The objective for the proposed study is to determine the feasibility of using novel small molecule poly(ADPribose) polymerase (PARP) inhibitors as an adjunct treatment to enhance the antitumor activities of chemotherapeutic agents, especially against metastatic malignancy in brain. Most cancer chemotherapies suffer from innate or treatment-induced resistance of neoplastic cells to cytotoxic agents. Inhibition of PARP, a key nuclear enzyme to facilitate DNA repair, has proved an effective way to increase the killing of tumors by DNA methylating agents such as temozolomide (TMZ) in rodents. In the past, lack of PARP inhibitors capable of penetrating the blood brain barrier hindered testing whether PARP inhibition could synergistically increase the efficacy of TMZ against CNS tumors such as glioma, metastatic melanoma ,and brain lymphoma. Now, Guilford Pharmaceuticals Inc. has identified a series of water-soluble PARP inhibitors that 1) achieved high-level accumulation in brain after intravenous dosing and 2) provided neuroprotection in a rat model of stroke. We intend to test our proprietary PARP inhibitors in murine models of CNS malignancy. In collaboration with Dr. Grazia Graziani (University of Rome), we demonstrated that our leading PARP inhibitor, GPI 15427, greatly increased the survival rate, life span, and decreased metastasis when the compound was used in combination with TMZ in mice with intracranially injected melanoma or lymphoma, or with xenographted glioma, in comparison to TMZ treatment alone. To achieve the objective of the current study, we have designed a series of experiments that are aimed at 1) optimizing the chemical properties of the GPI 15427 series compounds for """"""""drug like"""""""" properties; 2) characterizing the pharmacokinetic and toxicological profiles of the GPI 15427; and 3) determine the optimal dose-effect relationship of the GPI 15427 series of compounds in mouse models of CNS malignancy. We expect results from this phase I study will yield information for assessing the prospect of a phase II preclinical development towards clinical trials and commercialization of PARP inhibitors as enhancers of chemotherapy.
