H. Richard Alexander, MD
University of Maryland

Title: Inhibition of Il-1 as a Novel Target in Peritoneal Mesothelioma
Specific Aims: Aim 1: Study the role of IL-1 in MPM tumor angiogenesis and growth --

The immediate goal of this portion of the proposal is to determine if IL-1 induces an angiogenic phenotype via production of IL-8 and VEGF and if interruption of IL-1 signaling through the receptor complex inhibits tumor growth. We found a significant transcriptional down-regulation of IL-8 and VEGF in IL-1RAcP induced cells in vitro. Here we specifically study the mechanism by which IL-1 mediates tumor growth by targeting two pathways; IRAK/NFκB activation and PI3K/AKT/NFκB activation; both drive downstream angiogenic and proliferative molecules. We will use two different strategies to inhibit IL-1 in derived human MPM cell lines and in murine xenograft models to study the effect of moderate or complete inhibition of IL-1 in MPM.

We will use a tetracycline inducible IL-1 receptor antagonist (ra) expression (IL-1ra Tet off/on) system to produce high local concentrations of the IL-1ra protein at desired time-points in vitro or in vivo which will allow us to increase IL-1ra concentration in established tumors. Alternatively, we will use IL-1RAcP siRNA stable knockdown (IL-1RAcPkd) in MPM cell lines to block IL-1 signaling.

Aim 2: Conduct pre-clinical studies evaluating the use of a novel IL-1 Trap for the treatment of MPM -- Here we will examine the use of a novel cytokine inhibitor for the treatment of MPM, the IL-1 Trap (rilonacept), a high affinity fusion protein designed to attach and neutralize IL-1. Once bound to the ‘trap’, the cytokine cannot bind to its cell surface receptor and is eliminated from the body. The prolonged in vivo bioavailability and neutralizing abilities of a cytokine trap makes them ideally suited for sustained IL-1 inhibition within tumor xenografts. Thus, we will use the IL-1 trap to inhibit the proximal mediator of angiogenesis and tumor growth in MPM which will provide the foundation for the initial clinical testing of these agents in MPM or other cancers that over-express IL-1. Our long-term goal is to study the mechanism through which IL-1, a cytokine with potent putative angiogenic and growth properties, results in an angiogenic phenotype and tumor growth in MPM and to evaluate the efficacy of IL-1 inhibition in pre-clinical tumor models that will serve as the basis for clinical testing of IL-1 inhibitors as novel targets specific for treatment of patients with MPM and other cancers that over-express IL-1.

Lay Description: Dr. Alexander’s lab has identified that genes in the Interleukin -1 pathway are over-expressed and associated with a poor prognosis in peritoneal mesothelioma. His project seeks to inhibit malignant mesothelioma tumor growth by targeting this pathway. If the project succeeds in the laboratory, we envision that this will lead to new targeted therapy for those tumors that over express Interleukin-1. What makes this particularly exciting is that there is already an FDA-approved agent that targets Interleukin-1, which would mean that we could move from the “bench to the bedside” in a relatively short period of time.

Gang Logan Liu, Ph.D.
University of Illinois at Urbana-Champaign

Title: Enhanced Diagnostic Imaging and High Precision Gene Therapy of Mesothelioma Using Nontoxic Nanocarriers

Specific Aims: Aim 1: Devise optically activated nanoparticles carrying Mesothelin-1 antisense oligo DNA or doublestrand RNA (dsRNA) which contains Mesothelin-1 targeted siRNA, internalize the nanocarriers in Mesothelioma cells at different clinical and pathological stages, remotely activate interference process of Mesothelin-1 expression by light, and repress cancer progression locally.

Aim 2: Devise radio-frequency (RF) wave activated nanoparticles carrying Mesothelin-1 antisense oligo DNA or double-strand RNA (dsRNA) which contains Mesothelin-1 targeted siRNA, internalize the nanocarriers in Mesothelioma cells at different clinical and pathological stages, remotely activate interference process of Mesothelin-1 expression by RF waves, and repress cancer progression locally.

Aim 3: Devise nanocarriers carrying other antisense DNA and siRNA targeted to more oncogenes and functionalize the nanocarriers with Mucin-1 antibody to recognize Mesothelioma cells. Achieve high specificity and efficiency of gene therapy than those in Aim2 and Aim3.

Lay Description: Dr. Liu proposes a new method to improve mesothelioma diagnosis and treatment efficacy using nontoxic multifunctional nanocarriers. The nanocarrier particles can be designed to only be taken up by mesothelioma tumor cells. This will enhance radiographic imaging for diagnosis and monitoring. Moreover, they can carry therapeutic genes and can release them only in mesothelioma tumors and at desired moments via remote activation. This could prove very important in mesothelioma as conventional radiation and chemotoxic therapies often have lethal side effects to normal tissue and/or lose effectiveness because of non-localized and uncontrollable dosage administration. Dr. Liu’s method would deliver the therapies directly into the tumor, thus sparing healthy tissue.

Steven Mutsaers, MD, Ph.D.
Lung Institute of Western Australia

Title: The Hedgehog Signaling Pathway As A Target For Inhibiting Malignant Mesothelioma Growth
Specific Aim: To address this hypothesis, we propose three interrelated, but nonetheless specific aims, designed to elucidate the role of the Hh signaling pathway in MM growth.

Aim 1: Determine the expression of key Hh signaling molecules in human and mouse MM cell lines, pleural effusion cells and tumors, and determine if Hh signaling occurs via ligand driven Hh pathway activation.

Aim 2: Assess the effect of blocking Hh signaling on expression of Hh target genes, cell viability, proliferation and tumorigenicity in MM cell lines and on tumour growth in animal models.

Aim 3: Examine the interaction between the Hh and TGFβ signaling pathways on MM cell function and its effect on tumor growth.

Lay Description: Increasing evidence points to the reactivation and aberrant expression of developmental signaling pathways as critical to the development of certain cancers. The hedgehog signaling pathway has been shown to be a critical target in other cancers and there are drugs being tested to target this pathway. Dr. Mutsaers will seek to prove that the hedgehog signaling pathway regulates mesothelioma and that blocking this pathway results in inhibiting tumor growth. If he succeeds, then drugs targeting this pathway could rapidly move into clinical trials for mesothelioma patients.

Joseph Testa, PhD
Fox Chase Cancer Center

Title: Combinatorial Targeting of Tyrosine Kinases that are Aberrantly Activated in Malignant Mesothelioma

Specific Aim: We propose to test the efficacy of combinatorial targeting of the tyrosine kinases identified in our screen (SFK, EGFR, and MET) and specifically identify which combinations are therapeutic in preclinical models of MM. The specific aims of this proposal are: Aim 1: Evaluate the efficacy of targeting SFK, EGFR, and/or MET alone versus in combination to inhibit downstream signaling and tumor cell survival and proliferation in vitro

Aim 2: Assess the efficacy of targeting these tyrosine kinases alone versus in combination to inhibit MM tumor growth in vivo

Aim 3: identify other important tyrosine kinases activated in MM cells as alternative therapeutic targets using antibody pathway array membranes.

Lay Description: Dr. Testa’s lab recently identified a novel family of cellular enzymes (chemicals in cells that catalyze or speed up biologic activity) often over-activated in mesothelioma cells. These enzymes promote tumor cell survival and drug resistance, making them potential therapeutic targets. Dr. Testa will test if combination therapies targeting more than one of these enzymes enhance mesothelioma cell death and tumor regression. He will test tyrosine-kinase inhibitors which, as targeted agents, should have less toxic side effects than traditional chemotherapeutic agents.

Haining Yang, Ph.D.
University of Hawaii

Title: Studies of Tumor Necrosis Factor alpha as a New Target for Human Malignant Mesothelioma Prevention and Therapeutic Strategies
Specific Aim: Aim 1: To establish the In vitro model of HM malignant transformation induced by asbestos through two approaches: (A) the combination of asbestos exposure and TNF−α treatment; (B) co-culture of HM with macrophages during asbestos exposure.

Aim 2: MM preventive study. To assess whether by blocking TNF-α, we will be able to prevent asbestos-induced carcinogenicity. For this purpose, we will use the in vitro model (Aim 1) and the in vivo hamster mesothelioma model that we have already developed.

Aim 3: MM therapeutic study. To assess whether by blocking TNF-α, we will be able to inhibit tumor growth and invasion.

Lay Description: Dr. Yang’s lab has discovered that TNF-a (tumor necrosis factor alpha) plays a critical role in the mechanisms of asbestos-induced malignant mesothelioma. TNF-a increases the percentage of primary human mesothelioma cells that – when damaged by exposure to asbestos – nevertheless avoid necrosis and survive. TNF-a thus results in an increase of asbestos-damaged cells susceptible to malignant transformation. Dr. Yang’s lab will now explore TNF-a as a potential target to prevent the development of mesothelioma in asbestos-exposed tissue, and to treat mesothelioma tumors.