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原发性肝癌的疾病结局。 （早期）癌症，然而，30%的人尽管接受了治愈性治疗，仍然会复发。复发（转移） 这种病目前是无法治愈的。因此，有效的策略，以防止疾病复发，在这些患者中， 最高风险具有重大临床意义。 运动疗法是一种耐受性良好的策略，也可能在控制MRD方面具有重要的前景。 乳腺癌前列腺癌和结肠直肠癌观察性研究表明，自我报告的运动与 原发性乳腺癌、前列腺癌和结直肠癌复发风险降低20%至60%。此外，委员会认为， 这些观察延伸到具有高风险的患者（例如，3期，淋巴结阳性）疾病。临床前支持 在这些数据中，我们已经证明运动可以显著抑制侵袭性小鼠的原发性肿瘤生长， 乳腺癌、结肠直肠癌和前列腺癌的模型。最后，我们翻译了运动的发展 许多前瞻性试验表明，运动训练是安全的，良好的， 耐受，并表现出显著的药效学（PD）活性，如通过在药物代谢中的有利改变所示。 多种生长因子和激素以及炎症免疫效应物的循环利用率 已知其影响乳腺癌、前列腺癌和结肠直肠癌中的癌细胞增殖和存活。统称 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 对原发性实体瘤患者有益处。 我们将在疾病高危的原发性癌症患者中开展一项1a/1b期运动研究 复发我们将利用循环肿瘤DNA（ctDNA）的分析来：（1）识别那些复发风险高的患者， 和（2）监测对运动的治疗反应。该补助金有两个具体目标：（1）目标1：1a期剂量- 结果和（2）目的2：Ib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.