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

描述（由申请人提供）：三阴性乳腺癌（TNBC）是最具侵袭性的BC亚型，与其非TNBC对应物相比，其转移率、复发率和总生存率均较高。由于缺乏雌激素和孕激素受体，以及Her 2过表达，没有FDA批准的靶向疗法对TNBC有效。因此，这种侵袭性BC亚型通常用全身化疗作为TNBC的护理标准进行治疗。我们先前通过其对EMT、侵袭性和转移表型的抑制将c-Abl确立为TNBC肿瘤发生的新型抑制剂。从机制上讲，这些c-Abl介导的事件通过其p53和p21表达的再激活而发生，从而减轻小鼠中的TNBC肿瘤发展。最近，我已经将c-Abl表达与TNBC对多西他赛的反应联系起来，并确定了古老的中国草药Securinine通过p73和c-Abl依赖性机制介导对休眠和转移性TNBC的抗癌活性。因此，我假设能够激活c-Abl的措施将缓解TNBC发展和转移进展。我的创新和转化研究将通过确定（i）c-Abl的化疗激活是否抑制TNBC致瘤性;（ii）c-Abl预测TNBC对多西他赛的反应的价值;和（iii）一叶秋碱根除TNBC的治疗有效性来解决上述假设。总的来说，我的申请将阐明通过施用别构c-Abl激活剂DPH与一叶秋碱一起根除TNBC的TNBC的主要翻译进展。最后，c-Abl是 将被确立为能够将TNBC患者分层为多西他赛应答者和无应答者的首个预测性生物标志物。

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.