Targeting Tryptophan Metabolism in Rectal Cancer

靶向直肠癌中的色氨酸代谢

• 批准号: 10754178
• 负责人: MATTHEW AARON CIORBA
• 金额: $ 51.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10754178
• 关键词: Address; Adjuvant; Age; Anus; Apoptosis; Biological Markers; Blood; Cancer Center; Cancer Model; Cancer Patient; Cervix Uteri; Chemotherapy and/or radiation; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Colorectal Cancer; DNA Damage; Data; Diagnosis; Disease; Dose; Enzyme Inhibition; Excision; Experimental Models; Failure; Feces; Gender; Goals; Growth; Height; Immune; Immunity; Immunooncology; Immunosuppression; Immunotherapy; In complete remission; Incidence; Infrastructure; Institution; Intestines; Kynurenine; Lead; Local Therapy; Malignant Neoplasms; Mediating; Mediator; Mismatch Repair; Morbidity - disease rate; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; Oncology; Operative Surgical Procedures; Organoids; Outcome; PD-1 inhibitors; PI3K/AKT; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacodynamics; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Positioning Attribute; Pre-Clinical Model; Radiation; Radiation Protection; Radiation therapy; Randomized; Rectal Cancer; Rectum; Regimen; Resistance; Safety; Sampling; Site; Small Intestines; Solid Neoplasm; Statistical Models; Therapeutic; Toxic effect; Treatment Efficacy; Treatment-related toxicity; Tryptophan; Tryptophan 2,3 Dioxygenase; Tryptophan Metabolism Pathway; Tumor Immunity; Tumor Suppressor Proteins; Tumor Tissue; Universities; Washington; Work; arm; beta catenin; biobank; biomarker identification; cancer therapy; chemoradiation; chemotherapy; clinical diagnosis; cohort; efficacy evaluation; experience; genotoxicity; improved; inhibitor; novel; novel therapeutic intervention; novel therapeutics; overexpression; patient population; phase 1 study; phase II trial; phase III trial; precision medicine; predicting response; programmed cell death protein 1; radiation delivery; rectal; repair function; response; standard of care; synergism; therapy resistant; treatment response; treatment strategy; tumor

Project Summary/Abstract: More than 40,000 new rectal cancers occur annually in the US and the majority are locally advanced when diagnosed (LARC). Current total neoadjuvant therapy (TNT) with chemoradiation followed by surgery provides modest outcomes with a 20-25% pathologic complete response (pCR) rate and 5-year disease survival of only 65%. Therefore, there is an unmet need for new treatment approaches that improve LARC clinical outcomes and reduce morbidity. Using LARC patient samples and pre-clinical modeling, we recently identified a rationale for combining short course radiation therapy (SCRT) with inhibitors of the immuno-oncology target IDO1. Indoleamine 2,3 dioxygenase 1 (IDO1) metabolizes tryptophan along the kynurenine pathway and is recognized as a potent suppressor of tumor reactive immunity. Our robust findings identify IDO1 overexpression as a pathologic response in LARC therapy leading to immune-independent treatment resistance and an immunosuppressive TME. We found that: 1) Radiation induces IDO1 overexpression universally across LARC patients and in colorectal cancer (CRC) models regardless of MSI status. 2) IDO1 activity directly promotes critical mediators of CRC growth and treatment resistance (β-catenin and PI3K/AKT; 3) In mice, the potent IDO1 inhibitor epacadostat (EPA) sensitizes CRC to simulated SCRT radiation by relieving immune suppression and augmenting radiation induced CRC apoptosis. We have conducted a Phase I dose escalation study of epacadostat in combination with SCRT/chemotherapy, and identified EPA 400mg BID to be safe and shows preliminary evidence of efficacy. These findings lead us to conclude with following central hypothesis: IDO1 inhibition is a rationally selected adjunctive immunotherapy in CRC that enhances anti-tumor immunity, synergizes with DNA damaging therapy, and protects the normal small intestine. Project goals include: Defining efficacy of EPA/SCRT/chemotherapy as TNT for LARC and a pharmacodynamic basis for EPA in a biospecimen accruing Phase II trial with a randomized biomarker cohort (Aim 1). Defining biomarkers and identifying precision medicine approaches to support the further clinical study of this combination (Aim 2). We will leverage institutional experience and expertise, our established clinical trial infrastructure (NCT03516708), and a standard-of-care cohort, to address this central hypothesis Impact: If successful, we will take this approach to a potentially practice-changing, randomized phase III clinical trial using precision medicine approaches to address the unmet need to improve LARC patient outcomes. As IDO1 is also upregulated in other solid tumors treated by RT (cervix, anal, etc), the approach of combining EPA with genotoxic therapies might be expanded to other solid tumor types.

项目概要/摘要： 在美国，每年发生超过40，000例新发直肠癌，其中大多数是局部晚期， 诊断（LARC）。目前的全新辅助治疗（TNT）与放化疗后手术提供了 结果中等，病理完全缓解（pCR）率为20-25%，5年疾病生存率仅为 百分之六十五因此，对改善LARC临床结局的新治疗方法的需求尚未得到满足 降低发病率。使用LARC患者样本和临床前建模，我们最近确定了一个基本原理， 用于将短程放射治疗（SCRT）与免疫肿瘤学靶点IDO 1的抑制剂组合。 吲哚胺2，3双加氧酶1（IDO 1）沿着犬尿氨酸途径代谢色氨酸，并被识别 作为肿瘤反应性免疫的有效抑制剂。我们强有力的发现将IDO 1过表达鉴定为一种 LARC治疗中的病理反应导致免疫非依赖性治疗抗性， 免疫抑制性TME。我们发现：1）辐射诱导IDO 1在LARC中普遍过表达 患者和结直肠癌（CRC）模型中的MSI状态。2)IDO 1活性直接促进 CRC生长和治疗抗性的关键介质（β-连环蛋白和PI 3 K/AKT）; 3）在小鼠中， 抑制剂epacadostat（EPA）通过缓解免疫抑制使CRC对模拟SCRT辐射敏感， 增强辐射诱导CRC凋亡。我们进行了一项I期剂量递增研究， epacadostat联合SCRT/化疗，并确定EPA 400 mg BID是安全的， 疗效的初步证据。这些发现使我们得出以下中心假设：IDO 1 抑制是CRC中合理选择的连续免疫疗法，其增强抗肿瘤免疫， 与DNA损伤治疗协同作用，保护正常小肠。项目目标包括： 将EPA/SCRT/化疗的有效性定义为LARC的TNT和EPA的药效学基础， 生物样本累积II期试验，随机生物标志物队列（目标1）。定义生物标志物和 确定精确医学方法，以支持该组合的进一步临床研究（目标2）。我们 将利用机构经验和专业知识，我们已建立的临床试验基础设施（NCT 03516708）， 和标准治疗队列，以解决这一中心假设影响：如果成功，我们将采取这一措施， 一项使用精准医学的可能改变实践的随机III期临床试验的方法 解决改善LARC患者结局的未满足需求的方法。由于IDO 1也上调， RT治疗的其他实体瘤（宫颈、肛门等），EPA与遗传毒性治疗相结合的方法 可能会扩展到其他实体瘤类型。