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

项目 2：针对三阴性乳腺癌的 RTK 相互依赖性

• 批准号: 10219970
• 负责人: Thomas Westbrook
• 金额: $ 33.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219970
• 关键词: Adjuvant Therapy; Animal Model; Breast Cancer Patient; Cancer and Leukemia Group B; Cell Compartmentation; Chronic; Clinical Data; Clinical Research; Data; Dependence; Disease; ERBB2 gene; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Equilibrium; Evaluation; Exhibits; Family; Feedback; Genome; Genomics; Goals; Human; Hyperactivity; Hypersensitivity; Immune; Immune checkpoint inhibitor; Immune system; Immunocompetent; In Vitro; Knowledge; Malignant Neoplasms; Mitotic; Modeling; Molecular; Mutate; Mutation; Normal tissue morphology; Oncogenic; PDGFRB gene; PTPN12 gene; Paclitaxel; Pathogenesis; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Platelet-Derived Growth Factor alpha Receptor; Play; Pre-Clinical Model; Protein Tyrosine Phosphatase; Proteins; Proteome; Proxy; Reagent; Receptor Activation; Receptor Protein-Tyrosine Kinases; Resistance; Role; Signal Transduction; Therapeutic; Tissue Microarray; Translating; Translational Research; Tumor Suppressor Proteins; Tumor Tissue; Tyrosine; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Work; anti-tumor immune response; base; breast cancer progression; checkpoint therapy; chemotherapy; combat; efficacy evaluation; inhibitor; innovation; inorganic phosphate; insight; kinase inhibitor; malignant breast neoplasm; member; neoplastic cell; next generation; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; phase II trial; pre-clinical; preclinical study; preclinical trial; predictive marker; randomized trial; receptor binding; receptor function; response; standard of care; taxane; therapeutic target; triple-negative invasive breast carcinoma; tumor

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.

项目摘要 尽管广泛的努力来表征三阴性乳腺癌的基因组和蛋白质组， 在TNBC中，没有显性作用的突变RTK成为TNBC中的治疗靶标。相反， 广泛的，而不是选择性的，过度激活的RTK信号，与几个原癌基因的RTK过度活跃 在同一个肿瘤中。最近的发现表明，在TNBC中观察到的RTK的协调激活 是蛋白酪氨酸磷酸酶PTPN 12失活的结果。在目前的提案中，我们的目标是将 我们对RTK如何被异常激活并推动TNBC进展为一种新的治疗方法的新知识 TNBC患者的治疗方法。 我们团队的数据并得到其他人的证实表明PTPN 12具有肿瘤抑制因子的功能， 抑制一组选择的原癌基因RTK的活性，包括MET和PDGFR β，结合这些 受体和抑制下游信号传导。PTPN 12在45-55%的TNBC中受损，并且我们发现， 在TNBC的体外和临床前模型中显示，PTPN 12的失活导致MET的超活化， PDGFR RTK和其他RTK的一小部分。重要的是，这引发了治疗假设， PTPN 12缺陷型TNBC可以通过联合靶向RTK如MET、PDGFR和潜在的靶向TNBC来治疗。 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 在治疗方法中，我们将评估耐受性良好的MET/PDGFR抑制剂西曲替尼的疗效， 单药治疗转移性TNBC患者，制定合理的策略，将联合收割机sitravitinib与标准 护理疗法，并探索新的方法来利用西曲替尼的抗肿瘤和促免疫作用， 免疫检查点疗法的背景。 在此，我们的机制，临床前和临床研究将评估使用的概念验证 西曲替尼治疗PTPN 12缺陷型TNBC，并为下一代联合治疗奠定基础 用于TNBC和其他RTK依赖性癌症的方法。