eRapa for bladder cancer prevention

eRapa 用于预防膀胱癌

• 批准号: 10206080
• 负责人: Robert Scott Svatek
• 金额: $ 45.71万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206080
• 关键词: Address; Adverse effects; Affect; Age; Antigens; Attention; Autologous; BCG Live; Biopsy; Bladder; Bladder Neoplasm; Bladder Tissue; Cancer Patient; Cells; Cessation of life; Cognition; Data; Development; Diagnosis; Dose; Double-Blind Method; Elderly; Encapsulated; Event; Excision; Exhibits; Formulation; Foundations; Genomic Instability; Growth Factor; Human; Human Resources; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Surveillance; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Mediating; Medical; Memory; Monitor; Newly Diagnosed; Nutrient; Organ Transplantation; Organism; Outcome; Outcome Measure; Pathologic; Patient Outcomes Assessments; Patients; Phase; Phase II Clinical Trials; Physical Function; Physical Performance; Placebos; Plant Roots; Population; Pre-Clinical Model; Prevention; Procedures; Production; Property; Public Health; Publishing; Quality of life; Questionnaires; Randomized; Randomized Controlled Trials; Recurrence; Recurrent disease; Relapse; Reporting; Risk; Safety; Secondary Cancer Prevention; Secondary Prevention; Sirolimus; Symptoms; T cell differentiation; T memory cell; T-Lymphocyte; Testing; Training; Transitional Epithelium; Tumor Immunity; Tumor-Derived; Work; age related; antitumor effect; base; bladder cancer prevention; cancer immunotherapy; cancer prevention; cancer risk; chemotherapeutic agent; cognitive function; cost estimate; cytokine; detrusor muscle; early phase clinical trial; exhaust; exhaustion; high risk; immune function; improved; insight; instrument; intravesical; mTOR Inhibitor; mTOR inhibition; men; neoplastic cell; non-muscle invasive bladder cancer; novel; novel strategies; older patient; performance tests; pharmacokinetics and pharmacodynamics; phenotypic biomarker; prevent; primary outcome; relapse patients; response; standard care; standard of care; tumor

Urinary bladder tumors arise from the transitional epithelium and rarely penetrate the bladder’s detrusor muscle. Thus, complete tumor resection is frequently possible using a transurethral instrument to remove the tumor at its root without total bladder removal. Unfortunately, genomic instability is rampant throughout the transitional epithelium in most patients and tumor relapse is common despite complete tumor removal. As a result, patients require lifelong endoscopic monitoring, multiple biopsies, and repeated intravesical therapies. mTOR inhibition treats and prevents bladder cancer (BC) in preclinical models and is thought to work by directly targeting bladder tumors. While this dogma is true, it provides an incomplete picture of the potential activity of this therapy in BC. Our preliminary data shows favorable pharmacokinetic and pharmacodynamic activity of low dose rapamycin in bladder tissues. We also show that a novel encapsulated formulation of rapamycin (eRapa) modulates immune responses and these effects favor improved anti-BC immunity and improved responses towards BCG, which is standard-of-care immune therapy for high-grade non-muscle invasive bladder cancer (BC). We propose investigating eRapa for secondary cancer prevention in patients with newly diagnosed non-muscle invasive bladder cancer. Aim 1 conducts a phase II double-blind randomized controlled trial of long-term (one year) prevention with eRapa versus placebo. Outcome measures include efficacy, tolerability, and effects on cognition and physical function. Efficacy is assessed through standard-of-care surveillance monitoring to capture relapses and to estimate recurrence-free survival. Tolerability is measured with validated BC-specific symptom assessments and global quality of life questionnaires. Cognition and physical function are assessed with validated executive/memory function testing and by physical performance testing. Aim 2 test the hypothesis that eRapa improves immune function in patients with BC by examining the effects of eRapa on circulating immune cells, including memory T cell differentiation, and tumor-specific immunity. For patients concurrently receiving intravesical BCG, the ability of eRapa to boost BCG-specific immunity is tested. If successful, this project will facilitate a phase III registration trial for a new secondary prevention agent for BC patients. In addition, this work provides foundational insights into immune events in elderly BC patients that are useful to developing other cancer immunotherapies.

膀胱肿瘤起源于移行上皮，很少穿透膀胱逼尿肌。