Targeting HPV Consequences in a Cervical Cancer Clinical Trial

在宫颈癌临床试验中针对 HPV 后果

• 批准号: 9492554
• 负责人: DORIS Mangiaracina BENBROOK
• 金额: $ 17.69万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9492554
• 关键词: Adjuvant; Adverse effects; Aftercare; Antineoplastic Agents; Apoptosis; Binding; Bioavailable; Biological Markers; Biopsy; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Cycle; Cell Cycle Arrest; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Proteins; Cervical; Cervical dysplasia; Cervix Neoplasms; Cessation of life; Chemoprevention; Clinical Trials; Cold Therapy; Congresses; Cyclin A; Cyclin D1; Defect; Detection; Developing Countries; Development; Drug Kinetics; E2F transcription factors; E2F1 gene; EGF gene; Epidermal Growth Factor Receptor; Event; Excision; Formulation; Future; G1 Arrest; Genes; Genome; Genomic DNA; Growth; HPV-High Risk; Histology; Human; Human Papillomavirus; Human papillomavirus 16; Infection; Infertility; Investigational Drugs; Knock-out; Knowledge; Lesion; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Mus; Mutation; Oral; Oral Administration; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phosphorylation; Proteins; Quality of life; Regulation; Resistance; Retinoblastoma; Risk; S Phase; SHetA2; Suppositories; TP53 gene; Teratogens; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Transfection; Transgenic Mice; Treatment-related toxicity; Tumor Suppressor Proteins; Ubiquitination; United States Food and Drug Administration; Vaccination; Vaccines; Vagina; Vaginal Suppository; Vaginal delivery procedure; Woman; cancer clinical trial; cancer therapy; cancer type; capsule; carcinogenesis; cell transformation; cervical cancer prevention; chemotherapy; cost; first-in-human; high risk; improved; in vitro activity; in vivo; mutant; outcome forecast; pharmacodynamic biomarker; preclinical study; prevent; public health relevance; retinoblastoma tumor suppressor; screening; small molecule; tumor; tumor progression

 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.

 描述（由申请人提供）：高危人乳头瘤病毒（HPV）导致宫颈发育不良，可进展为宫颈癌，宫颈癌是女性癌症相关死亡的第二大原因。宫颈癌的治疗方法具有很高的毒性，通常会对生活质量产生负面影响。宫颈癌可以通过检测和破坏宫颈发育异常来预防，这涉及巨大的成本、不适和潜在的生育能力丧失，尽管大多数这些病变不会进展为癌症。我们开发了一种无毒的癌症药物，具有适用于宫颈发育不良和癌症的机制。我们的药， 称为SHetA 2（NSC 721689）的细胞周期调节因子抵消高危HPV的细胞周期调节结果。SHetA 2的广泛临床前研究证明了体外和体内的癌症治疗和化学预防活性，缺乏致突变性或致畸性，无毒性，并且具有适合口服治疗剂的药理学特征。美国食品和药物管理局（FDA）的一份新药研究前（IND）会议报告没有列出我们在宫颈癌中进行SHetA 2 0期临床试验的障碍。在这个项目中，我们假设SHetA 2通过抵消HPV引起的细胞周期蛋白D1和其他细胞周期调节蛋白的改变，导致人类和小鼠宫颈肿瘤的G1期阻滞和细胞凋亡。我们将通过在IB 2-IVB期宫颈癌患者中进行0期临床试验来验证这一假设，以确定口服SHEtA 2胶囊是否可以达到已知调节细胞周期蛋白A、D1和E以及RB磷酸化事件的SHEtA 2的全身和宫颈组织浓度。治疗前和治疗后的宫颈肿瘤活检和本试验中收集的外周血单核细胞（PBMC）的时间过程将用于确定宫颈癌中发现的哪些Rb通路缺陷被SHEtA 2治疗改变。此外，我们将比较口服胶囊和阴道栓剂SHetA 2制剂的细胞周期调节蛋白的改变与K14-HPV 16转基因小鼠宫颈肿瘤形成的减少。将测试受HPV和SHetA 2反调节的细胞周期蛋白，例如细胞周期蛋白A、D和E，以确定它们是否直接参与SHetA 2对G1细胞周期停滞和细胞凋亡的调节。这些研究将通过确定SHetA 2的药代动力学（PK）和药效学（PD），并通过确定口服或阴道给药是否会实现更高的SHetA 2组织浓度，细胞周期蛋白的更大改变以及HPV转基因小鼠中宫颈癌的更大预防，为未来宫颈发育不良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生物标志物，用于计划用于宫颈不典型增生的未来临床试验，并将提供更多关于宫颈不典型增生和癌症中HPV相关细胞周期缺陷的知识。