Abstract B77: Perillyl alcohol derivatives as anticancer agents

Abstract

Abstract The use of the monoterpene perillyl alcohol (POH) for intranasal delivery to brain tumors was first popularized in Brazil. As monotherapy, POH has been found to be nontoxic, and to have anticancer activity in a subset of patients with malignant gliomas. The presumed route of delivery is presumed to be a cranial nerve (olfactory, trigeminal) to brain delivery, bypassing the blood-brain barrier. POH, itself, as a monoterpene is a clear liquid that we have found to be lipophilic in its consistency. We have explored the possibility of taking drugs that are out of patent, but with antibrain tumor activity, chemically conjugating them to POH, and creating a new drug. The process of drug discovery consisted of preclinical determination of: 1) feasibility of chemical conjugation, 2) determination of increased BBB penetrance using a BBB permeability program, 3) determination of functional activity via MTT and colony formation assays, 4) determination of mechanism of action, 5) determination of pharmacokinetic and pharmacodynamics action, and 6) functional activity against intracranial tumors (gliomas, metastatic breast carcinoma, medulloblastomas) demonstrated using established in vivo syngeneic and immune-deficient rodent models. Once these six preclinical steps are validated, formal application for IND status can be prepared by: 1) GMP production of drug, 2) formal toxicity testing using large and small animal models under acute and chronic administration, and 3) clinical trial indication for Phase I/IIa. This method has been successfully employed using temozolomide (TMZ) to create TMZ-POH linked via a carbamate bond (TMZ-POH; NEO212). The same method has been performed for the phosphodiesterase type IV inhibitor rolipram (RP-POH, NEO214), valproic acid (VA-POH; NEO216), 3 bromopyruvate (3BP-POH; NEO218). In each case, we were surprised by the mechanistic differences observed from the native compound to the new drug after POH conjugation. For instance, NEO212 is a DNA-alkylating agent, but with 3x the BBB penetration, 10x the cytotoxic potency, and 3x the stability. This presentation will demonstrate our discovery process using our POH conjugates, and our current IND process for NEO212, which we hope to bring to the clinic in the next 6 months. Citation Format: Thomas C. Chen, Axel H. Schonthal, Florence H. Hofman. Perillyl alcohol derivatives as anticancer agents [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B77.