Therapeutic synergism of PARP and dipeptidyl pepti-dase-4 inhibition in triple-negative breast cancer

PARP 和二肽基肽酶 4 抑制在三阴性乳腺癌中的协同治疗作用

• 批准号: 437439250
• 负责人: Privatdozent Dr. Holger Bronger
• 金额: --
• 依托单位: Klinik und Poliklinik für Frauenheilkunde
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/437439250?language=en
• 关键词: Therapeutic; synergism; PARP; dipeptidyl; pepti

Triple-negative breast cancer has the worst prognosis of all breast cancer subtypes, and classic chemotherapies remained the only systemic therapy option until now. Most recently, inhibitors of the poly(ADP-ribose) polymerase 1 (PARPi) have been approved for patients with metastatic breast cancer and a mutation in one of the DNA repair genes BRCA1 or BRCA2. However, many patients do not respond to PARPi therapy which raises the question of underlying resistance mechanisms and predictive biomarkers.During the past months several research groups have independently shown that PARPi induce certain chemokines (CXCL9, CXCL10, CCL5) in tumor cells. These chemokines chemotactically attract tumor-suppressive lymphocytes to the tumor microenvironment, thereby inducing an immune reaction against the tumor. In preclinical models the success of a PARPi therapy was even dependent on this immune activation, and this mechanism of action might explain the PARPi effects especially in BRCA wild-type tumors. The chemokines induced by PARPi are exactly the same known to be cleaved and inactivated by the protease dipeptidyl peptidase-4 (DPP4). Our preliminary results show that about 70% of all TNBC express DPP4 and that this expression is associated with a significantly reduced progression-free and overall survival. We therefore postulate that a DPP4 overexpression impairs PARPi effect by proteolytic chemokine inactivation. As DPP4 inhibitors (e.g. sitagliptin) are generically available and clinically well characterized, this approach of breaking PARPi resistance would be easy to implement into future clinical trials.To test this hypothesis we will examine which chemokines are secreted from TNBC cells upon PARPi stimulation and which of them are responsible for lymphocytic chemotaxis. In syngeneic mouse models of TNBC we will then study to what extend the success of a PARPi therapy depends on this chemokine release and if there is a difference between BRCA mutated and non-mutated tumors in this regard. Next, we want to clarify what impact DPP4 overexpression or DPP4 inhibition has on PARPi reponse. Finally, in an exploratory clinical study we will examine if this chemokine induction is also seen in the blood of TNBC patients under PARPi therapy and if it predicts therapy response.The results are intended to define DPP4 overexpression as a new resistance mechanism against PARPi and to improve PARPi therapy by synergistically inhibiting DPP4.

三阴性乳腺癌是所有乳腺癌亚型中预后最差的，到目前为止，经典化疗仍然是唯一的全身治疗选择。最近，聚（ADP-核糖）聚合酶1（PARPi）的抑制剂已被批准用于患有转移性乳腺癌和DNA修复基因BRCA 1或BRCA 2之一突变的患者。然而，许多患者对PARPi治疗没有反应，这引发了潜在的耐药机制和预测生物标志物的问题。在过去的几个月里，几个研究小组独立地表明PARPi在肿瘤细胞中诱导某些趋化因子（CXCL 9，CXCL 10，CCL 5）。这些趋化因子趋化性地吸引肿瘤抑制性淋巴细胞至肿瘤微环境，从而诱导针对肿瘤的免疫反应。在临床前模型中，PARPi治疗的成功甚至依赖于这种免疫激活，这种作用机制可能解释PARPi的作用，特别是在BRCA野生型肿瘤中。由PARPi诱导的趋化因子与已知被蛋白酶二肽基肽酶-4（DPP 4）切割和失活的趋化因子完全相同。我们的初步结果表明，约70%的TNBC表达DPP 4，并且这种表达与无进展生存期和总生存期显著降低相关。因此，我们推测，DPP 4过表达通过蛋白水解趋化因子失活损害PARPi效应。由于DPP 4抑制剂（例如西他列汀）是一般可用的并且临床上充分表征的，因此这种打破PARPi抗性的方法将容易实施到未来的临床试验中。为了检验这一假设，我们将检查哪些趋化因子在PARPi刺激后从TNBC细胞分泌，以及哪些趋化因子负责淋巴细胞趋化性。在TNBC的同基因小鼠模型中，我们将研究PARPi疗法的成功在多大程度上取决于这种趋化因子释放，以及BRCA突变和非突变肿瘤在这方面是否存在差异。接下来，我们想阐明DPP 4过表达或DPP 4抑制对PARPi反应的影响。最后，在一项探索性临床研究中，我们将检查在PARPi治疗下的TNBC患者的血液中是否也观察到这种趋化因子诱导，以及它是否预测治疗反应。结果旨在将DPP 4过表达定义为针对PARPi的新耐药机制，并通过协同抑制DPP 4来改善PARPi治疗。