ABSTRACT This proposal describes an innovative solution to a primary cause of treatment failure in mesothelioma: drug resistance. The solution is the controlled and targeted delivery of a novel epigenetic modifying agent ? verticillin A or one of its analogs ? which re-establishes chemotherapeutic susceptibility in chemotherapeutic resistant tumors via re-expression of epigenetically silenced tumor suppressor genes. Unlike other small molecule epigenetic agents, including FDA-approved drugs, which are global DNA methylation and histone deacetylase inhibitors, Verticillin A selectively targets H3K9me2/3. A stimuli-responsive particle drug delivery system employing a unique materials-based targeting strategy is used in order to ensure that the verticillin and chemotherapeutic agents localize and concentrate in peritoneal tumors. This pH-responsive drug delivery system leverages fundamental pathophysiological properties of tumors (e.g., mildly acidic extracellular environment and high metabolic rate) to induce compositional and architectural changes (e.g., particle swelling from 0.1 to 1 micron) resulting in tumor-specific accumulation. This materials-based targeting approach overcomes limitations of traditional strategies (e.g., passive targeting via the enhanced permeability and retention effect, and active targeting via antibody-based affinity) while providing a platform to deliver both hydrophobic and hydrophilic drugs via single- and double-emulsions, respectively. The proposed experiments will test the hypothesis that delivery of a verticillin agent with a chemotherapeutic (combination therapy either as single agents or co-formulation with encapsulated or free drug) to mesothelioma tumors will overcome drug resistance and extend survival compared to the delivery of verticillin or the chemotherapeutic alone. Importantly, key preliminary data are in support of the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross- disciplinary collaborations and expertise are in place to address this hypothesis. The specific aims of this five- year proposal are: Aim 1. Evaluate the epigenetic activity of verticillin A and five of its analogs in human mesothelioma cells (MSTO-211H) and tumor cells collected from patient pleural effusions as well as the toxicity profile via in vitro assays for hepatotoxicity, cardiotoxicity, and mitochondrial toxicity. Aim 2. Optimize the co-formulation of the two verticillin agents with paclitaxel, cisplatin, or pemetrexed to achieve the maximum cytotoxic effect in drug resistant mesothelioma cell lines and tumor cells collected from patient pleural effusions. Aim 3. Assess toxicity in healthy mice and PK and PD / efficacy of the optimized formulation in patient-derived xenograft (PDX) murine models of drug resistant mesothelioma.