Novel adjuvant therapy for triple negative breast cancer

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。用来治疗这种疾病的化疗有许多不良的副作用，患者最终会因为化疗耐药而复发。肥胖在美国很普遍，许多TNBC也受到这一问题的困扰。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， 对于正常乳腺细胞，TNBC细胞过度表达瘦素受体，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)参与了TNBC获得性耐药性的产生。抗血管生成药物对TNBC的治疗效果有限，但这些缺陷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、高度特异的瘦素信号抑制物--瘦素多肽受体拮抗剂-2(LPrA2)。聚乙二醇偶联肽(20 kDa；聚乙二醇wLPrA2)静脉给药后半衰期为68小时，显著抑制TNBC生长。初步数据还显示，聚乙二醇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PEGwLPrA2作为TNBC的辅助治疗，与目前的TNBC治疗方法(如阿霉素+环磷酰胺+紫杉醇)相比，将提高疗效，减少剂量和毒副作用。PEG-wLPrA2将针对瘦素在TNBC中的增殖、促血管生成和BCSC相关的作用。这项研究将在临床相关的(肥胖)TNBC模型中评估这种新的辅助疗法。具体地说，毒性和辅助治疗研究将与阿霉素、环磷酰胺和/或紫杉醇治疗一起在托管人类和小鼠TNBC异种移植和同基因移植的瘦小鼠和肥胖小鼠中进行。从STTR第一阶段提案中产生的实验数据将使一种创新的、有针对性的TNBC辅助疗法能够快速转化。这一新的策略将产生一种有效的治疗方法，通过耗尽BCSC来减少TNBC的化疗耐药、复发和转移，这些都是由瘦素信号维持的。我们建议的研究对TNBC患者至关重要，特别是那些超重或肥胖的患者，这表明瘦素和TNBC的发病率最高。

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.