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.

Like a Trojan Horse, the genetically modified cells enter the pleural space but carry the seeds of destruction.

This article presents the results in humans of the first intrapleural instillation of a genetically modified cell line carrying a thymidine kinase suicide gene in mesothelioma.  From prior work, these instilled cells are thought to adhere to the intrapleural tumor and to form gap junctions.  Then, a pro-drug, ganciclovir, is delivered intravenously, diffuses into the pleural space and is converted by the TK gene in the cells to a toxic drug, ganciclovir-triphosphate, which kills the instilled cells and neighboring tumor cells via a ‘bystander effect’.  The process may also induce an anti-tumor immune response.

In this Phase I study of 15 patients, no objective radiographic response was observed.  Therapeutic levels of GCV in both serum and pleura were achieved within 1h, and GCV trough levels remained above the therapeutic threshold for the duration of GCV treatment. The treatment was well tolerated without any Grade 3 or 4 toxicity. The authors show significant induction of both Th1 and Th2 cytokines, both in serum and pleural effusion.

This article demonstrated that gene-modified cell-based intrathoracic therapy for compartmentalized tumor such as mesothelioma is feasible. Further studies may combine this with efforts to suppress the Th2 cytokine response to enhance an unopposed Th1 response.

Read the article here.

Coactivation of multiple RTKs in mesothelioma cell lines analyzed by phospho-RTK array

Although inhibition of EGFR has not shown promise in clinical trials of mesothelioma, broader inhibition of growth pathways might be more effective.  In this study, mesothelioma cells were propagated from human mesothelioma tumors of different histologies and found to have activation of several receptor tyrosine kinases.  In the figure, one sees an array from one mesothelioma cell line with evidence of activation of EGF-R, ERBB3, IGF1R, AXL, and MET, not seen in the normal mesothelial cells.  (The two spots in each corner are positive controls)  Inhibition of a chaperone protein (HSP90) involved in maintenance of proper protein folding was more effective in inhibiting all active RTK than was individual or combined inhibition of the receptors themselves.  The HSP90 inhibitor (geldanamycin, 17-AAG) was also effective at decreasing mesothelioma proliferation, perhaps by virtue of its inhibition of the RTK or perhaps by its other effects.   The 17-AAG inhibitor is now in clinical trials for several tumors.  The authors of this study propose that it be considered for use in clinical trials for mesothelioma.

Read the article here.

A mesothelioma tumor section with high thymidylate synthase staining (see brown). High staining was a poor prognostic factor in patients treated with carboplatin & pemetrexed.

In this retrospective study by Italian and Dutch researchers, mesothelioma samples from 99 patients treated with carboplatin and pemetrexed were analysed for markers of clinical outcome.

A low level of protein expression of thymidylate synthase (TS), the major folate-dependent enzyme inhibited by pemetrexed, correlated with improved outcome: better disease control, longer progression free survival and longer overall survival. In contrast, the level of protein expression of ECRR1, an excision repair gene associated with platin resistance in some tumors, did not. This study is the first to show that immunohistochemical detection of TS is a predictor of clinical outcome. It adds to the understanding of differences in mesothelioma tumors that may underlie differences in response to therapy. If this finding is confirmed by prospective studies, the level of TS may help select patients for pemetrexed therapy.

In a future in which multiple effective therapies exist, such potential prognostic and/or predictive markers could select patients for optimal treatment regimens.

Read article here.

Mesothelioma cells express high levels of mesothelin. From Ordóñez NG.Mod Pathol. 2003 Mar;16(3):192-7.

Here is an interesting article by Dr Hassan reporting the results of a phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009.

Mesothelin is expressed on the surface of many different cancer cells, particularly in the epithelioid type of mesothelioma.  Mesothelin provides a target for anti-mesothelin antibodies.  At least 2 treatment strategies are being tested currently, the SS1P (a recombinant immunotoxin with anti-mesothelin Fv linked to a truncated Pseudomonas exotoxin) and the MORAb-009 (a high-affinity monoclonal antibody, a chimera between mouse Fv and human IgG1/k Fc).  The MORAb-009 may accomplish two therapeutic tasks – 1) binding to tumor cells and activating an antibody-dependent cellular cytotoxicity (ADCC) and 2) blocking the interaction of mesothelin with CA-125 and possibly limited the spread of tumor along mesothelial surfaces.

A phase I trial has just been reported with MORAb-009 in 24 patients with mesothelin-expressing tumors (13 with mesothelioma) who had failed treatment.   The MORAb-009 was found to be safe and a dose was found which produced serum levels higher than the concentration required in in vitro studies to induce ADCC and to block mesothelin-CA-125 interactions.   Of the 24 patients, none had a complete or partial response but 11 showed stable disease.  A phase II trial is currently testing MORAb-009 together with pemetrexed and cisplatin in patients with mesothelioma and 89 patients have been enrolled (NCT00738582). The results of this study are expected to be available towards the end of this year.

The article is available through PubMed here.

V. Courtney Broaddus, MD

The incidence of mesothelioma parallels asbestos usage with a latency of 20 to 40+ years; thus, patient numbers are declining in the United States but rising in the developing world. Radiation, genetics, and possibly simian virus 40 are less common causes.

Diagnosis can be challenging, since the results of pleural fluid cytology testing are often negative despite repeated sampling. No staging system adequately predicts prognosis in the unresected patient.

Newly described biomarkers, including soluble mesothelin-related peptide, megakaryocyte potentiation factor, and osteopontin, may predict which asbestos-exposed individuals will develop mesothelioma, and may prove useful in assessing response to treatment. Since surgery cannot eradicate all residual microscopic disease, a multimodality approach is encouraged.

Metaanalysis suggests that pleurectomy/decortication may achieve outcomes similar to those of extrapleural penumonectomy. The standard first-line chemotherapy for unresectable disease is pemetrexed plus cisplatin. This combination improves response, survival, time to progression, pulmonary function, and disease-related symptoms. Carboplatin is often substituted, with similar results. Other active agents include raltitrexed, gemcitabine, and vinorelbine. Novel agents in clinical trials include inhibitors of the epidermal growth factor receptor, vascular endothelial growth factor, mesothelin, and histone deacetylases.

Although disappointing results of early trials did not confirm promising preclinical data, recent studies have suggested that some novel agents may be effective. As we learn more about mesothelioma biology, molecularly targeted agents may become treatment options.

More here.

Read here: 2006 January Vol4 Issue1