Novel adjuvant therapy for triple negative breast cancer

三阴性乳腺癌的新型辅助疗法

基本信息

批准号：
8834729
负责人：
Ruben Rene Gonzalez-Perez
金额：
$ 22.5万
依托单位：
JYANT, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8834729
关键词：
Acute Acute Toxicity Tests Adjuvant Adjuvant Therapy Adverse effects Affinity Angiogenesis Inhibitors Antineoplastic Agents Aurothioglucose Binding Biological Biological Availability Body Weight Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Cell Cycle Cell Line Cells Complex Cyclophosphamide Data Diet Disease Dose Dose-Limiting Doxorubicin Drug resistance ERBB2 gene Eating Effectiveness Estrogens Fatty acid glycerol esters Growth Half-Life Health Status Hour Human Hypothalamic structure Incidence Leptin Lethal Dose 50 Link Longitudinal Studies Luc Gene MDA MB 231 Mammary gland Methodology Mitosis Modeling Molecular Target Mus Neoplasm Metastasis Nude Mice Obese Mice Obesity Oncogenic Overweight Paclitaxel Parents Patients Peptide Receptor Peptides Pharmaceutical Preparations Phase Polyethylene Glycols Process Production Progesterone Receptors Proliferating Proteins Relapse S Phase Signal Pathway Signal Transduction Small Business Innovation Research Grant Small Business Technology Transfer Research Systems Analysis Tamoxifen Technology Testing Therapeutic TimeLine Toxic effect Toxicity Tests Translations Validation Xenograft procedure base cancer stem cell chemotherapy clinically relevant design dosage effective therapy efficacy testing imaging system improved in vivo imaging inhibitor/antagonist innovation intravenous administration leptin receptor malignant breast neoplasm mortality mouse model nanoparticle novel novel strategies outcome forecast overexpression pandemic disease public health relevance receptor standard of care success targeted treatment triple-negative invasive breast carcinoma tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Triple negative breast cancer (TNBC) is very difficult to treat and has no specific targeted therapies. Chemotherapies used to treat this disease have many undesirable side-effects and patients eventually relapse as a result of chemoresistance. Obesity is pandemic in the US and many TNBC suffer from this as well. Obesity is accompanied by high levels of leptin and is linked to the highest mortality rates in TNBC patients. In contrast to normal mammary cells, TNBC cells overexpress the leptin receptor and significantly proliferate under leptin interactions. Our exciting findings suggest leptin is involved in TNBC acquired drug resistance through the induction of breast cancer stem cells (BCSC). Anti-angiogenic drugs show limited success for TNBC, but these shortcomings could be due in part to angiogenic signal redundancy, i.e., leptin. JYANT Technologies, Inc. has designed a proprietary, potent and highly specific inhibitor of leptin-signaling, leptin peptide receptor antagonist-2 (LPrA2). The peptide conjugated to polyethylene glycol (20 kDa; PEG-wLPrA2) has a 68 hour half-life after intravenous administration and significantly reduces TNBC growth. Preliminary data also show that PEG-wLPrA2 does not induce changes in food intake, body weight or general health status. We propose the use of PEG-wLPrA2 as an adjuvant therapy for TNBC that will improve the efficacy and reduce dosage and toxicities associated with current TNBC therapy (e.g., doxorubicin + cyclophosphamide + paclitaxel). PEG-wLPrA2 will target leptin's proliferative, pro-angiogenic and BCSC related actions in TNBC. This study will evaluate this novel adjuvant therapy in clinically relevant (obesity) TNBC models. Specifically, toxicity an adjuvant therapy studies along with doxorubicin, cyclophosphamide and/or paclitaxel treatments will be carried out in lean and obese mice hosting human and mouse TNBC xenografts and syngeneic grafts. The experimental data generated from this STTR Phase I proposal will allow for the rapid translation of an innovative and targeted adjuvant therapy for TNBC. This novel strategy will generate an effective therapy for reducing chemoresistance, relapse and metastasis of TNBC via depletion BCSC, which are maintained by leptin-signaling. Our proposed studies are of paramount importance for TNBC sufferers, especially those that are overweight or obese, which shows the highest levels of leptin and TNBC incidence.

描述（申请人提供）：三阴性乳腺癌（TNBC）非常难以治疗，并且没有特定的靶向治疗方法。用于治疗这种疾病的化疗有许多不良副作用，患者最终会因化疗耐药而复发。肥胖在美国很普遍，许多 TNBC 也深受其害。肥胖伴随着高水平的瘦素，并且与 TNBC 患者的最高死亡率有关。相比之下与正常乳腺细胞相比，TNBC 细胞过度表达瘦素受体，并在瘦素相互作用下显着增殖。我们令人兴奋的发现表明，瘦素通过诱导乳腺癌干细胞 (BCSC) 参与 TNBC 获得性耐药性。抗血管生成药物对 TNBC 的成功有限，但这些缺点可能部分归因于血管生成信号冗余，即瘦素。 JYANT Technologies, Inc. 设计了一种专有的、有效的、高度特异性的瘦素信号传导抑制剂——瘦素肽受体拮抗剂-2 (LPrA2)。与聚乙二醇 (20 kDa；PEG-wLPrA2) 缀合的肽在静脉注射后具有 68 小时的半衰期，可显着减少 TNBC 的生长。初步数据还表明，PEG-wLPrA2 不会引起食物摄入量、体重或一般健康状况的变化。我们建议使用 PEG-wLPrA2 作为 TNBC 的辅助治疗，这将提高疗效并减少与当前 TNBC 治疗（例如阿霉素 + 环磷酰胺 + 紫杉醇）相关的剂量和毒性。 PEG-wLPrA2 将针对 TNBC 中瘦素的增殖、促血管生成和 BCSC 相关作用。本研究将在临床相关（肥胖）TNBC 模型中评估这种新型辅助疗法。具体而言，毒性和辅助治疗研究以及阿霉素、环磷酰胺和/或紫杉醇治疗将在承载人类和小鼠TNBC异种移植物和同基因移植物的瘦和肥胖小鼠中进行。 STTR I 期提案产生的实验数据将有助于快速转化针对 TNBC 的创新型靶向辅助疗法。这种新策略将产生一种有效的疗法，通过消耗由瘦素信号传导维持的 BCSC 来减少 TNBC 的化疗耐药性、复发和转移。我们提出的研究对于 TNBC 患者至关重要，尤其是那些超重或肥胖的患者，这表明瘦素和 TNBC 的发病率最高。