Targeting the cell cycle in triple negative breast cancer

描述(申请人提供)：缺乏针对三阴性乳腺癌(TNBC)患者的特定目标仍然是一个重大挑战，因为许多患者可能无法通过标准治疗，并在随访的头五年内复发。我们已经发现，细胞周期的一个重要调节因子--细胞周期蛋白E在TNBC中高表达。这种过度表达是以周期蛋白E的低分子量裂解产物的形式出现的，称为LMW-E，在所有TNBC中存在70%，而在非三重阴性肿瘤中只有20%。LMW-E具有比全长细胞周期蛋白E更高的激酶活性，在转基因小鼠模型中具有致癌作用，是一个新的治疗靶点。我们的目标是使用LMW-E来识别TNBC患者，这些患者可以靶向使用临床上可用的LMW-E激酶活性抑制剂Roscovitine(Seliclib)进行治疗。这种疗法在与化疗结合使用时最有效。与正常和非TNBC相比，TNBC细胞系对罗可维汀和化疗的协同细胞毒作用更敏感。最后，我们证明了LMW-E的诱导导致了基因组的不稳定性。因此，在TNBC患者中，有必要联合使用罗可维汀和化疗，以利用基因组的不稳定性和对DNA损伤途径的影响。我们假设LMW-E的表达导致TN乳腺癌的发生，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验证这一假设：(1)应用基因组-蛋白质组学综合方法来确定驱动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)利用体外和体内异种移植和转基因小鼠模型系统，设计针对TNBC中LMW-E的最有效的治疗策略。(3)阐明罗可维汀与化疗或抑制PARP对TNBC的协同作用机制。(4)剂量扩展的I期试验，以确定转移性TNBC患者在脂质体阿霉素之前给予罗可维汀(Seliclib)抑制CDK2的最大耐受量(MTD)、应答率(RR)和生物效应。总体而言，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，这种治疗方法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)患者的具体目标仍然是医生和患者面临的主要挑战。我们已经为TNBC确定了一种新的、可用药的靶点，不仅可以用来识别那些对靶向治疗有反应的人，而且还可以为这类患者提供新的治疗策略，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.