A novel multi-targeted therapy for breast cancer resistance

 描述(申请人提供)：在过去的十年中，乳腺肿瘤学中最重要的革命性进展是FDA批准了针对生长因子受体的靶向治疗，包括人类表皮生长因子受体(HER1和HER2)和激素受体阳性疾病的药物。然而，尽管取得了如此令人鼓舞的结果，最初对这些药物有反应的患者最终在治疗一年内就产生了抗药性。目前已提出多种耐药机制，包括与交替受体酪氨酸激酶(即HER1-4、IGF-1R)的代偿性串扰、下游MAPK-PI3K/Akt/mTor信号的过度激活、凋亡蛋白抑制物(IAPs)的激活以及PTEN和P53的失活。我们已将可溶性E-钙粘蛋白(SECAD)确定为一种新的治疗靶点，并已开发出针对sECAD的单抗，作为一种直接杀死癌细胞、保留正常细胞并克服这些宿主耐药途径的创新疗法。因此，在这项拨款申请中，我们建议首先缩小她或非她的受体(或组合)与我们基于抗体的治疗效果有关的范围。然后，我们将测试涉及Her或非Her抑制剂的组合策略，这些策略通过与我们的抗体不同的作用机制(S)发挥作用，是否可以相加或协同作用来抑制肿瘤生长，并剖析其中的一些机制(S)。最后，我们建议用一组PD标志物来补充我们的抗体，以确保抗体发挥其预期的生物学结果，并进行初步研究，以确认没有脱靶效应。总之，我们相信，我们的创新疗法将在治愈率和非HER阳性乳腺癌患者的无进展生存率方面取得实质性进展，这些患者的进步超过了靶向或其他传统疗法。

 DESCRIPTION (provided by applicant): Over the last decade, the most significant revolutionary advances in breast oncology have been the FDA approval of targeted therapies against growth factor receptors, including the human epidermal growth factor receptors (HER1 and HER2) and drugs for hormone-receptor-positive disease. However, despite such encouraging results, patients that are initially responsive to these drugs eventually become resistant within one year of therapy. Multiple mechanisms responsible for resistance have been proposed, including compensatory crosstalk with alternate receptor tyrosine kinases (i.e. HER1-4, IGF-1R), hyper-activation of downstream MAPK-PI3K/Akt/mTOR signaling, activation of the inhibitor of apoptotic proteins (IAPs) and inactivation of PTEN and p53. We have identified soluble E-cadherin (sEcad) as a novel therapeutic target and have developed monoclonal antibodies targeting sEcad as an innovative therapy that directly kills cancer cells, spares normal cells and overcomes these host resistance pathways. Therefore, in this grant application we propose to first narrow down which HER or non-HER receptors (or combinations) are involved in the efficacy of our antibody- based therapy. We then will test whether combinatorial strategies involving HER or non-HER inhibitors, that act via different mechanism(s) of action than our antibody, may act additively or synergistically to suppress tumor growth and dissect some of the mechanism(s) involved. Lastly, we propose to complement our antibody with a panel of PD markers so as to ensure that the antibody is exerting its intended biologic outcome and perform preliminary studies to confirm no off-target effects. Altogether, we believe that our innovative therapy will make substantial strides in cure rates and in progression-free survival of patients with HER and non-HER-positive breast cancers that progress beyond targeted or other conventional therapies.