Project 2: Targeting RTK Co-Dependencies in Triple-Negative Breast Cancer

项目总结 尽管对三阴性乳腺癌的基因组和蛋白质组进行了广泛的研究 (TNBC)，没有显性作用的突变RTK成为TNBC的治疗靶点。相反，TNBCs展示了 RTK信号的广泛性而不是选择性的高激活，以及几个原癌RTK的高活性 在同一个肿瘤里。最近的发现表明，在TNBC中观察到的RTK的配位激活 是蛋白质酪氨酸磷酸酶PTPN12失活的结果。在目前的提案中，我们的目标是将 我们关于RTK如何异常激活并推动TNBC进展为新的治疗方法的新知识 对TNBC患者的治疗方法。 来自我们团队的数据并得到其他人的证实表明，PTPN12通过以下方式发挥肿瘤抑制作用 抑制一组选定的原癌RTK的活性，包括MET和PDGFR，结合它们 受体和抑制下游信号。PTPN12在45%-55%的TNBC中受到损害，我们有 在体外和临床前的TNBC模型中显示，PTPN12的失活会导致MET的过度激活， PDGFR和其他RTK的一小部分。重要的是，这引发了一种治疗假说 PTPN12缺陷的TNBCs可以通过联合靶向RTK来治疗，如MET、PDGFR和潜在的 锁定在长期活动状态的其他RTK。将这些临床前的发现转化为一种新的 治疗方法，我们将评估耐受性良好的MET/PDGFR抑制剂西特拉瓦替尼的疗效 转移性TNBC患者的单一疗法，制定合理的策略将西特拉维替尼与标准的 关注治疗，并探索利用西特拉瓦替尼抗肿瘤和促进免疫的新途径 免疫检查点疗法的背景。 在此，我们的机械性、临床前和临床研究将评估概念验证的使用 西特拉瓦替尼治疗PTPN12缺陷的TNBC，为下一代联合治疗奠定基础 TNBC和其他依赖RTK的癌症的治疗方法。

PROJECT SUMMARY Despite extensive efforts to characterize the genomes and proteomes of triple-negative breast cancer (TNBC), no dominantly-acting mutated RTK has emerged as therapeutic target in TNBC. Instead, TNBCs exhibit broad, rather than selective, hyper-activation of RTK signaling, with several proto-oncogenic RTKs hyper-active in the same tumor. Recent discoveries have revealed that the coordinate activation of RTKs observed in TNBC is a result of inactivation of the protein tyrosine phosphatase PTPN12. In the current proposal, we aim to translate our new knowledge of how RTKs are aberrantly activated and drive TNBC progression into a new therapeutic approach for TNBC patients. Data from our team and confirmed by others indicates that PTPN12 functions as a tumor suppressor by restraining the activity of a select set of proto-oncogenic RTKs, including MET and PDGFR, binding these receptors and suppressing downstream signaling. PTPN12 is compromised in 45-55% of TNBCs, and we have shown in in vitro and pre-clinical models of TNBC that inactivation of PTPN12 leads to hyper-activation of MET, PDGFR, and a small subset of other RTKs. Importantly, this provokes the therapeutic hypothesis that PTPN12-deficient TNBCs can be treated by combined targeting of RTKs like MET, PDGFR, and potentially other RTKs that are locked in the chronically active state. To translate these pre-clinical findings into a new therapeutic approach, we will evaluate the efficacy of the well-tolerated MET/PDGFR inhibitor sitravatinib as monotherapy in metastatic TNBC patients, develop rational strategies to combine sitravitinib with standard of care therapies, and explore new ways to capitalize on the anti-tumoral and pro-immune effects of sitravatinib in the context of immune checkpoint therapies. Herein, our mechanistic, pre-clinical, and clinical studies will evaluate the proof-of-concept for the use of sitravatinib to treat PTPN12-deficient TNBC and lay the groundwork for the next generation of combination approaches for TNBC and other RTK-dependent cancers.