of BRCA1 following selection for vinorelbine resistance
4. re-expression of BRCA1 in resistant cells significantly augments their apoptotic response

Furthermore, the analysis of 144 primary mesothelioma specimens showed a loss of BRCA1 expression in ~40% of samples.

Altogether, the data presented highlights that BRCA1-immunonegativity can effectively predict resistance to vinorelbine and microtubule-directed chemotherapy .

Of note, it has been shown that BRCA1-deficiency correlates with a better outcome following platinum chemotherapy and clinical trials report on significant antitumor activity following PARP inhibitor treatment in BRCA-deficient patients.
Accordingly, mesotheliomas lacking expression of BRCA1, resistant to vinorelbine and microtubule-directed chemotherapy, might also represent a molecularly defined subgroup of tumors with sensitivity to PARP inhibition and platinum therapy.

Full article here.

PRC2 is shown with PRC1 and various recruiting molecules at a CpG-rich site where it mediates transcriptional repression. The actual mechanism of repression is not yet understood (http://goo.gl/HXwf5).

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 and promoting stem cell self-renewal. A recent study demonstrated that enhanced EZH2 levels led to growth of Ewing tumors and a consequential inhibition of endothelial and neuroectodermal differentiation. Here the authors find that EZH2, a core component of polycomb repressor complex-2 (PRC-2) is overexpressed in the majority of pleural mesotheliomas and that elevated EZH2 correlates with decreased patient survival.

Inhibition of PRC-2 expression by knock-down or with 3-deazaneplanocin A (DZNep), an S-adenosylhomocysteine hydrolase inhibitor, significantly inhibited proliferation, migration, clonogenicity and tumorigenicity of pleural mesothelioma cells. Furthermore, authors identified a loss of miR-101 or miR-26 in primary MPM specimens, which may explain the EZH2 overexpression. Authors do not conclusively show that DZNep inhibited the malignant phenotype by blocking PRC-2. Nevertheless, these findings warrant further analysis of PcG protein expression in mesotheliomas, and the development of agents targeting PRC-2 expression/activity for treatment.

Read the article here.

Vandetanib mechanism of action

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 was associated with suppression of phosphorylated Akt. The promise from this and other studies is that clinical trials using targeted agents may be designed in the future in subpopulations with evidence of dependence on that target (“addiction”). The targeted agent may then be effective on its own or by decreasing resistance to standard chemotherapy.

Read the article here.

BAP1 may target histones and cell cycle checkpoints.  Reintroduction of BAP1 in BAP1-null cells resulted in a modest increase in proliferation, quite a paradoxical result for a gene that supports a tumor suppression factor. Several groups have shown that BAP1 also has a role in cell cycle progression and that re-expression of BAP1 causes growth suppression in vitro and in vivo. So it is possible that, in mesothelioma, inactivation of BAP1 allows for a slower cell proliferation, with a more permissive G1/S checkpoint, causing cells to grow more slowly but uncontrollably.

This paper, published on Nature Genetics in July 2011, has been followed by another paper on BAP1 germline mutations in mesothelioma.  Together, these articles shed more light on the pathogenesis of mesothelioma and the implication of transcriptional deregulation in this highly lethal cancer.

Read the article here.

Structure of the new SRC inhibitors

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, which bind the ATP pocket of the SRC kinase and inhibit SRC activity at nanomolar concentrations.

They found that two of these molecules, in particular, were indeed able to inhibit SRC activation and reduce cell viability by induction of apoptosis, p27 stabilization and nuclear localization.
Moreover, they observed a decrease in AKT activity and cyclin D1 levels.

These inhibitors may hold promise against mesothelioma, although in vivo and clinical trials will be needed to assess efficacy and toxicity.

Read the article here.

Read the paper here.

The authors show that the HDAC inhibitors, depakine (valproic acid) and vorinostat (SAHA), and a demethylating agent, decitabine (5-azaCdR), increase tumor antigen expression both in vitro and in vivo which promotes lymphocyte infiltration and recognition of mesothelioma cells by specific CD8+ cytotoxic T-cells.

These results show the potential promise of the combined treatment of mesothelioma with HDAC inhibitors and demethylating agents.

Read paper here.