Monobody therapy for gynecologic cancers

妇科癌症的单体疗法

基本信息

批准号：
8646675
负责人：
JAMES W LARRICK
金额：
$ 22.5万
依托单位：
PANORAMA RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-15 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8646675
关键词：
Address Adverse effects Affinity Agar American Animal Model Animals Antibodies Area Binding Cancer Etiology Cancer cell line Carcinoma Cell Proliferation Cessation of life Data Disease Dose Drug Kinetics Endometrial Endometrial Carcinoma Endometrial Hyperplasia Endometrial Neoplasms Epithelial Cells Family history of Goals Growth Half-Life Human In Vitro Induction of Apoptosis Innovative Therapy Lead Libraries Life Ligands Living Costs Malignant - descriptor Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Measures Messenger RNA Modeling Mono-S Mus Nude Mice Outcome Ovarian Ovarian Tissue Paracrine Communication Pathogenesis Phage Display Phase Pituitary Gland Plasma Premalignant Prolactin Prolactin Receptor Receptor Inhibition Receptor Signaling Risk Role SCID Mice Serum Signal Transduction Specificity Staging Testing Time Toxic effect Tumor Tissue Up-Regulation Western World Woman Work Xenograft Model Xenograft procedure advanced disease antibody engineering autocrine base cancer cell carcinogenesis cell transformation chemotherapy experience hormone therapy human monoclonal antibodies in vitro Assay in vivo inhibitor/antagonist innovation mouse model mutant neonatal Fc receptor ovarian neoplasm pre-clinical prevent professor public health relevance ras Oncogene receptor expression reproductive hormone response therapeutic target tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Monobody Therapy for Gynecologic Cancers Endometrial cancer is the most common gynecologic cancer in the western world. Systemic treatments for advanced disease have traditionally included hormonal therapy and chemotherapy. Responses to treatment are short-lived, and advanced-stage disease remains incurable. Ovarian cancer is the eighth most common cancer and causes more deaths than any other gynecologic cancer. Increasing evidence implicates prolactin (PRL) as a key factor in endometrial and ovarian cancer. Elevated levels of circulating PRL in gynecologic cancer suggest a role for PR L in endometrial and ovarian carcinogenesis. Recent studies have found significantly elevated expression of PRL in women with a strong family history of ovarian cancer. In addition, PRL receptor (PRLR) expression is upregulated in endometrial tumors, as well as in premalignant endometrial hyperplasia. Recent histochemical data found PRLR expression in >80% of ovarian tumors, but in none of the normal ovarian tissues tested. Increased expression of both PRLR and PRL mRNA in endometrial tumors indicates the importance of autocrineiparacrine signaling by extra pituitary PRL in tumor tissues. PRL induces proliferation in ovarian and endometrial cancer cell lines, and promotes malignant transformation of normal ovarian epithelial cells through activation of Ras. PRL-transformed cells acquire the ability to grow in soft agar and to form tumors in a SCID mouse model. These data validate PRL as a therapeutic target in endometrial and ovarian cancer. The overall goal of this project is to develop and characterize a human anti-PRLR monobody as an innovative treatment for gynecologic cancer. An anti-PRLR monobody will be a best-inclass inhibitor of PRLR signaling because unlike conventional antibodies or ligand-based biomolecules it is incapable of dimerizing PRLR thereby preventing adventitious initiation of signaling. In Phase I, we will identify a high-affinity anti-PRLR monobody from our phage display library. Clones will be rank-ordered by their affinity and specificity for PRLR. Finally, we will evaluate function in vitro andin a murine tumor model. Successful identification of a monobody with a nanomolar Kd, high specificity for PRLR, and ability to suppress tumor growth in vivo, will merit submission of a Phase II application. Phase II work will focus on obtaining the preclinical data necessary for submission of an IND. Pharmacokinetics and toxicity studies, as well as animal studies to demonstrate efficacy, will be performed.

描述（由申请人提供）：妇科癌症子宫内膜癌的单体疗法是西方世界上最常见的妇科癌。传统上，用于晚期疾病的全身治疗包括荷尔蒙治疗和化学疗法。对治疗的反应是短暂的，晚期疾病仍然无法治愈。卵巢癌是第八种常见的癌症，并且与任何其他妇科癌症相比，死亡人数更多。越来越多的证据表明催乳素（PRL）是子宫内膜和卵巢癌的关键因素。妇科癌症中循环PRL水平升高表明PR L在子宫内膜和卵巢癌中的作用。最近的研究发现，患有卵巢癌的家族史的女性中PRL的表达显着升高。另外，在子宫内膜肿瘤以及预呼应性子宫内膜增生中，PRL受体（PRLR）表达上调。最近的组织化学数据发现> 80％的卵巢肿瘤中PRLR的表达，但在卵巢组织中没有测试。在子宫内膜肿瘤中PRLR和PRL mRNA的表达增加表明，肿瘤组织中垂体额外PRL的自分泌氨基氨酸信号传导的重要性。 PRL诱导卵巢和子宫内膜癌细胞系的增殖，并通过激活Ras促进正常卵巢上皮细胞的恶性转化。 PRL转换的细胞具有在软琼脂中生长并在SCID小鼠模型中形成肿瘤的能力。这些数据将PRL验证为子宫内膜和卵巢癌的治疗靶标。该项目的总体目标是开发和表征人类的抗PRLR单一镜头作为妇科癌的创新治疗方法。抗PRLR单体将是PRLR信号传导的最佳内部抑制剂，因为与常规抗体或基于配体的生物分子不同，它无能力降低PRLR，从而防止信号传导的不定期启动。在第一阶段，我们将从我们的噬菌体展示库中确定一个高亲和力的抗PRLR单体。克隆将按照其亲和力和对PRLR的特异性的排名。最后，我们将在体外和鼠肿瘤模型中评估功能。成功识别具有纳摩尔KD的单体，PRLR的高特异性以及抑制体内肿瘤生长的能力，值得提交II期应用。第二阶段的工作将集中于获取提交IND所需的临床前数据。将进行药代动力学和毒性研究以及证明功效的动物研究。