A novel multi-targeted therapy for breast cancer resistance

 描述（由申请人提供）：在过去十年中，乳腺肿瘤学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，包括人表皮生长因子受体（HER 1和HER 2）和用于乳腺癌受体阳性疾病的药物。然而，尽管有这样令人鼓舞的结果，最初对这些药物有反应的患者最终在治疗一年内变得耐药。已经提出了导致抗性的多种机制，包括与替代受体酪氨酸激酶（即HER 1 -4、IGF-1 R）的补偿性串扰、下游MAPK-PI 3 K/Akt/mTOR信号传导的超活化、凋亡蛋白抑制剂（IAP）的活化以及PTEN和p53的失活。 我们已经确定可溶性E-钙粘蛋白（sEcad）作为一种新的治疗靶点，并开发了靶向sEcad的单克隆抗体作为一种创新疗法，直接杀死癌细胞，保留正常细胞并克服这些宿主抗性途径。因此，在本授权申请中，我们提出首先缩小HER或非HER受体（或组合）参与我们的基于抗体的疗法的功效。然后，我们将测试涉及HER或非HER抑制剂的组合策略，其通过与我们的抗体不同的作用机制起作用，是否可以相加或协同作用以抑制肿瘤生长并剖析所涉及的一些机制。最后，我们建议用一组PD标志物补充我们的抗体，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无脱靶效应。总而言之，我们相信我们的创新疗法将在HER和非HER阳性乳腺癌患者的治愈率和无进展生存率方面取得实质性进展，这些进展超过了靶向或其他常规疗法。

 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.