Development of the New Synthetic Triterpenoid CDDO-2P-IM (TTX01) for Glioblastoma

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma multiforme (GBM; grade IV glioma) is the most common primary brain tumor. An estimated 700,000 people in the United States (US) are living with a primary brain tumor, and over 86,000 more will be diagnosed in 2019. GBM is the most aggressive primary brain tumor and remains a frequently incurable cancer, resulting in more than 17,000 annual deaths in the US alone. The outlook for patients with GBM is invariably dismal, with only 5% surviving beyond 5 years. Those who do survive suffer significant therapy-related complications that greatly diminish their quality of life and they also endure a significant financial burden. Indeed, brain tumors have the highest per-patient initial cost of care for any cancer group, with annualized mean net costs of care in US dollars at well over $150,000. However, despite this prevalence and the devastating prognosis, there have only been four FDA approved drugs to treat brain tumors in the past 30 years, without significant improvement in outcomes over this same time period. These facts regarding GBM highlight a desperate need for new and innovative approaches to treat this lethal disease. Notably, it has been over 14 years since the U.S. Food and Drug Administration (FDA) approved temozolomide ( Temodar / TMZ) for the treatment of adult patients with newly diagnosed GBM, which is now given concomitantly with radiotherapy and then as maintenance treatment as the standard of care. Despite the addition of TMZ to the standard of care, the average length of survival for a patient with GBM remains at 14 months. Moreover, prolonged exposure to TMZ is associated with significant toxicity, including profound lymphopenia, and with the development of drug resistance. Because GBM is currently often incurable, there is a dire need for novel drugs that target mechanisms that underlie therapy resistance in GBM and that can enhance the response TMZ and radiation. This project will provide essential new information, required by the FDA, to allow approval of an IND for use of a new drug for treatment of GBM. The drug is CDDO-2-Pyridyl Imidazolide (“2P-Im” or TTX01), a new triterpenoid synthesized and tested for anti-cancer activities at Dartmouth, and now licensed by Dartmouth to Triterpenoid Therapeutics, Inc. The goal of this Phase 1 grant application will be to determine the in vivo efficacy and pharmacodynamics of TTX01 in relevant mouse models of human GBM. To advance TTX01 toward clinical application, we will define both optimal dose and dosing schedule to provide the most durable clinical response in well-established, human PDX and xenograft models and in an immune competent syngeneic murine model of GBM (Aim 1). Moreover, we will also provide proof-of-concept data that TTX01 administration can enhance the response to either Temodar or radiation (Aim 2). Variations in combined dosing regimens will be studied, as will the possibility that TTX01 could suppress the development of important pathology (toxicity) in normal brain. After having completed these in vivo studies with TTX01, we will be able to progress to a more extensive, complete IND-enabling body of work in Phase II, with our long-term goal to commercialize TTX01 as a therapy for GBM.