Novel Targeted Therapy for Breast Cancer

乳腺癌新型靶向治疗

基本信息

批准号：
7270094
负责人：
Ginette Serrero
金额：
$ 12.06万
依托单位：
A AND G PHARMACEUTICAL, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-11 至 2008-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7270094
关键词：
Address Adverse effects Affect Affinity Antibodies Antigens Benign Binding Biological Biological Response Modifier Therapy Breast Cancer Cell Cell model Cells Cellular biology Characteristics Clinical Clinical Trials Complementary DNA Development Development, Other Disease Dissociation Doxorubicin Faslodex(ICI 182,780)Goals Growth Growth Factor Hormonal Human In Vitro Incidence Kinetics Libraries Malignant Neoplasms Mammary Gland Parenchyma Mediating Modeling Monoclonal Antibodies Mus Normal tissue morphology Nude Mice Outcome PC cell-derived growth factor Patients Phase Play Principal Investigator Protein Overexpression Proteins Rate Resistance Roche brand of trastuzumab Role Serum Small Business Funding Mechanisms Small Business Innovation Research Grant Specificity Tamoxifen Therapeutic Therapeutic Agents Tissues Tumorigenicity Validation Woman Xenograft procedure angiogenesis autocrine base cancer cell cancer therapy clinical efficacy design improved in vivo innovation malignant breast neoplasm malignant phenotype mortality neoplastic cell neutralizing antibody neutralizing monoclonal antibodies novel outcome forecast pre-clinical programs research study size tumor tumor growth tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Breast cancer remains one of the top three cancers to affect and cause mortality in women. Major shortcomings with current treatment are the high level of side effects and insufficient efficacy, particularly for patients with metastatic disease. Targeted cancer therapy is designed to treat only the cancer cells and minimize damage to healthy cells. These targets are critical to the tumor's malignant phenotype but not to the host's normal tissues, improving outcomes while minimizing systemic side effects. Anti-HER2, Herceptin, leads the way for targeted therapy in breast cancer with a definite efficacy in a specific but small subset of patients. There is a clear need for additional therapeutic options including other novel targeted therapies. The 88 kDa autocrine growth factor PC-Cell Derived Growth Factor (PCDGF), also known as granulin precursor (GP88), is a novel and preclinically validated candidate of choice as it plays a critical role in breast cancer cell biology, exemplified by the following: 1) GP88 is an autocrine growth/survival factor for breast cancer cells, 2) increased GP88 expression in breast cancer cells is associated with increased tumorigenicity, 3) GP88 mediates tumor cell angiogenesis and invasiveness, 4) breast cancer cells overexpressing GP88 are resistant to current therapies - Tamoxifen, Faslodex, doxorubicin and Herceptin, 5) increased GP88 expression in breast cancer tissue correlates with clinical parameters of poor prognosis while normal and benign breast tissue are negative, 6) patients with poor prognosis have elevated GP88 serum levels. These results highlight GP88 as a novel targeted therapy of breast cancer via the development of anti-GP88 therapeutic neutralizing monoclonal antibodies (Mabs). We have generated a large library of mouse monoclonal antibodies specific to GP88 using a variety of GP88-specific immunogens. Initial preliminary results indicate that an anti-GP88 antibody can abrogate GP88 functional activity. This phase I SBIR application is focused on fully characterizing this Mabs library in order to identify the Mabs with the optimal characteristics to serve as development candidates. The Specific Aims are: 1. Characterize the binding kinetics and specificity of anti-GP88 Mabs by Biacore analysis. 2. Identify Mab's with maximal efficacy and potency in relevant in vitro functional cellular models. 3. Determine efficacy and potency in nude mouse xenograft tumorigenicity models. At the conclusion of this Phase I, we will have identified a mouse Mab (or Mabs) with the optimal in vitro and in vivo pre-clinical efficacy and potency for targeting breast cancer. These Mabs will require further development activities as potential therapeutic candidates in order to be considered for clinical trials in breast cancer during phase II. The first step will be to generate a mouse-human chimeric Mab from the mouse Mab candidate selected during phase I. This chimeric Mab will then be taken further into pre-clinical development. This and other development activities will serve as the basis for a Phase II SBIR application as a basis for the development of novel biological therapy for breast cancer. Breast cancer remains one of the top three cancers to affect and cause mortality in women. Major shortcomings with current treatment are the high level of side effects induced in patients and insufficient efficacy, particularly for patients with advanced disease. The innovative breast cancer therapy to be developed in this proposal will target a mechanism inherent in breast cancer but avoid the side effects associated with many current breast cancer therapies.

描述（由申请人提供）：乳腺癌仍然是影响和导致女性死亡的三大癌症之一。目前治疗的主要缺点是副作用高且疗效不足，特别是对于患有转移性疾病的患者。靶向癌症治疗旨在仅治疗癌细胞并尽量减少对健康细胞的损害。这些靶点对于肿瘤的恶性表型至关重要，但对于宿主的正常组织则不然，从而改善结果，同时最大限度地减少全身副作用。抗 HER2 药物赫赛汀引领了乳腺癌靶向治疗的潮流，对一小部分特定的患者具有明确的疗效。显然需要额外的治疗选择，包括其他新颖的靶向疗法。 88 kDa 自分泌生长因子 PC 细胞衍生生长因子 (PCDGF)，也称为颗粒蛋白前体 (GP88)，是一种新型且经过临床前验证的候选药物，因为它在乳腺癌细胞生物学中发挥着关键作用，例如：：1) GP88 是乳腺癌细胞的自分泌生长/存活因子，2) 乳腺癌细胞中 GP88 表达增加与致瘤性增加相关， 3) GP88 介导肿瘤细胞血管生成和侵袭性，4) 过度表达 GP88 的乳腺癌细胞对当前的治疗方法（他莫昔芬、Faslodex、多柔比星和赫赛汀）具有耐药性，5) 乳腺癌组织中 GP88 表达增加与预后不良的临床参数相关，而正常和预后良好的临床参数与预后不良的临床参数相关。良性乳腺组织呈阴性，6)预后不良的患者血清GP88水平升高。这些结果凸显了 GP88 通过开发抗 GP88 治疗性中和单克隆抗体 (Mab) 成为乳腺癌的一种新型靶向疗法。我们使用多种 GP88 特异性免疫原生成了一个大型 GP88 特异性小鼠单克隆抗体文库。初步初步结果表明，抗 GP88 抗体可以消除 GP88 功能活性。该 I 期 SBIR 应用的重点是全面表征该 Mab 库，以便识别具有最佳特性的 Mab，作为开发候选药物。具体目标是： 1. 通过 Biacore 分析表征抗 GP88 Mab 的结合动力学和特异性。 2. 鉴定在相关体外功能细胞模型中具有最大功效和效力的单克隆抗体。 3. 确定裸鼠异种移植致瘤模型的功效和效力。在第一阶段结束时，我们将鉴定出一种具有最佳体外和体内临床前疗效和靶向乳腺癌功效的小鼠单克隆抗体（或多种单克隆抗体）。这些单克隆抗体将需要作为潜在的治疗候选者进行进一步的开发活动，以便考虑在 II 期乳腺癌临床试验中进行。第一步是从第一阶段选择的小鼠单克隆抗体候选物中产生小鼠-人嵌合单克隆抗体。然后，该嵌合单克隆抗体将进一步进入临床前开发。这项开发活动和其他开发活动将作为 II 期 SBIR 应用的基础，作为开发乳腺癌新型生物疗法的基础。乳腺癌仍然是影响和导致女性死亡的三大癌症之一。目前治疗的主要缺点是对患者产生的副作用较高且疗效不足，特别是对于晚期疾病患者。该提案中将开发的创新乳腺癌疗法将针对乳腺癌固有的机制，但避免与许多当前乳腺癌疗法相关的副作用。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Breast cancer risk prediction and individualised screening based on common genetic variation and breast density measurement.

基于常见遗传变异和乳腺密度测量的乳腺癌风险预测和个体化筛查。

DOI：
发表时间：
2012-02-07
期刊：
影响因子：
0
作者：
Darabi, Hatef;Czene, Kamila;Zhao, Wanting;Liu, Jianjun;Hall, Per;Humphreys, Keith
通讯作者：
Humphreys, Keith

Increased Circulating Level of the Survival Factor GP88 (Progranulin) in the Serum of Breast Cancer Patients When Compared to Healthy Subjects.

与健康受试者相比，乳腺癌患者血清中生存因子 GP88（颗粒体蛋白前体）的循环水平升高。

DOI：
发表时间：
2011
期刊：
影响因子：
0
作者：
Tkaczuk, Katherine Rak;Yue, Binbin;Zhan, Min;Tait, Nancy;Yarlagadda, Lavanya;Dai, Huifang;Serrero, Ginette
通讯作者：
Serrero, Ginette

GP88 (PC-Cell Derived Growth Factor, progranulin) stimulates proliferation and confers letrozole resistance to aromatase overexpressing breast cancer cells.

GP88（PC 细胞衍生生长因子，颗粒体蛋白前体）可刺激增殖并赋予过度表达芳香酶的乳腺癌细胞来曲唑耐药性。

DOI：
发表时间：
2011
期刊：
影响因子：
3.8
作者：
Abrhale, Tesfom;Brodie, Angela;Sabnis, Gauri;Macedo, Luciana;Tian, Changsheng;Yue, Binbin;Serrero, Ginette
通讯作者：
Serrero, Ginette

Signaling Pathway of GP88 (Progranulin) in Breast Cancer Cells: Upregulation and Phosphorylation of c-myc by GP88/Progranulin in Her2-Overexpressing Breast Cancer Cells.

乳腺癌细胞中 GP88（颗粒体蛋白前体）的信号通路：Her2 过表达乳腺癌细胞中 GP88/颗粒体蛋白前体对 c-myc 的上调和磷酸化。