权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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妇女死亡的三大癌症之一。目前治疗的主要缺点是高水平的副作用和疗效不足，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限度地减少对健康细胞的损害。这些靶点对肿瘤的恶性表型至关重要，但对宿主的正常组织却不重要，从而改善了预后，同时最大限度地减少了全身副作用。抗HER 2药物赫赛汀（Herceptin）引领了乳腺癌靶向治疗的方向，在特定但小部分患者中具有明确的疗效。显然需要额外的治疗选择，包括其他新的靶向治疗。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（GP 88），是一种新型的临床前验证的候选药物，因为它在乳腺癌细胞生物学中起着关键作用，例如：1）GP 88是乳腺癌细胞的自分泌生长/存活因子，2）乳腺癌细胞中GP 88表达增加与致瘤性增加相关，3）GP 88介导肿瘤细胞血管生成和侵袭性，4）过表达GP 88的乳腺癌细胞对目前的疗法-他莫昔芬、芙仕得、多柔比星和赫赛汀具有抗性，5）乳腺癌组织中GP 88表达增加与预后不良的临床参数相关，而正常和良性乳腺组织为阴性，（6）预后不良者血清GP 88水平升高。这些结果突出了GP 88作为一种新的靶向治疗乳腺癌通过开发抗GP 88治疗性中和单克隆抗体（单克隆抗体）。我们已经使用多种GP 88特异性免疫原产生了GP 88特异性的小鼠单克隆抗体的大型文库。最初的初步结果表明，抗GP 88抗体可以消除GP 88功能活性。该阶段I SBIR应用的重点是充分表征该Mab文库，以鉴定具有最佳特性的Mab，作为开发候选物。具体目标是：1。通过Biacore分析表征抗GP 88单抗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Mab。3.确定在裸小鼠异种移植致瘤性模型中的功效和效价。在I期结束时，我们将鉴定出具有最佳体外和体内临床前疗效和靶向乳腺癌效力的小鼠单克隆抗体。这些单克隆抗体将需要进一步的开发活动，作为潜在的治疗候选药物，以考虑在乳腺癌的临床试验在第二阶段。第一步将是从阶段I期间选择的小鼠Mab候选物产生小鼠-人嵌合Mab。这种嵌合单克隆抗体将进一步进入临床前开发。这项和其他开发活动将作为第二阶段SBIR应用的基础，作为开发乳腺癌新生物疗法的基础。乳腺癌仍然是影响和导致妇女死亡的三大癌症之一。目前治疗的主要缺点是在患者中引起的高水平副作用和疗效不足，特别是对于晚期疾病患者。该提案中开发的创新性乳腺癌治疗方法将针对乳腺癌固有的机制，但避免与目前许多乳腺癌治疗相关的副作用。