Novel c-Abl-directed Therapies to Alleviate Metastatic Breast Cancer

描述(申请人提供)：三阴性乳腺癌(TNBC)是最具侵袭性的BC亚型，与非TNBC患者相比，其转移率、复发率和总体生存率较低。由于缺乏雌激素和孕激素受体，以及Her2过度表达，FDA没有批准对TNBCs有效的靶向治疗。因此，这种侵袭性的BC亚型通常采用全身化疗作为TNBCs的标准护理。我们先前通过抑制EMT、侵袭性和转移性表型，将c-Abl确定为一种新的TNBC肿瘤发生抑制因子。从机制上讲，这些c-Abl介导的事件通过其对p53和p21表达的重新激活而发生，从而减轻了小鼠TNBC肿瘤的发展。最近，我将c-Abl的表达与TNBCs对多西紫杉醇的反应联系起来，并发现古老的中草药一叶皂苷通过p73和c-Abl依赖的机制介导对潜伏期和转移性TNBCs的抗癌活性。因此，我假设能够激活c-Abl的措施将减缓TNBC的发展和转移进展。我的创新性和转化性研究将通过确定(I)c-Abl的化疗激活是否抑制TNBC的致瘤性；(Ii)c-Abl对预测TNBC对多西紫杉醇的反应的价值；以及(Iii)一叶绿碱根除TNBCs的疗效来解决上述假设。总而言之，我的申请将阐明通过给药变构c-Abl激活剂DPH和一叶菜碱来根除TNBCs的主要翻译进展。最后，c-Abl是 将被确立为第一个预测生物标记物，能够将TNBC患者分为多西他赛有效组和无效组。

DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) is the most aggressive BC subtype and exhibits enhanced rates of metastasis, recurrence, and poor overall survival as compared to their non-TNBC counterparts. Due to the lack of estrogen and progesterone receptors, as well as that of Her2 overexpression, no FDA approved targeted therapies that are effective against TNBCs. As such, this aggressive BC subtype is typically treated with systemic chemotherapies as the standard of care for TNBCs. We previously established c-Abl as a novel suppressor of TNBC tumorigenesis through its inhibition of EMT, invasive, and metastatic phenotypes. Mechanistically, these c-Abl-mediated events transpired through its reactivation of p53 and p21 expression, thereby alleviating TNBC tumor development in mice. Recently, I have associated c-Abl expression with the response of TNBCs to docetaxel, as well as identified the ancient Chinese herb Securinine to mediate anticancer activities against dormant and metastatic TNBCs via a p73- and c-Abl-dependent mechanism. Therefore, I hypothesize that measures capable of activating c-Abl will alleviate TNBC development and metastatic progression. My innovative and translational studies will address the aforementioned hypothesis by determining (i) whether chemotherapeutic activation of c-Abl inhibits TNBC tumorigenicity; (ii) the value of c-Abl to predict for TNBC response to docetaxel; and (iii) the therapeutic effectiveness of Securinine to eradicate TNBCs. Collectively, my application will elucidate major translational advancements for TNBCs through administration of the allosteric c-Abl activator, DPH, together with Securinine to eradicate TNBCs. Finally, c-Abl is will be established as the first predictive biomarker capable of stratifying TNBC patients into docetaxel responders and nonresponders.