Targeting the cell cycle in triple negative breast cancer

描述（由申请人提供）：缺乏针对三阴性乳腺癌（TNBC）患者的特异性靶点仍然是一个主要挑战，因为许多患者可能在标准治疗失败并在随访的前五年内复发。我们已经发现细胞周期的一个重要调节因子cyclin E在TNBC中过度表达。这种过表达表现为周期蛋白E的低分子量裂解产物，称为LMW-E，在70%的TNBC中存在，而在非三阴性肿瘤中只有20%存在。LMW-E比全长周期蛋白E具有更高的激酶活性，在转基因小鼠模型中具有致癌性，是一种新的治疗靶点。我们的目标是使用lw - e来识别TNBC患者，这些患者可以靶向使用罗斯科维汀（seliciclib）进行治疗，这是一种临床可用的lw - e激酶活性抑制剂。这种疗法与化疗联合使用时效果最好。与正常和非TNBC相比，TNBC细胞系更容易受到罗斯科维汀和化疗的协同细胞毒性影响。最后，我们表明LMW-E的诱导导致基因组不稳定。因此，在TNBC患者中，罗斯科维汀联合化疗利用基因组不稳定性和对DNA损伤途径的影响是有必要的。我们假设LMW-E的表达导致了TN乳腺癌的产生，并且靶向LMW-E将为TN乳腺癌提供新的靶向和有效的治疗策略。以下四个特定目标将验证这一假设：(1)应用整合的基因组-蛋白质组学方法来识别驱动LMW-E阳性乳腺癌侵袭性表型的关键基因和蛋白质，作为分子亚型的功能。(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LMW-E在TNBC中最有效的治疗策略。(3)阐明罗斯科维汀在TNBC中与化疗或PARP抑制协同作用的机制。(4)在转移性TNBC患者中，扩大剂量以确定最大耐受剂量（MTD）、缓解率（RR）和CDK2抑制的生物学效应，在多柔比星脂质体之前给予罗斯科维汀（Seliciclib）。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。

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.