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

项目总结/摘要 多形性胶质母细胞瘤（GBM; IV级胶质瘤）是最常见的原发性脑肿瘤。估计有70万 在美国，有1000人患有原发性脑瘤，在2015年， 2019. GBM是最具侵袭性的原发性脑肿瘤，并且仍然是一种经常无法治愈的癌症， 每年仅在美国就有超过17,000人死于这种疾病GBM患者的前景总是令人沮丧，只有 5%存活超过5年。那些幸存下来的人遭受了严重的治疗相关并发症， 降低了他们的生活质量，他们还承受着沉重的经济负担。事实上，脑肿瘤具有 任何癌症组中每例患者的初始护理成本最高，年平均净护理成本以美元计 超过15万美元然而，尽管这种流行和毁灭性的预后，只有四个 在过去的30年里，FDA批准了治疗脑肿瘤的药物，但结果没有显着改善。 同一时期。这些关于GBM的事实突出了对新的和创新的方法的迫切需要 来治疗这种致命的疾病值得注意的是，自美国食品和药物管理局（FDA） （FDA） 批准替莫唑胺（ Temodar / TMZ）用于治疗新诊断的GBM成人患者， 目前，该疗法与放射疗法同时给予，然后作为标准护理的维持治疗。 尽管将TMZ添加到标准治疗中，但GBM患者的平均生存期仍然很短。 在14个月的时候。此外，长期暴露于TMZ与显著的毒性相关，包括深刻的 淋巴细胞减少症，并随着耐药性的发展。由于GBM目前通常是不可治愈的， 迫切需要靶向GBM中耐药性的基础机制并且可以增强GBM中的耐药性的新药物。 TMZ和辐射的反应。该项目将提供FDA要求的重要新信息， 允许批准IND用于治疗GBM的新药。药物为CDDO-2-吡啶基咪唑 （“2 P-Im”或TTX 01），一种在达特茅斯合成并测试抗癌活性的新三萜类化合物，和 现由达特茅斯授权给三萜类药物治疗公司。第一阶段拨款申请的目标是 确定TTX 01在人类相关小鼠模型中的体内功效和药效学 GBM。为了推进TTX 01的临床应用，我们将确定最佳剂量和给药方案 在完善的人PDX和异种移植模型中以及在 GBM的免疫活性同系小鼠模型（目的1）。此外，我们还将提供概念验证 数据表明TTX 01给药可增强对Temodar或放射的反应（Aim 2）。变化 将研究联合给药方案中TTX 01的可能性，以及TTX 01可能抑制 正常大脑中的重要病理学（毒性）。在用TTX 01完成这些体内研究后，我们 将能够在第二阶段取得更广泛、更完整的IND使能工作， 长期目标是将TTX 01商业化作为GBM的疗法。

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.