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.

A Forest plot of the sensitivity of serum mesothelin at a common diagnostic threshold of 2.00 nmol/L displays the heterogeneity among the different studies.

Mesothelin is currently considered the best available serum biomarker for malignant pleural mesothelioma. To examine the reported diagnostic accuracy of mesothelin and evaluate its value for early diagnosis, the authors performed a meta-analysis on the individual patient data (IPD) of 16 diagnostic studies, representing a total of 4,491 individuals, including 1,026 patients with malignant pleural mesothelioma.
They found a significant heterogeneity in reported diagnostic accuracies of mesothelin (see Figure for sensitivity of mesothelin in different studies). Differences in study population can explain this heterogeneity, since the type of control group, mesothelioma stage, and histological subtype were found to affect the diagnostic accuracy.

Moreover, they examined mesothelin in two clinically relevant settings: as an adjunct to rule in or to rule out early-stage mesothelioma. Results indicated that it would not be advisable to use a negative mesothelin test to exclude mesothelioma, even at a high-sensitivity threshold. Conversely, a positive mesothelin test at a high-specificity threshold would provide a strong incentive to urge ensuing diagnostic steps, but the associated poor sensitivity (about 30%) at that level clearly limits the added value to early diagnosis.

Several approaches to anticipate the limited accuracy of serum mesothelin are discussed in this manuscript, together with other directions for further biomarker research. For any novel candidate biomarker of mesothelioma, it will be essential to evaluate its accuracy in direct comparison with mesothelin in a sufficiently large study population, including relevant controls, such as healthy asbestos-exposed individuals and patients with lung cancer, and patients with early stage mesothelioma.

Read more here.

(Suggested by Kevin Hollevoet, PhD)

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.

Mark your calendar!

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.

Building on the success of previous meetings, the Conference will feature workshops, debates, poster sessions and breakout symposia including topics such as immunology, immunotherapy, imaging, pathology as well as surgical pitfalls and challenges.

The Conference will provide the ideal forum to stimulate ideas and establish collaborations as well as to initiate intense discussions about surgery, pathology, new treatments, relevance of biological data and animal models. Poster viewing opportunities and interactive sessions will foster communications between delegates. Another scientific emphasis will be molecular biology and the sequencing of the mesothelioma genome.

We invite our members to read the Declaration and sign the petition.

Sign the petition here.

Read the Press release here.

Read the North American Declaration for the Elimination of Asbestos.