Temozolomide Perillyl Alcohol Conjugate as Treatment for Recurrent Malignant Brain tumors

DESCRIPTION provided by applicant Glioblastoma multiforme GBM the most common and malignant of all gliomas has a median survival time of months Standard of care chemotherapy using temozolomide TMZ is effective initially but the GBM inevitably recurs and these recurrent tumors are resistant to TMZ There are currently no effective treatment options for patients with TMZ resistant recurrent tumors Therefore identifying drugs that target TMZ resistant tumors is critical Recently a monoterpene perillyl alcohol POH was shown to have moderate success for recurrent GBM but only when used at high doses which unfortunately results in toxicity Our approach is to conjugate TMZ to POH to produce a novel agent TMZ POH to target TMZ resistant recurrent GBMs Based on the hypothesis that these drugs together are more effective than either drug alone in collaboration with our small business partner we have successfully conjugated TMZ to POH In preliminary data we demonstrate that this novel conjugate has as much as times more cytotoxic against TMZ resistant glioma cells as compared to either agent alone or the mixture of the two at equimolar doses Furthermore the TMZ POH conjugate is effective against a variety of TMZ resistant GBM cells and glioma stem cells GSC the chemo and radiation resistant population responsible for initiating recurrent GBMs In vivo data show that TMZ POH is well tolerated and is effective in intracranial tumors The proposed aims will identify the mechanism s of TMZ POH activity on TMZ resistant glioma cells and glioma cancer stem cells in vitro and determine effects of TMZ POH at different doses and modes of administration on intracranial glioma tumor growth in vivo in immune incompetent and immune competent animals and measure the biodistribution of TMZ POH in these different protocols Completion of these aims will identify ways to optimize the potency of this agent to insure maximum efficacy The present investigation will provide pre clinical data to determine efficacy of TMZ POH in reducing or eliminating TMZ resistant brain tumors The overall goal is to validate and establish TMZ POH as a novel chemotherapeutic agent with outstanding activity against drug resistant recurrent GBM tumors

PUBLIC HEALTH RELEVANCE Glioblastoma multiforme GBM is a deadly disease there is no therapy for the inevitable temozolomide TMZ resistant recurrent tumor We have synthesized a TMZ perillyl alcohol POH conjugate TMZ POH through our collaboration with our business partner which is effective against TMZ resistant GBM Thus TMZ POH can be used to treat TMZ resistant recurrent brain tumors Successful completion of this project will lead to a novel therapy and provide new hope for patients with drug resistant gliomas