Novel Therapeutics Targeting HER2 Positive Breast Cancer Brain Metastasis

针对 HER2 阳性乳腺癌脑转移的新疗法

• 批准号: 8811762
• 负责人: Xinli Liu
• 金额: $ 7.6万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811762
• 关键词: Address; Amino Acids; Animal Model; Antitumor Response; Apoptosis; Autoradiography; Binding; Blood - brain barrier anatomy; Brain; Breast Cancer Cell; Breast Cancer Patient; Characteristics; Chemistry; Clinic; Clinical; Data; Disulfides; Drug Targeting; ERBB2 gene; Effectiveness; Equilibrium; Erlotinib; Exhibits; FDA approved; Gefitinib; Glutathione; Goals; Health; Homing; Human; Immunodeficient Mouse; Immunohistochemistry; In Situ; In Vitro; Incidence; Injection of therapeutic agent; LDL-Receptor Related Protein 1; Lead; Length; Lesion; Life; Luciferases; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Metabolic; Metastatic Neoplasm to the Central Nervous System; Metastatic breast cancer; Metastatic malignant neoplasm to brain; Methods; Mission; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Nude Mice; Organ; Outcome; Patients; Penetration; Peptides; Perfusion; Pharmaceutical Preparations; Phosphorylation; Polyethylene Glycols; Property; Protocols documentation; Regimen; Research; SKBR3; Serum; Site; Solubility; Survival Rate; System; Techniques; Testing; Therapeutic; Transferrin; Trastuzumab; Treatment Efficacy; Tyrosine Kinase Inhibitor; Vertebral column; Woman; Work; analog; bioluminescence imaging; burden of illness; cytotoxic; cytotoxicity; design; disability; efficacy testing; hydrophilicity; improved; indexing; lapatinib; liquid chromatography mass spectrometry; malignant breast neoplasm; mouse model; new therapeutic target; novel; overexpression; prototype; public health relevance; receptor; small molecule; thioether; transcytosis; treatment effect; tumor; tumor growth; uptake; vector

DESCRIPTION (provided by applicant): Breast cancer brain metastasis, which occurs in more than one third of metastatic patients with HER2- positive tumors, is extremely difficult to treat and has a typical survival rate of < 1 year. Although aberrant HER2 receptor overexpression in breast cancer is highly correlated with brain metastasis, molecularly-targeted anti-HER2 therapy, such as trastuzumab and lapatinib, poorly cross the blood brain barrier (BBB) to reach the metastatic site at therapeutic concentrations. This proposal seek to overcome a critical barrier for delivery of the "molecularly-targeted" anti-HER2 drug, lapatinib, t a specific metastatic site - the brain. Our approach exploits the unique properties of a brain homing peptide, Angiopep-2, to improve penetration of lapatinib across the BBB in order to treat HER2+ brain metastasis. The 19-amino acid peptide, Angiopep-2, binds to the low-density lipoprotein receptor-related protein (LRP-1) receptor and is transcytosed into the brain with more efficiency than transferrin. The goal of this research is to develop brain-permeable lapatinib Angiopep-2 conjugates that can enhance therapeutic drug levels in the brain to treat HER2+ breast cancer brain metastasis. We hypothesize that lapatinib-Angiopep-2 conjugates will cross the BBB more efficiently than lapatinib itself and lead to higher lapatinib accumulation in the brain metastasis. Consequently, therapeutic benefits will be obtained in targeting and destroying HER2+ breast cancer brain metastasis. We plan to test the hypothesis through three specific aims: (1) optimize lapatinib-Angiopep conjugates with improved solubility, serum stability, and ability to achieve localized lapatinib release; (2) demonstrate the effectiveness of brain penetration, cellular uptake and release, and cytotoxic potency of the optimized conjugates; (3) validate enhanced brain accumulation and therapeutic efficacy of optimized conjugates in HER2-overexpressing breast cancer brain metastasis models in immunodeficient mice. We will optimize synthetic protocols to chemically attach lapatinib to the peptide backbone of Angiopep-2 via different cross-linkers. We will study the stability of conjugates in mouse and human serum and cytotoxicity in HER2-overexpressing breast cancer cells. We will determine BBB transport rates of the conjugates using an in situ mouse brain perfusion technique. We will test the efficacy of conjugates in our established breast cancer brain metastasis mouse models by intracardiac and intracranial injection of brain-seeking HER2- overexpressing human breast cancer cells into nude mice, and will monitor tumor growth and/or regression after conjugate treatment. Successful completion of this project will identify a lapatinib delivery system that is able to cross the BBB and is active against breast cancer brain metastases animal models. If successful, the research can be translatable into the clinic and will potentially lead to a major step forward in extending the lives of breast cancer patients with HER2-positive brain metastases. This work will have a broader impact upon the delivery of other molecularly-targeted tyrosine kinase inhibitors, such as gefitinib and erlotinib, which are structural analogs of lapatinib, for the treatment of CNS metastases originating from other cancers.

描述（由申请人提供）：乳腺癌脑转移，发生在超过三分之一的HER 2阳性肿瘤转移患者中，非常难以治疗，典型的生存率< 1年。尽管乳腺癌中异常HER 2受体过表达与脑转移高度相关，但分子靶向抗HER 2治疗（如曲妥珠单抗和拉帕替尼）在治疗浓度下难以穿过血脑屏障（BBB）到达转移部位。该提案旨在克服将“分子靶向”抗HER 2药物拉帕替尼递送至特定转移部位-脑的关键障碍。 我们的方法利用脑归巢肽Angiopep-2的独特性质来改善拉帕替尼穿过BBB的渗透，以治疗HER 2+脑转移。19个氨基酸的肽，血管肽素-2，与低密度脂蛋白受体相关蛋白（LRP-1）受体结合，并以比转铁蛋白更高的效率被转运到大脑中。本研究的目标是开发脑渗透性拉帕替尼Angiopep-2缀合物，其可以提高脑中的治疗药物水平，以治疗HER 2+乳腺癌脑转移。我们假设拉帕替尼-血管肽素-2偶联物比拉帕替尼本身更有效地穿过血脑屏障，并导致拉帕替尼蓄积更高 在脑转移瘤中因此，将在靶向和破坏HER 2+乳腺癌脑转移中获得治疗益处。我们计划通过三个具体目标来检验该假设：（1）优化拉帕替尼-血管肽缀合物，其具有改善的溶解度、血清稳定性和实现局部拉帕替尼释放的能力;（2）证明拉帕替尼-血管肽缀合物的有效性。 优化的缀合物的脑渗透、细胞摄取和释放以及细胞毒性效力;（3）验证优化的缀合物在免疫缺陷小鼠中的HER 2过表达乳腺癌脑转移模型中的增强的脑积累和治疗功效。 我们将优化合成方案，通过不同的交联剂将拉帕替尼化学连接到Angiopep-2的肽骨架上。我们将研究偶联物在小鼠和人血清中的稳定性以及在HER 2过表达乳腺癌细胞中的细胞毒性。我们将使用原位小鼠脑灌注技术测定缀合物的BBB转运速率。我们将通过向裸小鼠心内和颅内注射过表达脑寻求性HER 2的人乳腺癌细胞来测试缀合物在我们建立的乳腺癌脑转移小鼠模型中的功效，并将监测缀合物治疗后的肿瘤生长和/或消退。该项目的成功完成将确定一种拉帕替尼给药系统，该系统能够穿过血脑屏障，并对乳腺癌脑转移动物模型有效。如果成功，这项研究可以转化为临床，并可能在延长HER 2阳性脑转移乳腺癌患者的生命方面向前迈出重要一步。这项工作将对其他分子靶向酪氨酸激酶抑制剂的递送产生更广泛的影响，例如吉非替尼和厄洛替尼，它们是拉帕替尼的结构类似物，用于治疗源自其他癌症的CNS转移。