A novel combinatorial approach for treating HPV-associated malignancies

治疗 HPV 相关恶性肿瘤的新组合方法

基本信息

批准号：
9408055
负责人：
PENELOPE J DUERKSEN-HUGHES
金额：
$ 19.11万
依托单位：
ISPIN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9408055
关键词：
Adaptive Immune System Affect Animal Model Anus Apoptosis Apoptosis Promoter Apoptotic Binding Biological Assay CASP8 gene Cells Cervical Cervix carcinoma Cisplatin Code Combined Modality Therapy DNA Damage Data Developing Countries Development Diagnosis Disease Dose Doxorubicin Effectiveness Goals Growth HIV Infections Head and neck structure Human Human Papillomavirus Immune system Immunocompromised Host In Vitro Induction of Apoptosis Laboratories Lead Ligands Malignant Neoplasms Malignant neoplasm of cervix uteri Maximum Tolerated Dose Mediating Medical Modeling Molecular Mus Nude Mice Oncoproteins Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Preparations Positioning Attribute Proteins Radio Reagent Resistance TNFSF10 gene TP53 gene Testing Therapeutic Therapeutic Agents Time Toxic effect UBE3A gene Vaccines Virus Vulva Work Xenograft Model base cancer cell chemoradiation combinatorial conventional therapy design effective therapy experimental study high risk improved in vivo mouse model neoplastic cell novel novel strategies prevent screening small molecule tumor tumor growth virtual

项目摘要

SUMMARY High-risk types of human papillomaviruses (HPV) are responsible for virtually all cases of human cervical carcinoma, as well as an increasing number of other malignancies including those of the head and neck, anus and vulva. Unfortunately, good treatment options for late-stage HPV+ malignancies are not currently available, in large part because the virus encodes a protein, E6, which disables cellular apoptotic pathways by accelerating the degradation of molecules such as FADD, caspase 8 and p53. This makes it difficult to eliminate HPV+ cancer cells using conventional inducers of apoptosis. To overcome this obstacle, our laboratory has identified several small molecules that block the binding between E6 and partners such as caspase 8 and E6AP. According to our working model, the use of such molecules in a combinatorial manner will greatly increase the effectiveness of standard radio- and chemotherapeutic treatments. Both in vitro binding data and cellular data from our laboratory provide strong data in support of this working model, and it is now time to test our approach in an in vivo context. The overall objective of this current application, therefore, is to move our exciting in vitro and cellular observations into a mouse xenograft model. We will do this by combining spinacine, our best molecular candidate, with two potential therapeutic agents: TRAIL, a biologic, and cisplatin, a more conventional chemotherapeutic, asking whether either of these combinations can reduce or eliminate the growth of HPV+ tumors, of either cervical or head and neck origin, in a nude mouse model. In particular, we will: 1) Determine the toxicity of spinacine in mice. We will assess the toxicity of spinacine in mice, defining the maximum tolerated dose and identifying the optimum dose with which to carry out experiments designed to test its efficacy, and 2) Evaluate the ability of spinacine to synergize with TRAIL- and/or chemo-based therapies to reduce or eliminate HPV+ tumor growth. We will assess the ability of spinacine to synergize with hrTRAIL and/or the DNA damaging drug cisplatin to inhibit tumor growth in a xenograft model. At the conclusion of this work, we will have 1) Determined the toxicity of the E6-inhibiting molecule spinacine in mice, and 2) Evaluated the effectiveness of combining spinacine with TRAIL- and cisplatin-based treatments in an animal model. This work has the potential to save the lives of thousands of patients suffering from HPV-associated malignancies.

概括高风险的人乳头瘤病毒（HPV）几乎是所有人类宫颈的原因癌，以及越来越多的其他恶性肿瘤，包括头部和颈部，肛门和外阴。不幸的是，目前尚不可用的晚期HPV+恶性肿瘤的良好治疗方法大部分是因为该病毒编码蛋白质E6，该蛋白质通过加速而禁用细胞凋亡途径诸如FADD，caspase 8和p53之类的分子的降解。这使得消除HPV+很难癌细胞使用凋亡的常规诱导剂。为了克服这一障碍，我们的实验室已经确定几个小分子，可以阻止E6与伴侣之间的结合，例如caspase 8和E6AP。根据我们的工作模型，以组合方式使用此类分子将大大增加标准放射和化学治疗的有效性。体外结合数据和细胞数据从我们的实验室提供强大的数据来支持这种工作模型，现在是时候测试我们的方法了在体内环境中。因此，此当前应用的总体目标是移动我们令人兴奋的体外和细胞观测到小鼠异种移植模型。我们将通过结合甲氨酸来做到这一点分子候选者，具有两个潜在的治疗剂：TRAIL，一种生物学和顺铂，一种更常规的化学治疗性，询问这些组合中的任何一种都可以减少或消除HPV+的生长裸鼠模型中的肿瘤，颈椎或头颈起源。特别是，我们将：1）确定脊汀在小鼠中的毒性。我们将评估脊汀在小鼠中的毒性，定义最大耐受剂量并确定旨在测试其功效的实验的最佳剂量， 2）评估脊汀与基于TRAIL和/或化学疗法协同作用的能力减少或消除HPV+肿瘤生长。我们将评估脊汀与Hrtrail协同作用的能力和/或DNA破坏药物顺铂可在异种移植模型中抑制肿瘤生长。在此结束时工作，我们将有1）确定E6抑制分子脊汀在小鼠中的毒性，以及2）评估在动物模型中，将旋转酸与基于越野铂和顺铂的治疗相结合的有效性。这工作有可能挽救成千上万患有与HPV相关的恶性肿瘤患者的生命。