Early prediction of response to combined modality therapy by functional imaging

描述（由申请人提供）：正在开发分子靶向治疗剂，以选择性抑制驱动不受控制的肿瘤增殖的信号转导途径。然而，越来越清楚的是，只有那些依赖于特定增殖途径的肿瘤才对该途径的抑制敏感。因此，开发用于鉴定具有敏感性或抗性肿瘤的患者的方法，使临床医生能够将个体患者与最有效的治疗剂和方案相匹配，具有重大意义。不幸的是，靶向的信号通路是复杂的，并且在确定反应的分子预测因子方面的进展缓慢。我们假设，短期药物治疗前后的肿瘤增殖功能成像可用于识别对特定治疗方案敏感或耐药的肿瘤。3-脱氧-3-[18 F]-氟胸苷（18 F-FLT）正在开发作为增殖特异性正电子发射断层扫描（PET）放射性示踪剂，我们和其他人已经证明，表皮生长因子受体（EGFR）抑制剂在动物模型中开始治疗后48至72小时内显著抑制F-FLT肿瘤摄取。这些数据表明，FLT PET成像可用于快速识别对EGFR抑制剂治疗有反应的肿瘤。用治疗性抗EGFR抗体西妥昔单抗治疗显著提高了放疗或顺铂的疗效，放疗、顺铂和西妥昔单抗的三联疗法目前正在几项大型随机试验中进行测试。在本申请中，将在多个时间点用PET对参加该组合的前瞻性试验的头颈癌患者进行成像。虽然肿瘤增殖与FLT摄取的相关性比2-脱氧-2-[18 F]-氟-D-葡萄糖（18 F-FDG）摄取更密切，但18 F-FDG PET通常用于头颈癌分期。因此，我们将比较FLT和FDG PET监测治疗反应。在单独使用西妥昔单抗之前和之后需要进行PET成像和肿瘤活检，我们假设西妥昔单抗诱导的增殖和EGFR信号抑制与F-FDG摄取相比，与F-FLT摄取的变化更密切相关。治疗前和治疗后活检将用于研究药物治疗后抑制FLT摄取的分子机制。PET成像也将在放疗中途进行，以测试18 F-FLT（或18 F-FDG）摄取抑制的程度是否可预测最终的局部控制。拟议的研究对PA-05-144、PA-04-045和PA-04-155有直接反应，如果这项研究证明了FLT PET可用于在治疗过程中早期预测反应的概念验证，那么这种方法可以整合到癌症治疗的个体化方法中。分子靶向治疗剂仅在那些依赖于肿瘤生长或维持的特定途径的肿瘤中有效。本申请的重点是测试FLT PET成像是否可用于在开始治疗的几天内识别肿瘤对靶向治疗的反应。如果成功，这种方法将有助于为个别患者选择最有效的治疗方法。

DESCRIPTION (provided by applicant): Molecularly targeted therapeutics are being developed to selectively inhibit signal transduction pathways that drive uncontrolled tumor proliferation. However, it is becoming increasingly clear that only those tumors which are dependent on a specific pathway for proliferation will be sensitive to inhibition of that pathway. Thus, there is significant interest in developing methods for identifying patients with sensitive or resistant tumors that would enable clinicians to match individual patients with the most efficacious therapeutic agents and regimen. Unfortunately, the targeted signaling pathways are complex, and progress in identifying molecular predictors of response has been slow. We hypothesize that functional imaging of tumor proliferation before and after a short course of drug therapy can be used to identify tumors that are sensitive or resistant to a specific treatment regimen. 3-deoxy-3-[18F]-fluorothymidine (18F-FLT) is being developed as a proliferation- specific positron emission tomography (PET) radiotracer, and we and others have demonstrated that inhibitors of the epidermal growth factor receptor (EGFR) markedly suppress F-FLT tumor uptake within 48 to 72 hours of starting treatment in animal models. These data suggest that FLT PET imaging could be used to rapidly identify tumors that are responding to EGFR inhibitor treatment. Treatment with the therapeutic anti-EGFR antibody cetuximab significantly improves the efficacy of radiation or cisplatin, and the triple combination of radiation, cisplatin and cetuximab is now being tested in several large randomized trials. In the current application, head and neck cancer patients enrolled on a prospective trial of this combination will be imaged at multiple time points with PET. Although tumor proliferation correlates more closely with FLT uptake than 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake, 18F-FDG PET is routinely used for head and neck cancer staging. Therefore, we will compare FLT and FDG PET for monitoring treatment response. PET imaging and tumor biopsies are required before and after a run-in of cetuximab alone, and we hypothesize that cetuximab-induced suppression of proliferation and EGFR signaling will correlate more closely with changes in F-FLT uptake as compared to F-FDG uptake. The pre- and post-treatment biopsies will be used to study the molecular mechanisms responsible for suppression of FLT uptake following drug therapy. PET imaging also will be performed half-way through radiotherapy to test whether the extent of 18F-FLT (or 18 F-FDG) uptake suppression is predictive for ultimate local control. The proposed studies are directly responsive to PA-05-144, PA-04-045 and PA-04-155, and if this study demonstrates the proof-of-concept that FLT PET can be used to predict response early during a course of therapy, then this approach could integrate into an individualized approach to cancer therapy. Molecularly targeted therapeutics are efficacious only in those tumors which are dependent on a specific pathway for tumor growth or maintenance. The focus of this application is to test whether FLT PET imaging could be used to identify tumor response to a targeted therapy within days of starting treatment. If successful, this approach would facilitate the selection of the most efficacious therapies for individual patients.