Targeting HPV Consequences in a Cervical Cancer Clinical Trial

 描述(申请人提供)：高危人乳头瘤病毒(HPV)导致宫颈发育不良，可发展为宫颈癌，是女性癌症相关死亡的第二大原因。宫颈癌的治疗方法毒性很大，往往会对生活质量产生负面影响。宫颈癌的预防是通过检测和破坏宫颈不典型增生来预防的，这涉及到巨大的成本、不适和潜在的生育能力丧失，尽管这些病变中的大多数不会进展为癌症。我们开发了一种无毒的抗癌药物，它具有适用于宫颈异型增生和癌症的机械特性。我们的药物， 名为SHetA2(NSC 721689)的药物可中和高危HPV对细胞周期的调节作用。广泛的临床前研究表明，SHetA2在体外和体内具有癌症治疗和化学预防活性，无致突变性或致畸性，无毒性，适合作为口服治疗剂。美国食品和药物管理局(FDA)的一份研究前新药(IND)会议报告列出了SHetA2在宫颈癌0期临床试验中没有任何障碍。在这个项目中，我们假设SHetA2通过对抗HPV引起的细胞周期蛋白D1和其他细胞周期调节蛋白的变化，导致人和小鼠宫颈肿瘤的G1期停滞和细胞凋亡。我们将通过对IB2-IVB期宫颈癌患者进行0期临床试验来验证这一假设，以确定口服SHetA2胶囊是否可以实现全身和宫颈组织中已知的调节细胞周期蛋白A、D1和E以及Rb磷酸化事件的SHetA2浓度。在这项试验中收集的治疗前后的宫颈肿瘤活检和收集的外周血单核细胞(PBMC)的时间进程将被用来确定SHetA2治疗改变了宫颈癌中发现的哪些Rb途径缺陷。此外，我们将比较口服胶囊和阴道栓剂SHetA2制剂在K14-HPV16转基因小鼠中细胞周期调节蛋白的变化与减少宫颈肿瘤形成的关系。被HPV和SHetA2反向调节的细胞周期蛋白，如细胞周期蛋白A、D和E，将被测试它们是否直接参与了SHetA2对G1细胞周期停滞和凋亡的调节。这些研究将通过确定SHetA2的药代动力学(PK)和药效学(PD)，以及确定口服或经阴道给药是否会在HPV转基因小鼠中实现更高的组织SHetA2浓度、细胞周期蛋白的更大变化和更好的预防宫颈癌，为未来的宫颈异型增生和癌症的临床试验奠定基础。我们的机制研究将开发候选PD生物标记物，用于未来计划用于宫颈异型增生的临床试验，并将提供更多关于宫颈异型增生和癌症中HPV相关细胞周期缺陷的知识。

 DESCRIPTION (provided by applicant): High risk human papillomavirus (HPV) causes cervical dysplasia which can progress to cervical cancer, the second leading cause of cancer-related deaths among women. Therapeutic treatments for cervical cancer are highly toxic and often negatively impact quality of life. Cervical cancer is prevented by detection and destruction of cervical dysplasia involving significant cost, discomfort and potential loss of fertility, althogh the majority of these lesions will not progress to cancer. We developed a non-toxic cancer drug that has a mechanistic profile suitable for application in cervical dysplasia and cancer. Our drug, called SHetA2 (NSC 721689) counteracts the cell cycle regulatory consequences of high risk HPV. Extensive preclinical studies of SHetA2 demonstrated cancer therapeutic and chemoprevention activity in vitro and in vivo, lack of mutagenicity or teratogenicity, no toxicity and a pharmacologic profile suitable for an oral therapeutic agent. A pre-Investigational New Drug (IND) meeting report from the US Food and Drug Administration (FDA) listed no obstacles for our moving forward to a Phase 0 Clinical trial of SHetA2 in cervical cancer. In this project, w hypothesize that SHetA2 causes G1 arrest and apoptosis in human and murine cervical tumors by counteracting the alterations in cyclin D1 and other cell cycle regulatory proteins caused by HPV. We will test this hypothesis by conducting a Phase 0 clinical trial in Stage IB2-IVB cervical cancer patients to determine if oral administration of SHetA2 capsules can achieve systemic and cervical tissue concentrations of SHetA2 known to regulate cyclins A, D1 and E, and RB phosphorylation events. Pre- and post-treatment cervical tumor biopsies and a time course of collected peripheral blood mononuclear cells (PBMCs) collected in this trial will be used to determine which Rb pathway defects found in cervical cancer are altered by SHetA2 treatment. In addition, we will compare oral capsule and vaginal suppository SHetA2 formulations for alterations of cell cycle regulatory proteins in association with reduction of cervical tumor formation in K14-HPV16 transgenic mice. Cell cycle proteins, such as cyclins A, D and E, that are counter- regulated by HPV and SHetA2 will be tested for their direct involvement in SHetA2 regulation of G1 cell cycle arrest and apoptosis. These studies will lay the groundwork for future clinical trials in cervical dysplasia and cancer by determining the pharmacokinetics (PK) and pharmacodynamics (PD) of SHetA2, and by determining whether oral or vaginal delivery will achieve higher tissue concentrations of SHetA2, greater alterations in cell cycle proteins and greater prevention of cervical cancer in HPV transgenic mice. Our mechanistic studies will develop candidate PD biomarkers for use in future clinical trials planned for cervical dysplasia and will provide increased knowledge of HPV associated cell cycle defects in cervical dysplasia and cancer.