Novel adjuvant therapy for triple negative breast cancer

三阴性乳腺癌的新型辅助疗法

• 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
• 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

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（由申请人提供）：三阴性乳腺癌（TNBC）非常难以治疗，并且没有特异性靶向治疗。用于治疗这种疾病的化学疗法具有许多不期望的副作用，并且患者最终由于化学抗性而复发。肥胖在美国是一种流行病，许多TNBC也患有肥胖症。肥胖伴随着高水平的瘦素，并与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细胞过表达瘦素受体并在瘦素相互作用下显著增殖。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显示出有限的成功，但这些缺点可能部分是由于血管生成信号冗余，即，瘦素JYANT Technologies，Inc.设计了一种专有的，有效的和高度特异性的瘦素信号抑制剂，瘦素肽受体拮抗剂-2（LPrA 2）。与聚乙二醇（20 kDa; PEG-wLPrA 2）缀合的肽在静脉内施用后具有68小时的半衰期，并且显著降低TNBC生长。初步数据还显示，PEG-wLPrA 2不会引起食物摄入量、体重或一般健康状况的变化。我们提出使用PEG-wLPrA 2作为TNBC的辅助疗法，其将提高功效并降低与当前TNBC疗法相关的剂量和毒性（例如，阿霉素+环磷酰胺+紫杉醇）。PEG-wLPrA 2将靶向瘦素在TNBC中的增殖、促血管生成和BCSC相关作用。本研究将在临床相关（肥胖）TNBC模型中评价这种新型辅助疗法。具体地，将在接受人和小鼠TNBC异种移植物和同基因移植物的瘦和肥胖小鼠中进行毒性辅助疗法研究沿着阿霉素、环磷酰胺和/或紫杉醇治疗。从STTR I期提案中产生的实验数据将允许快速转化为TNBC的创新和靶向辅助治疗。这种新的策略将产生一种有效的治疗方法，用于通过耗尽BCSC来减少TNBC的化疗耐药性、复发和转移，这是由瘦素信号传导维持的。我们提出的研究对TNBC患者至关重要，特别是超重或肥胖的患者，这些患者的瘦素水平和TNBC发病率最高。