A novel PARP inhibitor PET tracer for breast cancer

一种新型 PARP 抑制剂 PET 示踪剂用于乳腺癌

• 批准号: 10374063
• 负责人: Lilie Leming Lin
• 金额: $ 25.98万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-17 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374063
• 关键词: Aftercare; Autoradiography; BRCA mutations; Binding; Biological Assay; Biological Markers; Biopsy; Breast Cancer Patient; Breast Carcinoma; Cancer Center; Cancer-Predisposing Gene; Cells; Clinical; Clinical Management; Clinical Trials; Companions; Contralateral; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA strand break; Data; Defect; Drug Targeting; Enrollment; Epigenetic Process; Epithelial; Event; Foundations; Genes; Genetic; Germ-Line Mutation; Goals; Human; Image; Imaging technology; Left; Malignant Neoplasms; Mass in breast; Measurement; Measures; Medical Imaging; Metastatic breast cancer; Methods; Molecular; Molecular Target; Monitor; Multicenter Trials; Mus; Muscle; Mutate; Mutation; Neoplasm Metastasis; Oral; Outcome; Ovarian Carcinoma; Patient Care; Patient-Focused Outcomes; Patients; Pectoral; Pharmacodynamics; Phase II Clinical Trials; Phenotype; Pilot Projects; Poly(ADP-ribose) Polymerases; Population; Positron-Emission Tomography; Primary Lesion; Proteins; Reproducibility; Risk; Sampling; Scanning; Selection for Treatments; Signal Transduction; Spatial Distribution; Specificity; Specimen; Standardization; Technology; Testing; Therapeutic; Toxic effect; Tracer; Translations; Treatment-related toxicity; Tumor Tissue; Woman; X-Ray Computed Tomography; advanced breast cancer; brca gene; cancer cell; cancer therapy; clinical imaging; cohort; drug testing; homologous recombination; imaging biomarker; improved; in vivo; inhibitor; malignant breast neoplasm; non-invasive imaging; novel; novel imaging technology; patient derived xenograft model; predict responsiveness; protein expression; radiotracer; real time monitoring; repaired; response; targeted agent; targeted treatment; tool; trait; tumor; tumor heterogeneity; uptake

Project Description: A novel PARP inhibitor PET tracer for breast cancer Breast cancer is the most common cancer in women, and 1 in 8 women will develop invasive breast cancer in her lifetime. Approximately 5-10% of those patients have BRCA mutations (BReast CAncer susceptibility gene). Current therapeutic strategies take advantage of the DNA repair defect in patients with BRCA mutations (BRCAMUT). By selectively targeting cancer cells rather than healthy cells, molecularly targeted agents have the potential to improve cancer outcomes and reduce toxicity compared to standard therapy. Patients who have BRCA mutations are more sensitive to PARPi. Currently, PARPi are approved for patients with metastatic germline BRCA -mutated (BRCAMUT) breast cancer. Patients with other defects in the DNA repair pathway may also benefit. Under current methods, however, which require invasive tumor biopsies, it is difficult to identify which patients may benefit as the biopsies may provide only limited information about a patient’s sensitivity to PARPi, given tumor heterogeneity and under-sampling. Furthermore, not all patients with DNA repair defects in BRCA are responsive to PARPi. Current therapeutic strategies often fail to identify the patients who are most likely to benefit. Through positron emission tomography (PET) of PARP-1 using a novel PET tracer [18F] Fluorthanatrace (FTT) that binds to activated PARP1, we can non-invasively measure PARP1 protein levels in the tumor and direct therapy to patients who are most likely to benefit from PARPi, thereby sparing those who would not benefit the unnecessary toxicities. Additionally, this novel imaging technology is low risk and can be repeated throughout treatment. Patients with locally advanced or metastatic BRCA1/2 mutated breast cancer who are enrolled on a phase II clinical trial at MD Anderson Cancer Center in which they receive PARP inhibitors will be co-enrolled on our companion imaging clinical trial of repeat [18F] FTT PET/CT imaging. [18F] FTT PET/CT will occur pretreatment and soon after PARPi initiation or twice prior to treatment initiation. Our first goal is to validate our technology for measuring PARP1 protein levels in breast cancer patients. The next goal is to demonstrate the reproducibility of our measurements in patients by having a small group undergo two scans prior to treatment. Finally, we will image a larger group of patients before treatment and then soon after treatment initiation to evaluate if PARPi reached the target. Our ultimate goal is to validate this novel imaging technology, as an early, non-invasive method to measure target engagement of PARPi in patients with metastatic germline BRCAMUT breast cancer, and thus predict responsiveness to PARPi. At the completion of this study, we will be able to confirm that this imaging technology measures PARP1 protein expression in patients and demonstrate the value of this novel imaging technology in measuring target engagement in patients receiving PARPi.

项目描述：一种新型PARP抑制剂PET示踪剂用于乳腺癌 乳腺癌是女性最常见的癌症，8个女性中就有1个会发展为浸润性乳腺癌 在她的一生中。大约5-10%的患者有BRCA突变（BRast CAncer易感基因）。 目前的治疗策略利用BRCA突变患者的DNA修复缺陷 （BRCAMUT）。通过选择性地靶向癌细胞而不是健康细胞，分子靶向药物具有 与标准治疗相比，有可能改善癌症结局并降低毒性。的患者 BRCA突变对PARPi更敏感。目前，PARPi被批准用于转移性生殖细胞癌患者， BRCA突变（BRCAMUT）乳腺癌在DNA修复途径中有其他缺陷的患者也可能受益。 然而，根据目前的方法，需要侵入性肿瘤活检，很难确定哪些患者 可能受益，因为活检可能仅提供关于患者对PARPi敏感性的有限信息， 肿瘤异质性和采样不足。此外，并非所有BRCA中DNA修复缺陷的患者都是 响应PARPi。 目前的治疗策略往往无法确定最有可能受益的患者。通过 PARP-1的正电子发射断层扫描（PET），使用新型PET示踪剂[18 F] Fluorthanatrace（FTT）， 激活的PARP 1，我们可以非侵入性地测量肿瘤中的PARP 1蛋白水平，并指导对患者的治疗 最有可能从PARPi中受益的人，从而避免那些不会受益于不必要的人 毒性此外，这种新的成像技术风险低，可以在整个治疗过程中重复。 入组一期研究的局部晚期或转移性BRCA 1/2突变乳腺癌患者 在MD安德森癌症中心进行的II期临床试验中，他们将接受PARP抑制剂， 重复[18 F] FTT PET/CT成像的伴随成像临床试验。[18F]FTT PET/CT将在治疗前进行， PARPi开始后不久或治疗开始前两次。我们的首要目标是验证我们的技术， 测量乳腺癌患者的PARP 1蛋白水平。下一个目标是证明 我们的测量是通过在治疗前让一小组患者接受两次扫描来进行的。最后我们将 在治疗前和治疗开始后不久对更大的患者组进行成像，以评估PARPi是否 达到了目标。我们的最终目标是验证这种新的成像技术，作为一种早期的，非侵入性的 测量转移性生殖系BRCAMUT乳腺癌患者中PARPi的靶向接合的方法，和 从而预测对PARPi的反应性。在这项研究完成后，我们将能够证实，这一成像 这项技术测量了患者的PARP 1蛋白表达，并证明了这种新型成像的价值。 测量接受PARPi的患者的靶点参与的技术。