Project 2: Mitigation of radiation toxicity in treatment of sarcoma with FLASH vs. Standard dose rates

项目摘要 放射疗法（RT）用于治疗软组织肉瘤（STS），通常与化疗联合使用。 外科手术切除严重的疾病。对于术前RT，通常使用相当于50戈伊的2戈伊剂量（EQD 2）， 而术后RT需要60-66戈伊（EQD 2）。对于确定的（仅RT治疗）时间表，剂量从75- 需要100戈伊（EQD 2）。随着RT领域的变化，STS正在被越来越多的 低分割时间表，但高剂量和/或高剂量每部分RT的组合，以更大的肿瘤 体积可增加正常组织毒性。事实上，接受RT的STS患者的主要骨和软组织风险 组织问题，包括皮肤毒性、不愈合溃疡、坏死、水肿、骨折和第二次 恶性肿瘤（SMN）。该项目将测试FLASH质子放射治疗（F- 与标准PRT（S-PRT）相比，PRT（S-PRT）使正常软组织和骨免于早期/晚期毒性， 而这两种方式在控制肉瘤生长方面是同等有效的。初步数据显示 F-PRT与S-PRT的皮肤损伤、正常组织炎症、水肿和血管损伤。此外 为了模拟RT的典型副作用，作为需要高剂量RT以实现局部控制的恶性肿瘤， 肉瘤是一个很好的证明，以评估是否F-PRT充分调节RT治疗 在其他癌症的临床上有用的指数。在目标1中，F-PRT消除组织效应的能力， 用RT治疗肉瘤的障碍将使用以下假设在体内小鼠中进行测试 模型：（i）相对于S-PRT，F-PRT的正常组织毒性的炎性成分将减弱， 与S-PRT相比，F-PRT后通过减少 关键驱动因子，如TFG-b和VEGF-C（ii）F-PRT将对组织血管系统产生较少的损伤，并保留 它的相关基质，提供了比S- PRT。在目标2中，我们将评估F-PRT治疗小鼠肉瘤的临床结果。在长期 在全身照射治疗的小鼠的存活者中，我们发现F-PRT治疗组的肿瘤比对照组少。 S-PRT治疗组。在目标2.1中，我们将采用瞬时p53敲低的小鼠模型， 与野生型对照结合，以测试与野生型对照相比，F-PRT降低SMN发生率的能力。 S-PRT。在目标2.2中，我们将在荷肉瘤小鼠中进行剂量递增研究，以确定治疗方案。 当在术前设置中添加一个或三个分数时，F-PRT的窗口。在目标3中，我们将进行 I期剂量递增研究，采用术前（截肢）剂量21-30戈伊（4个剂量水平），一次给药， 确定F-PRT的安全性和耐受性，并提供疗效的病理学证据。对于第二阶段的最终 试验，我们将确定可行性，毒性和疗效的大分割（3部分）F-PRT在床匹配 I期研究告知的最大剂量水平，为未来F-PRT试验的设计提供参数 在STS和其他恶性肿瘤患者中。

Project Summary Radiotherapy (RT) is used in the treatment of soft tissue sarcomas (STS), frequently in conjunction with surgical removal of gross disease. For pre-op RT, 50 Gy equivalent in 2 Gy fractions (EQD2) is commonly used, while post-op RT requires 60–66 Gy (EQD2). For definitive (curative with RT alone) schedules, doses from 75– 100 Gy (EQD2) are needed. Paralleling changes in the RT field, STS are being treated with increasingly hypofractionated schedules, but the combination of high dose and/or high dose per fraction RT to larger tumor volumes can increase normal tissue toxicity. Indeed, patients with STS who receive RT risk major bone and soft tissue problems including skin toxicity, non-healing ulcers, necrosis, lymphedema, bone fractures and second malignant neoplasms (SMNs). This project will test the overall hypothesis that FLASH proton radiotherapy (F- PRT) spares normal soft tissues and bone from early/late toxicities compared with standard PRT (S-PRT), whereas the two modalities will be isoeffective in controlling sarcoma growth. Our preliminary data show reduced skin damage, normal tissue inflammation, lymphedema, and vascular damage with F-PRT vs S-PRT. In addition to modeling typical side effects of RT, as a malignancy that requires high dose RT to achieve local control, sarcoma represents a good proving ground to evaluate whether F-PRT sufficiently modulates RT therapeutic index to be clinically useful in other cancers. In Aim 1, the ability of F-PRT to abrogate tissue effects that pose barriers to the treatment of sarcomas with RT will be tested using the following hypotheses in in vivo mouse models: (i) the inflammatory component of normal tissue toxicity to F-PRT will be attenuated relative to S-PRT, leading to less severe fibrosis and lymphedema after F-PRT compared to S-PRT by reducing the production of pivotal drivers, such as TFG-b and VEGF-C (ii) F-PRT will produce less injury to tissue vasculature and preserve its associated matrix, providing for faster and more complete recovery of skin and bone than is feasible with S- PRT. In Aim 2, we will assess clinical outcome in murine sarcomas treated with F-PRT. Among the long-term survivors of mice treated with whole body irradiation, we find fewer tumors in the F-PRT-treated group than in the group treated with S-PRT. In Aim 2.1, we will employ a mouse model with transient p53 knockdown in conjunction with wildtype controls, to test the ability of F-PRT to reduce the incidence of SMNs compared with S-PRT. In Aim 2.2 we will perform dose escalation studies in mice bearing sarcomas to define the therapeutic window of F-PRT when added in the pre-op setting as either one or three fractions. In Aim 3, we will conduct a phase 1 dose escalation study using pre-op (amputation) doses from 21-30 Gy (4 dose levels) in one fraction to determine safety and tolerability of F-PRT and provide pathologic evidence of efficacy. For a phase 2 definitive trial, we will determine feasibility, toxicity and efficacy of hypofractionated (3 fraction) F-PRT at a BED-matched maximum dose level informed by the Phase I study to provide parameters for the design of future F-PRT trials in humans with STS and other malignancies.