A novel PARP inhibitor PET tracer for breast cancer

项目简介：一种用于乳腺癌的新型PARP抑制剂PET示踪剂 乳腺癌是女性最常见的癌症，每8名女性中就有1名患上浸润性乳腺癌 在她的一生中。大约5%-10%的患者有BRCA突变(乳腺癌易感基因)。 目前的治疗策略利用BRCA突变患者的DNA修复缺陷 (BRCAMUT)。通过选择性地针对癌细胞而不是健康细胞，分子靶向药物具有 与标准疗法相比，有可能改善癌症结果并减少毒性。曾患过 BRCA突变对PARPI更为敏感。目前，PARPI被批准用于转移性生殖系患者 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，在目前需要侵入性肿瘤活检的方法下，很难识别哪些患者 可能会受益，因为活检可能只提供关于患者对PARPI敏感性的有限信息，给出 肿瘤的异质性和采样不足。此外，并不是所有BRCA的DNA修复缺陷患者都是 对PARPI做出回应。 目前的治疗策略往往无法确定最有可能受益的患者。穿过 一种新型的PARP-1正电子发射断层扫描(PET)示踪剂[18F]，结合于 激活PARP1，我们可以无创性地检测肿瘤中PARP1的蛋白水平，并指导患者的治疗 最有可能从PARPI中受益的人，从而使那些不会受益于不必要的人 毒物。此外，这种新的成像技术风险很低，可以在整个治疗过程中重复使用。 局部晚期或转移性BRCA1/2突变乳腺癌患者 在MD Anderson癌症中心接受PARP抑制剂的II临床试验将在我们的 重复[18F]FTT PET/CT显像的伴行显像临床试验[18F]FTT PET/CT将进行前处理和 在PARPI开始后不久或治疗开始前两次。我们的第一个目标是验证我们的技术 检测乳腺癌患者的PARP1蛋白水平。下一个目标是证明 我们通过让一小群人在治疗前进行两次扫描来测量患者。最后，我们会 在治疗前和治疗开始后不久对更多的患者进行成像，以评估PARPI 达到了目标。我们的最终目标是验证这种新的成像技术是一种早期的、非侵入性的 方法检测转移性种系BRCAMUT乳腺癌患者PARPI的靶向接合 从而预测对PARPI的反应性。在这项研究完成后，我们将能够确认这种成像 技术测量患者中PARP1蛋白的表达并展示这一新成像的价值 在接受PARPI治疗的患者中测量目标投入的技术。

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.