Integrating Low-Cost Paper-Based Devices and Personalized Immunotherapeutics to Treat Triple Negative Breast Cancer

整合低成本纸基设备和个性化免疫疗法来治疗三阴性乳腺癌

基本信息

批准号：
10556823
负责人：
Brian Richard McNaughton
金额：
$ 32.82万
依托单位：
DELAWARE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-20 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556823
关键词：
Affect Affinity African American African American population Antibodies Antineoplastic Agents Appointment Binding Biological Markers Biological Products Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Cell Surface Proteins Cell Surface Receptors Cell surface Cells Childhood Clinic Combination immunotherapy Combined Modality Therapy Complex Delaware Development Devices Diagnostic Equipment Disease Drug Costs Drug usage Effectiveness Epidermal Growth Factor Receptor Escherichia coli Estrogen Receptors Excretory function Generations Goals High Risk Woman Hormone Receptor Human Immune Immune mediated destruction Immune system Immunotherapeutic agent Immunotherapy Incidence Left Localized Disease Low income Malignant Neoplasms Mammalian Cell Mastectomy Measures Methods Minority Groups Monitor Monoclonal Antibodies Mutate Operative Surgical Procedures Outcome Paper Patient Monitoring Patient-Focused Outcomes Patients Phage Display Pharmaceutical Preparations Population Production Progesterone Receptors Proteins Psyche structure Radiation Reporter Research Serum Signal Transduction Source Techniques Technology Tertiary Protein Structure Testing Therapeutic Tissues Trastuzumab Trauma Treatment Efficacy Treatment outcome Vaccination Woman Work aggressive breast cancer antibody-dependent cell cytotoxicity base cancer cell cancer health disparity cancer immunotherapeutics cancer immunotherapy cancer subtypes clinically significant cost design diagnostic platform drug discovery experimental study health equity hormone receptor-positive hormone therapy improved in vivo malignant breast neoplasm member nanobodies new technology novel strategies personalized approach personalized immunotherapy personalized medicine personalized therapeutic precision drugs receptor recruit side effect survival outcome targeted treatment triple-negative invasive breast carcinoma tumor virtual

项目摘要

Integrating Low-Cost Paper-Based Devices and Personalized Immunotherapeutics to Treat Triple Negative Breast Cancer Summary After a breast cancer patient has an initial appointment with her clinician, one possible outcome is that the cancer tests positive for one or more clinically significant cell surface “biomarkers”, most notably estrogen receptor (ER), progesterone receptor (PR), or HER2. In this relatively good scenario, the patient would likely be prescribed a personalized therapy such as a hormone therapy (in the case of ER+ and/or PR+ cancers) or with drugs that specifically target HER2+ cells (e.g. the monoclonal antibody, mAb, Herceptin™). These personalized drugs are less toxic than general anti- cancer drugs such as chemotherapeutic cocktails. In a different, and relatively dire scenario, a patient is told she has “triple negative” breast cancer (ER-, PR-, HER2-), meaning her cancer cells lack hormone receptors like ER or PR, and lack HER2. Triple negative breast cancer (TNBC) represents 15-20% of all breast cancer cases, and disproportionately affects minority populations. Without personalized therapies, this patient is now left to suffer through treatment with non-targeted and toxic drugs (chemotherapeutics) that come with a host of debilitating side effects. Commonly, drastic measures, such as mastectomy, are required in order to fully remove all tissue that could serve as a source of, or substrate for, new tumors. The five-year survival outcomes of populations that test positive for HR and/or HER2, and TNBC patients substantially differs as well. For patients who test positive for HR and/or HER2 with regional breast cancer, five-year survival is ~82-89%, but 65% for TNBC. Clearly, new technologies and approaches are required to target TNBC and provide these patients the same therapeutic opportunities that patients that test positive for HR or HER2 biomarkers have. Here, we propose a fundamentally different approach to personalized medicine, which will dramatically change how we treat TNBC, particularly in lower income minority populations. We will evolve small proteins to selectively bind a patient’s breast cancer cells, irrespective of the specific changes to the cell surface that have occurred as a result of breast cancer. These proteins will be fused to other proteins that provide stability in the body, and recruit antibodies from the patient’s serum to TNBC cells, resulting in their targeted destruction. We will pair our TNBC-targeting immunotherapies (drugs that use the immune system to destroy TNBC cells) with a low-cost paper-based platform, which will allow simple, accessible, and routine assessment of our TNBC-targeting proteins, and allow clinicians to select which members should make up a combination therapy. The diagnostic platform will also allow clinicians to monitor the effectiveness of each member of the cocktail over the course of treatment (as cancer cells mutate), and select alternative members and/or replacements when necessary. Collectively, this work represents necessary and exciting advances in the integration of low-cost approaches to TNBC-targeting, and personalized, drug discovery, and the optimization and monitoring of these immunotherapeutic cocktails over the course of treatment.

集成低成本纸质设备和个性化治疗三阴性乳腺癌的免疫疗法概括乳腺癌患者与临床医生初次预约后，可能的结果是癌症的一项或多项临床检测呈阳性重要的细胞表面“生物标志物”，最显着的是雌激素受体（ER），在这种相对较好的情况下，患者可能会接受黄体酮受体 (PR) 或 HER2 治疗。个性化治疗，例如激素治疗（对于 ER+ 和/或 PR+ 癌症）或药物治疗专门针对 HER2+ 细胞（例如单克隆抗体、mAb、Herceptin™）。与化疗鸡尾酒等一般抗癌药物相比，其毒性较小。在另一种相对可怕的情况下，患者被告知她患有“三阴性”乳腺癌（ER-、PR-、HER2-），这意味着她的癌细胞缺乏 ER 或 PR 等激素受体，并且缺乏三重 HER2。阴性乳腺癌 (TNBC) 占所有乳腺癌病例的 15-20%，且比例过高如果没有个性化治疗，该患者现在将遭受痛苦。使用非靶向和有毒药物（化疗药物）进行治疗，这些药物具有许多使人衰弱的副作用通常，需要采取严厉措施，例如乳房切除术，才能完全去除所有组织。可以作为新肿瘤的来源或基质人群的五年生存结果。 HR 和/或 HER2 检测呈阳性的患者与 TNBC 患者也有很大不同。 HR 和/或 HER2 检测呈阳性的区域性乳腺癌，五年生存率约为 82-89%，但对于区域性乳腺癌，五年生存率为 65% 显然，需要新技术和方法来针对 TNBC 并为这些患者提供服务。与 HR 或 HER2 生物标志物检测呈阳性的患者具有相同的治疗机会。在这里，我们提出了一种根本不同的个性化医疗方法，这将我们将彻底改变我们对待 TNBC 的方式，特别是在低收入少数群体中。进化出小蛋白质来选择性地结合患者的乳腺癌细胞，而不管具体的变化如何这些蛋白质会与其他蛋白质融合。提供体内稳定性的蛋白质，并将抗体从患者血清募集到 TNBC 细胞，我们将结合我们的 TNBC 靶向免疫疗法（使用的药物）。免疫系统破坏 TNBC 细胞）与低成本纸质平台，这将允许简单、对我们的 TNBC 靶向蛋白进行可访问的常规评估，并允许老年人选择哪些成员应该制定联合疗法。诊断平台也将允许在治疗过程中监测鸡尾酒中每个成员的有效性（如癌细胞 mutate），并在必要时选择替代成员和/或替代者。总的来说，这项工作代表了低成本集成方面必要且令人兴奋的进步 TNBC 靶向、个性化药物发现以及优化和监测的方法这些免疫治疗鸡尾酒在治疗过程中。