Platinum-Gold Compounds as Potential Chemo- and Targeted Agents for Ovarian Cancer

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PROJECT SUMMARY Ovarian cancer (OC) is the fifth in cancer mortality for women, and it is the deadliest for all types of gynecological cancers, affecting mainly postmenopausal women. In 80% of the cases the diagnosis comes at stages III and IV with 28% survival rate. The standard of care of OC is debulking surgery followed by platinum-based chemotherapy. FDA-approved platinum (II) compounds (cisplatin, carboplatin and oxaliplatin) present major drawbacks for OC which are: a) the acquired resistance of cancer cells after treatment, and b) the lack of selectivity which causes undesired secondary effects due to dose limiting effects. For as many as 62% patients the disease will recur after receiving chemotherapy, and maintenance therapies are required. Modified Pt(IV) compounds hold the potential to become alternatives to Pt(II)-based drugs, especially for OC, for which resistance to the treatment is a major problem, and for which first-line chemotherapy treatment may still be the most affordable option for years. This proposal aims to develop Platinum (IV)-Gold anticancer agents with potential dual- or multi-drug effects with improved pharmacological profile with respect to FDA-approved Pt(II) compounds. Our hypothesis is that the reduction of the heterometallic Pt(IV) compounds inside OC cells, will release not only conventional Pt(II) anticancer agents, but also highly cytotoxic gold derivatives that will target different biomolecules in the tumors and favor immunogenic cell death, overriding resistance. The specific aims of this proposal are: Aim 1. Synthesis and in vitro Evaluation of New Platinum(IV)- Gold Compounds in Ovarian Cancer Cell Lines. We will synthesize new Pt(IV)-Au(I) and Pt(IV)- Au(III) compounds and study their stability and interactions with DNA (target for Pt(II) compounds). We will evaluate their effects on a panel of epithelial ovarian cancer cell lines with varying degrees of genetic complexity, as well as on non-tumorigenic cell lines. For selected compounds, we will study their effects on other cancer hallmarks (migration, invasion and angiogenesis), on cell death and cell cycle, and inhibition of gold compounds’ targets. Aim 2. Optimize the Formulation and Targeting Properties of Selected Pt-Au Compounds. Preliminary in vivo Investigation. We will encapsulate best performing Pt-Au compounds into liposomes and immunoliposomes to further improve the safe delivery of these derivatives. In addition, we will assess the survival of mice treated with two selected Pt-Au compound and their two formulations (Pt-Au-Lip and Pt-Au-ImmunoLip) on a mouse metastatic orthotopic model (ovarian cell line resistant to cisplatin, C200) and compare it to that of those treated with cisplatin and carboplatin.