Exercise as Interception Therapy in Primary High Risk Cancer

摘要 筛查和辅助治疗的进展显著改善了初发患者的疾病结局 (早期)癌症，然而，尽管进行了根治治疗，仍有30%的人复发。复发(转移) 疾病目前是不治之症。因此，有效的策略，以防止这些患者的疾病复发 风险最高的是具有重大临床重要性的患者。 运动疗法是一种耐受性良好的策略，也可能在控制MRD方面具有重大前景 乳腺癌、前列腺癌和结直肠癌。观察性研究表明，自我报告的锻炼与 原发乳腺癌、前列腺癌和结直肠癌复发风险降低20%至60%。此外， 这些观察结果也适用于高危(如3期，结节阳性)疾病的患者。在临床前支持中 在这些数据中，我们已经证明运动显著抑制了侵袭性小鼠的原发肿瘤生长。 乳腺癌、结直肠癌和前列腺癌的模型。最后，我们对运动的发展进行了翻译 对临床的干预措施通过大量前瞻性试验证明运动训练是安全的， 耐受性，并表现出显著的药效学(PD)活性，如在 多种生长因子、激素以及炎症免疫效应物的循环有效性 已知会影响乳腺癌、前列腺癌和结直肠癌的癌细胞增殖和存活率。总体而言， 令人鼓舞的数据有力地支持了进一步的临床研究，即运动是否具有辅助治疗作用 对患有原发实体肿瘤的患者有利。 我们将在高危癌症患者中进行1a/1b期运动研究。 旧病复发。我们将利用循环肿瘤DNA(CtDNA)的分析来：(1)识别那些复发的高危人群， (2)监测运动的治疗反应。这笔赠款有两个具体目标：(1)目标1：1a期剂量-- 发现和(2)目标2：1b期剂量扩展。

ABSTRACT Advances in screening and adjuvant therapy have significantly improved disease outcomes in primary (early-stage) cancer, however 30% still experience relapse despite curative treatment. Recurrent (metastatic) disease is currently incurable. Thus, effective strategies to prevent disease recurrence in those patients at highest risk are of major clinical importance. Exercise therapy is a well-tolerated strategy that may also hold significant promise to control MRD in breast, prostate, and colorectal cancer. Observational studies show that self-reported exercise is associated with 20% to 60% reductions in the risk of relapse in primary breast, prostate, and colorectal cancer. Moreover, these observations extend to patients with high-risk (e.g., stage 3, node positive) disease. In preclinical support of these data, we have demonstrated exercise significantly inhibits primary tumor growth in aggressive mouse models of breast, colorectal, and prostate cancer. Finally, we have translated the development of exercise interventions to the clinic with numerous prospective trials demonstrating exercise training is safe, well- tolerated, and exhibits significant pharmacodynamic (PD) activity as illustrated by favorable alterations in the circulating availability of multiple growth factors and hormones as well as inflammatory-immune effectors known to affect cancer cell proliferation and survival in breast, prostate, and colorectal cancer. Collectively, the encouraging data strongly support further clinical investigation of whether exercise has adjuvant therapy benefit in patients with primary solid tumors. We will conduct a phase 1a/1b study of exercise in primary cancer patients at high-risk of disease relapse. We will leverage analysis of circulating tumor DNA (ctDNA) to: (1) identify those at high-risk of relapse, and (2) monitor therapeutic response to exercise. This grant has two specific aims: (1) Aim 1: Phase 1a Dose- Finding and (2) Aim 2: Phase 1b Dose Expansion.