Mesothelioma: Nintedanib Plus Chemotherapy Demonstrated Improved Progression-Free Survival

Professor Giorgio V. Scagliotti Chair of the Department of Oncology University of Torino,Italy

Prof. Scagliotti Interview with:
Professor Giorgio V. Scagliotti

Chair of the Department of Oncology
University of Torino,Italy What is the background for this study? What are the main findings?

Response: LUME-Meso II is an international study designed to evaluate the safety and efficacy of nintedanib plus pemetrexed/cisplatin, followed by nintedanib versus placebo plus pemetrexed/cisplatin, followed by placebo, for the treatment of patients with unresectable malignant pleural mesothelioma (MPM).

MPM is a rare cancer that affects the cells that make up the mesothelium of the pleura – the lining or membrane that covers and protects the lungs. It represents less than 1% of all cancers and is often related to long-term asbestos exposure with some suffering from malignant mesothelioma.

A significant improvement in progression-free survival (PFS), the study’s primary endpoint, was observed for patients receiving nintedanib plus chemotherapy compared to patients receiving placebo plus chemotherapy.

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Aspirin Inhibits Growth of Mesothelioma Cells in Mouse Model

Dr-Haining-Yang Interview with:
Haining Yang MD Ph.D
Associate Professor
Thoracic Oncology Program
University of Hawaii Cancer Center
University of Hawaii, Honolulu, HI

Medical Research: What is the background for this study?

Dr. Yang: Mesothelioma is often caused by asbestos and other carcinogenic mineral fibers.  When these fibers lodge in the pleura, mesothelial cells and macrophages try to phagocytize and eliminate them. However, asbestos is very bio-persistent and cannot be eliminated, which caused cells undergoing programmed necrosis that leads to the release of HMGB1 into the extracellular space.  HMGB1 is a damage-associated molecular pattern molecule (DAMP) that causes inflammation. Asbestos exposure induces HMGB1 release and chronic inflammatory process that overtime may lead to malignancy.  Mesothelioma cells develop out of an environment that is rich in HMGB1 and are often dependent on HMGB1 for their own growth.  In fact, most mesothelioma cells actively secrete HMGB1 extra-cellularly to promote their own tumor growth.  Accordingly HMGB1 levels are high in the serum of mesothelioma patients (reviewed in Yang and Carbone, Clinical Cancer Res 2013).  We tested several anti-inflammatory agents to see if we were able to reduce HMGB1-induced mesothelioma cell growth, and none of them worked except for aspirin, that led us to conduct a series of experiments in vitro and in vivo to test the hypothesis that aspirin inhibits HMGB1 activities, and that by doing so, inhibits mesothelioma growth.

Medical Research: What are the main findings?

Dr. Yang:  We found that aspirin inhibits the growth of human mesothelioma cells in a xenograft model, moreover in vitro experiments demonstrated that this effects was specifically mediated via inhibition of HMGB1 and not via COX2 inhibition.  We propose that the so far enigmatic anticancer activity of aspirin is mediated, at least partially, via inhibition of HMGB1, and that aspirin may help delay the onset of mesothelioma and may help inhibit the growth of mesothelioma.

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New Avenues Open Up for Mesothelioma Targeted Therapy

Newswise — July 25, 2011 (Philadelphia, PA) –Researchers from the lab of Antonio Giordano, M.D., Ph.D., the Founder and Director of the Sbarro Institute for Cancer Research and Molecular Medicine, have identified new potential anti-tumor agents that might be effective in treating mesothelioma, one of the deadliest cancer tumors.

Scientists tested new pyrazolo [3,4-d ]pyrimidine derivative inhibitors of the SRC kinase, a well-established molecular target in cancer therapy. They found that these SRC inhibitors effectively induced cell death, through apoptosis, in mesothelioma cell lines without affecting the normal mesothelial cells, thus supporting a possible use of these agents as a safe treatment for mesothelioma.
Their findings appear in the journal Oncogene.

Interestingly, the researchers also found that the SRC inhibitors induced cell death was accompanied by an increase in the nuclear stability of the cyclin-dependent kinase inhibitor p27. This is “particularly intriguing considering that the loss of nuclear p27 expression is a well established adverse prognostic factor in mesothelioma and p27 nuclear localization is crucial for its tumor suppressive function.” said the leading author of the study, Paola Indovina, Ph.D. of the University of Siena and assistant Professor at the Sbarro Institute.

“We think that these data represent a timely contribution and suggest that p27 status should be carefully analyzed when evaluating the use of kinase inhibitors affecting SRC in clinical trials for patients with mesothelioma,” said the corresponding author of the study Francesca Pentimalli, Ph.D. of the National Cancer Institute- “Pascale Foundation” – CROM- Cancer Research Center of Mercogliano in Avellino, Italy and assistant Professor at the Sbarro Institute.

“The findings support SRC as a critical therapeutic target in mesothelioma and reveal a new mechanism, dependent on p27 nuclear stabilization, by which SRC inhibition can induce apoptosis in mesothelioma cell lines, providing a new rationale for the use of SRC inhibitors in mesothelioma therapy,” says Prof. Antonio Giordano, another lead author. “It also shows that in this context, p27 is required to induce apoptosis in mesothelioma cell lines and, although this mechanism still needs to be precisely dissected, it adds further evidence supporting an active role for p27 in mediating apoptosis.”

The study was done in collaboration with Maurizio Botta full Professor of Medicinal Chemistry and Dean of the Faculty of Pharmacy, University of Siena, also adjunct Professor at the Sbarro Institute, who developed these new SRC inhibitors along with Prof. Silvia Schenone of the University of Genoa, Genoa, Italy.