PFK-015: An inhibitor of PFKFB3 to treat Glioblastomas

PFK-015:PFKFB3 抑制剂,用于治疗胶质母细胞瘤

基本信息

项目摘要

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.
描述(由申请人提供):在困扰美国人群的不同癌症类型中,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8,000例新发病例,仅占新发癌症患者的2%左右,这种疾病受益于孤儿药指定。此外,需要新的治疗方法来延长患者的生存期。 需要基于新的作用机制或抑制新的生物学途径的新疗法来改善癌症患者的存活率。瓦尔堡效应,即癌细胞的较高葡萄糖代谢率,在几十年前被确定为潜在的癌症靶点。PFKFB 3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。因此,抑制PFKFB 3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,博士)合作,在临床前验证PFKFB 3作为潜在的癌症靶点,提出在GBM临床前模型中完成PFK-015的表征。PFK-015是PFKFB 3的强效抑制剂,U87 GM异种移植模型的初步结果表明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以及与替莫唑胺的协同作用,完成PFK-015的体外表征; 2)PFK-015在小鼠中的PK特征表征,包括测定脑和血浆水平; 3)在几种原位模型中的肿瘤生长抑制研究。 上述研究中的阳性结果将保证额外的临床前研究(即疗效、毒理学),以确定PFK-015是否应进行IND使能试验,从而在GBM癌症患者中启动I期研究。 公共卫生关系:在困扰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。虽然它仅占所有新发癌症患者的约2%,每年约有8,000例新发病例,但这种受益于孤儿药指定的疾病显然需要新的治疗方法。本申请提出研究一类新型抗癌剂在GBM临床前模型中的用途。 PFKFB 3是一种参与糖酵解途径的蛋白质,通常在许多癌症(胰腺癌、肺癌、乳腺癌、脑癌、卵巢癌......)中过度表达。包括胶质母细胞瘤。在胶质母细胞瘤异种移植模型中使用PFK-015(PFKFB 3的有效抑制剂)获得的初步结果表明,其具有与替莫唑胺(目前用作治疗多形性胶质母细胞瘤的一线疗法的药物)相当的肿瘤生长抑制活性。此外,PFK-015抑制肿瘤对葡萄糖的摄取,如PET成像所示,并穿过血脑屏障。 在本申请中,将进行额外的PK和体外实验,以进一步了解PFK-015的性质,并确定其是否与替莫唑胺具有协同作用。将在几种胶质母细胞瘤模型中进行疗效研究,包括联合用药研究。基于新型作用机制的治疗剂将具有作为单一药剂的活性和与目前用作一线疗法的化合物的协同作用,这将是极其有价值的,并且癌症患者将极大地受益于这样的机会。

项目成果

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