PFK-015: An inhibitor of PFKFB3 to treat Glioblastomas

描述（由申请人提供）：在折磨美国人口的不同癌症类型中，多形性胶质母细胞瘤（GBM）是一种可怕的疾病，总体平均生存期为10个月。每年约有8000例新病例，仅占新癌症患者的2%左右，这种疾病受益于孤儿药的指定。此外，需要新的治疗方法来延长患者的生存时间。需要基于新的作用机制或抑制新的生物途径的新疗法来改善癌症患者的生存。沃伯格效应，癌细胞较高的葡萄糖代谢率在几十年前就被确定为潜在的癌症靶点。PFKFB3是参与糖酵解途径的关键酶，也是动物模型中肿瘤生长所必需的酶。因此，抑制PFKFB3可能被证明是开发针对癌细胞能量需求的新型抗肿瘤药物的有用策略。Advanced Cancer Therapeutics （ACT）与肯塔基州路易斯维尔大学布朗癌症中心的Jason Chesney医学博士合作，验证了临床前PFKFB3是潜在的癌症靶点，并建议在GBM临床前模型中完成PFK-015的表征。PFK-015是一种有效的PFKFB3抑制剂，在U87GM异种移植模型中的初步结果表明，PFK-015具有与替莫唑胺相当的活性，并且PFK-015可以穿过血脑屏障。本申请中提出的工作包括：1)通过筛选PFK-015在7种胶质母细胞瘤细胞系中的活性和与替莫唑胺的协同作用，完成PFK-015的体外鉴定；2)小鼠PFK-015的PK谱表征，包括测定脑和血浆水平；3)几种原位肿瘤模型的肿瘤生长抑制研究。上述研究的阳性结果将需要进一步的临床前研究（即疗效、毒理学），以确定PFK-015是否应该进行IND测试，以便在GBM癌症患者中启动I期研究。

DESCRIPTION (provided by applicant): Amongst the different cancer types afflicting the US population, glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. With about 8,000 new cases per year, representing only about 2% of new cancer patients, this disease benefits from an Orphan drug designation. Also, new therapies are needed to prolong patients' survival. New therapies based on novel mechanisms of action or inhibiting new biological pathways are required to improve cancer patients' survival. The Warburg effect, the higher rate of glucose metabolism of cancer cells was identified as a potential cancer target many decades ago. PFKFB3 is a key enzyme involved in the glycolytic pathway and is also required for tumor growth in animal models. Thus, inhibiting PFKFB3 may prove to be a useful strategy for the development of novel anti-neoplastic agents targeting the energy needs of cancer cells. Advanced Cancer Therapeutics (ACT), in collaboration with Jason Chesney, MD, PhD, at the Brown Cancer Center, University of Louisville, KY, who validated preclinically PFKFB3 as a potential cancer target, proposes to complete the characterization of PFK-015 in GBM preclinical models. PFK-015, is a potent inhibitor of PFKFB3, and preliminary results in a U87GM xenograft model have shown that PFK-015 has comparable activity to Temozolomide and that PFK-015 crosses the blood brain barrier. The work proposed in this application encompasses 1) completion of the in vitro characterization of PFK-015 by screening its activity in 7 glioblastoma cell lines and synergies with Temozolomide; 2) characterization of the PK profile of PFK-015 in mice including determining brain and plasma levels; and 3) tumor growth inhibition studies in several orthotopic models. Positive results in the studies described above would warrant additional preclinical studies (i.e. efficacy, toxicology) in order to determine if PFK-015 should undergo IND enabling testing to initiate a Phase I study in GBM cancer patients. PUBLIC HEALTH RELEVANCE: Amongst the different cancer types afflicting the US population, glioblastoma multiforme (GBM) is a dreadful disease with an overall average survival of 10 months. While it constitutes only approximately 2% of all new cancer patients, with about 8,000 new cases per year, new therapies are clearly needed for this disease that benefits from an Orphan drug designation. This application proposes to investigate the use of a novel class of anticancer agents in GBM preclinical models. PFKFB3 is a protein involved in the glycolytic pathway and commonly over expressed in many cancers (pancreatic, lung, breast, brain, ovarian...) including glioblastomas. Preliminary results obtained with PFK-015, a potent inhibitor of PFKFB3, in a glioblastoma xenograft model have shown that it has tumor growth inhibition activity comparable to that of Temozolomide, the drug currently used as first line therapy for the treatment of glioblastoma multiforme. Furthermore, PFK-015 inhibits glucose uptake by tumors as shown by PET imaging and crosses the blood brain barrier. In this application, additional PK and in vitro experiments will be done to further understand the properties of PFK-015 and determine if it has synergy with Temozolomide. Efficacy studies in several glioblastoma models will be performed, including combinations studies. A therapeutic agent based on a novel mechanism of action that would have activity as a single agent and synergies with the compound currently used as first line therapy would be extremely valuable and cancer patients would tremendously benefit from such an opportunity.