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.

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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.

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.

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.