Targeting the cell cycle in triple negative breast cancer

描述（由申请人提供）：三阴性乳腺癌（TNBC）患者缺乏特异性靶点仍然是一个主要挑战，因为许多患者可能无法通过标准治疗，并在随访的前五年内复发。我们已经确定，细胞周期的重要调节因子，细胞周期蛋白E，在TNBC中过表达。这种过度表达以细胞周期蛋白E的低分子量切割产物的形式出现，称为LMW-E，并且存在于70%的所有TNBC中，而非三阴性肿瘤仅为20%。LMW-E具有比全长细胞周期蛋白E增加的激酶活性，在转基因小鼠模型中是致癌的，并且是治疗的新靶点。我们的目标是使用LMW-E来识别TNBC患者，这些患者可以使用Roscovitine（seliciclib）进行靶向治疗，Roscovitine是一种临床可用的LMW-E激酶活性抑制剂。这种疗法在与化疗联合使用时最有效。与正常和非TNBC相比，TNBC细胞系对Roscovitine和化疗的协同细胞毒性更敏感。最后，我们表明，LMW-E的诱导导致基因组的不稳定性。因此，在TNBC患者中，需要Roscovitine与化疗的组合方法来利用基因组不稳定性和对DNA损伤途径的影响。我们假设LMW-E表达导致TN乳腺癌的产生，靶向LMW-E将为TN乳腺癌提供新的靶向和有效的治疗策略。以下四个具体目标将检验这一假设：（1）应用整合的基因组-蛋白质组学方法来鉴定驱动LMW-E阳性乳腺癌侵袭性表型的关键基因和蛋白质，作为分子亚型的函数。(2)使用体外和体内异种移植物和转基因小鼠模型系统来设计靶向TNBC中LMW-E的最有效治疗策略。(3)阐明Roscovitine与化疗或PARP抑制剂在TNBC中的协同作用机制。(4)在转移性TNBC患者中进行剂量扩展的I期试验，以确定在脂质体多柔比星之前给予roscovitine（Seliciclib）抑制CDK 2的最大耐受剂量（MTD）、缓解率（RR）和生物效应。总的来说，这笔赠款的成功完成将是向三阴性乳腺癌患者提供个性化治疗方法的一步，这有可能根除他们的疾病。 公共卫生相关性：缺乏针对三阴性乳腺癌（TNBC）患者的特异性靶标仍然是医生和患者的主要挑战。我们已经确定了一种新的、可药用的TNBC靶点，不仅可用于确定那些对靶向治疗有反应的患者，而且还为这组患者提供了新的治疗策略，并有可能根除他们的疾病。

DESCRIPTION (provided by applicant): The lack of specific targets for triple negative breast cancer (TNBC) patients remains a major challenge as many are likely to fail standard therapy and develop recurrence within the first five years of follow-up. We have identified that an important regulator of the cell cycle, cyclin E, is over expressed in TNBC. This over expression is seen in the form of low molecular weight cleavage products of cyclin E, termed LMW-E, and is present in 70% of all TNBC compared with only 20% of non-triple negative tumors. The LMW-E have increased kinase activity over full-length cyclin E, are oncogenic in a transgenic mouse model and are a novel target for therapy. It is our goal to use LMW-E to identify TNBC patients, which can be targeted for therapy using Roscovitine (seliciclib), a clinically available inhibitor of LMW-E kinase activity. This therapy is most effective when delivered in combination with chemotherapy. TNBC cell lines are more susceptible to synergistic cytotoxicity with Roscovitine and chemotherapy as compared to normal and non-TNBC. Lastly, we show that induction of LMW-E results in genomic instability. As such, a combinatorial approach of Roscovitine with chemotherapy to exploit the genomic instability and impact on DNA damage pathways is warranted in TNBC patients. We hypothesize that LMW-E expression leads to generation of TN breast cancer and that targeting the LMW-E will provide novel targeted and effective therapeutic strategies for TN breast cancer. The following four Specific Aims will test this hypothesis: (1) Apply an integrated genomic-proteomic approach to identify key genes and proteins that drive the aggressive phenotype of LMW-E positive breast cancer as a function of molecular subtypes. (2) Use of in vitro and in vivo xenograft and transgenic mouse model systems to design most effective treatment strategies targeting LMW-E in TNBC. (3) Elucidate the mechanism of synergism between Roscovitine and chemotherapy or PARP inhibition in TNBC. (4) Phase I trial with dose expansion to determine maximum tolerated dose (MTD), response rate (RR) and biologic effects of CDK2 inhibition with roscovitine (Seliciclib) given prior to liposomal doxorubicin in patients with metastatic TNBC. Collectively, the successful completion of this grant will be a step toward providing patients with triple negative breast cancer a personalized approach to therapy, which has the potential of eradicating their disease. PUBLIC HEALTH RELEVANCE: The lack of specific targets for the triple negative breast cancer (TNBC) patients remains a major challenge for physicians and patients. We have identified a novel, druggable target for TNBC that can be used not only to identify those that would respond to targeted therapy, but also provide novel treatment strategy for this group of patients and has the potential of eradicating their disease.