Targeting HPV Consequences in a Cervical Cancer Clinical Trial

在宫颈癌临床试验中针对 HPV 后果

基本信息

项目摘要

 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(由适用提供):高风险人乳头瘤病毒(HPV)会引起宫颈发育不良,这可以发展为宫颈癌,这是女性与癌症相关死亡的第二大原因。宫颈癌的治疗治疗疗法剧毒,通常会对生活质量产生负面影响。宫颈癌是通过检测和破坏宫颈发育不良的涉及大量成本,不适和潜在生育能力丧失的,这些病变中的大多数不会发展为癌症。我们开发了一种无毒的癌症药物,该药物具有适用于宫颈发育不良和癌症的机械特征。我们的药物, 称为sheta2(NSC 721689)抵消了高风险HPV的细胞周期调节后果。 SHETA2的广泛临床前研究表明,体外和体内表现出癌症治疗和化学预防活性,缺乏诱变或致死性,无毒性和适合口服治疗剂的药物特征。美国食品药品监督管理局(FDA)的投票前新药(IND)会议报告列出了我们前进到宫颈癌中Sheta2的0期临床试验的障碍。在该项目中,W猜测Sheta2通过抵消细胞周期蛋白D1和其他由HPV引起的细胞周期调节蛋白的改变而导致人和鼠宫颈肿瘤中的G1停滞和凋亡。我们将通过在IB2-IVB宫颈癌患者中进行0期临床试验来检验这一假设,以确定口服Sheta2胶囊是否可以实现已知的Sheta2的全身和宫颈组织浓度,已知可以调节细胞周期蛋白A,D1和E,以及RB磷酸化事件。在该试验中收集的外周血单核细胞(PBMC)的时间前后,治疗前和治疗后的宫颈肿瘤活检和时间过程将用于确定通过Sheta2处理改变了哪些RB途径缺陷。此外,我们将比较口腔胶囊和阴道栓剂sheta2公式,以改变细胞周期调节蛋白与K14-HPV16转基因小鼠中宫颈肿瘤形成的减少相关的细胞周期调节蛋白。由HPV和SHETA2对抗的细胞周期蛋白(例如细胞周期蛋白A,D和E)将通过直接参与Sheta2调节G1细胞周期停滞和凋亡。这些研究将通过确定sheta2的药代动力学(PK)和药物药物化合物(PD),并确定口服或阴道递送将实现较高的SHETA2的SHETA2是否实现SHETA2是否会在细胞周期蛋白质和更大的囊细胞中的更大变化来奠定基础。我们的机械研究将开发候选PD生物标志物,以用于宫颈发育不良计划的将来的临床试验中,并将提供对HPV相关细胞周期缺陷的知识,以宫颈发育不良和癌症的了解。

项目成果

期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Bioanalytical method development and validation of HPLCUV assay for the quantification of SHetA2 in mouse and human plasma: Application to pharmacokinetics study.
用于定量小鼠和人血浆中 SHetA2 的 HPLCUV 测定的生物分析方法开发和验证:在药代动力学研究中的应用。
Distinct mechanism of cervical cancer cell death caused by the investigational new drug SHetA2.
  • DOI:
    10.3389/fonc.2022.958536
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    4.7
  • 作者:
    Rai, Rajani;Chandra, Vishal;Kennedy, Amy L.;Zuna, Rosemary E.;Benbrook, Doris Mangiaracina
  • 通讯作者:
    Benbrook, Doris Mangiaracina
Influence of the estrus cycle of the mouse on the disposition of SHetA2 after vaginal administration.
Similarities and Differences of Hsp70, hsc70, Grp78 and Mortalin as Cancer Biomarkers and Drug Targets.
  • DOI:
    10.3390/cells10112996
  • 发表时间:
    2021-11-03
  • 期刊:
  • 影响因子:
    6
  • 作者:
    Rai R;Kennedy AL;Isingizwe ZR;Javadian P;Benbrook DM
  • 通讯作者:
    Benbrook DM
Pharmacokinetics and interspecies scaling of a novel, orally-bioavailable anti-cancer drug, SHetA2.
新型口服生物可利用抗癌药物 SHetA2 的药代动力学和种间缩放。
  • DOI:
    10.1371/journal.pone.0194046
  • 发表时间:
    2018
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Sharma,Ankur;Benbrook,DorisMangiaracina;Woo,Sukyung
  • 通讯作者:
    Woo,Sukyung
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DORIS Mangiaracina BENBROOK其他文献

DORIS Mangiaracina BENBROOK的其他文献

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{{ truncateString('DORIS Mangiaracina BENBROOK', 18)}}的其他基金

Project 1: Targeting HSPA Proteins in Advanced and Recurrent Endometrial Cancer Therapy
项目 1:针对晚期和复发性子宫内膜癌治疗中的 HSPA 蛋白
  • 批准号:
    10711636
  • 财政年份:
    2023
  • 资助金额:
    $ 20.45万
  • 项目类别:
Route 66 Endometrial Cancer SPORE
66 号公路子宫内膜癌孢子
  • 批准号:
    10711634
  • 财政年份:
    2023
  • 资助金额:
    $ 20.45万
  • 项目类别:
Gynecologic Cancers Research Program
妇科癌症研究计划
  • 批准号:
    10177891
  • 财政年份:
    2018
  • 资助金额:
    $ 20.45万
  • 项目类别:
Gynecologic Cancers Research Program
妇科癌症研究计划
  • 批准号:
    10413078
  • 财政年份:
    2018
  • 资助金额:
    $ 20.45万
  • 项目类别:
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:
    9052455
  • 财政年份:
    2016
  • 资助金额:
    $ 20.45万
  • 项目类别:
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
  • 财政年份:
    2016
  • 资助金额:
    $ 20.45万
  • 项目类别:
Ovarian Cancer Chemoprevention
卵巢癌化学预防
  • 批准号:
    9093746
  • 财政年份:
    2015
  • 资助金额:
    $ 20.45万
  • 项目类别:
Ovarian Cancer Chemoprevention
卵巢癌化学预防
  • 批准号:
    9316591
  • 财政年份:
    2015
  • 资助金额:
    $ 20.45万
  • 项目类别:
Ovarian Cancer Chemoprevention
卵巢癌化学预防
  • 批准号:
    8986266
  • 财政年份:
    2015
  • 资助金额:
    $ 20.45万
  • 项目类别:
Mechanism of SHeA2 Action in Ovarian Cancer
SHeA2 在卵巢癌中的作用机制
  • 批准号:
    7609055
  • 财政年份:
    2005
  • 资助金额:
    $ 20.45万
  • 项目类别:

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多域肽水凝胶作为癌症治疗的治疗传递平台
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Targeting HPV Consequences in a Cervical Cancer Clinical Trial
在宫颈癌临床试验中针对 HPV 后果
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在宫颈癌临床试验中针对 HPV 后果
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