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引起女性死亡率的前三名癌症之一。当前治疗的主要缺点是高水平的副作用和功效不足，特别是对于转移性疾病患者。靶向癌症治疗旨在仅治疗癌细胞并最大程度地减少对健康细胞的损害。这些靶标对于肿瘤的恶性表型至关重要，但对宿主的正常组织而言并不重要，从而改善了预后，同时最大程度地减少了全身副作用。抗HER2，Herceptin，在特定但较小的患者子群中具有明确的疗效的靶向治疗。显然需要其他治疗选择，包括其他新型靶向疗法。 88 kDa自分泌生长因子PC细胞得出的生长因子（PCDGF），也称为颗粒蛋白前体（GP88），是一种新颖且经过彻底验证的选择的选择，因为它在乳腺癌细胞生物学中起着至关重要的作用，在以下是乳腺癌细胞生物学中的关键作用，以下是乳腺癌的生长/乳腺癌细胞的相关性IS GP88与乳腺癌相关性，GP88与乳腺癌相关联。肿瘤性，3）GP88介导了肿瘤细胞血管生成和浸润性，4）过表达GP88的乳腺癌细胞对当前疗法具有抵抗力 - 他莫昔芬，faslodex，faslodex，doxorubicin和herceptin，5）在乳腺癌组织中与较差的乳腺癌相吻合，而在较差的患者中，较差的患者在较差的临床上与公par虫相吻合，而普通的公parie则是正常的，而普通人的公二症，同时公priansisiss，而普通的公二症，而普及的疗法则是较差的。预后升高GP88血清水平。这些结果通过开发抗GP88治疗性中和单克隆抗体（MABS）来强调GP88是一种新型的乳腺癌靶向治疗。我们使用各种GP88特异性免疫原子生成了大型小鼠单克隆抗体库。初步初步结果表明，抗GP88抗体可以消除GP88的功能活性。此阶段I SBIR应用的重点是充分表征此MABS库，以识别具有最佳特征的MAB，以作为开发候选者。具体目的是：1。通过BIACORE分析表征抗GP88 mAb的结合动力学和特异性。 2。在相关的体外功能细胞模型中识别具有最大功效和效力的mAb。 3。确定裸小鼠异种移植肿瘤模型的功效和效力。在本阶段I期间，我们将确定一个小鼠mAb（或mAb），具有最佳的体外和体内临床前效力和靶向乳腺癌的效力。这些mAB将需要进一步的开发活动，作为潜在的治疗候选者，以便在II期期间考虑进行乳腺癌的临床试验。第一步将是从阶段I中选择的小鼠mAb候选者生成小鼠嵌合mAb。然后将将此嵌合mAb进一步进入临床前发育。这项和其他开发活动将作为II期SBIR应用的基础，作为开发新型乳腺癌生物疗法的基础。乳腺癌仍然是影响和引起女性死亡率的前三名癌症之一。当前治疗的主要缺点是患者引起的高副作用和不足的功效，尤其是对于晚期疾病患者。该提案中要开发的创新乳腺癌疗法将针对乳腺癌固有的机制，但避免了与许多当前乳腺癌疗法相关的副作用。