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.

集成低成本的基于纸张的设备和个性化免疫治疗治疗三重阴性乳腺癌概括乳腺癌患者在她的临床上进行初次约会后，可能的结果是癌症在一个或多个临床上的测试呈阳性明显的细胞表面“生物标志物”，最著名的是雌激素受体（ER），孕酮受体（PR）或HER2。在这种相对较好的情况下，可能会开处方一种个性化疗法，例如Horsene Therapy（对于ER+和/或PR+癌症）或药物该专门针对HER2+细胞（例如单克隆抗体，mAb，Herceptin™）。这些个性化与普通抗癌药物（例如化学治疗鸡尾酒）相比，药物的毒性较小。在不同的，相对严峻的情况下，有人告诉患者她患有“三重阴性”乳腺癌（er-，pr-，her2-），这意味着她的癌细胞缺乏像ER或PR这样的马酮受体，并且缺乏HER2。三倍阴性乳腺癌（TNBC）占所有乳腺癌病例的15-20％，并且不成比例影响少数民族。没有个性化疗法，该患者现在将遭受痛苦用非靶向和有毒药物（化学治疗剂）的治疗效果。通常，为了完全去除所有组织，需要采取剧烈措施，例如乳房切除术这可以作为新肿瘤的来源或底物的来源。人口的五年生存成果该测试对HR和/或HER2的阳性以及TNBC患者的测试呈阳性。适用于患者测试HR和/或HER2患有区域性乳腺癌的阳性，五年生存率约为82-89％，但为65％ TNBC。显然，需要新技术和方法才能针对TNBC并为这些患者提供对HR或HER2生物标志物测试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学方法，这将动态地改变我们对待TNBC的方式，尤其是在低收入少数群体中。我们将进化小蛋白质以选择性地结合患者的乳腺癌细胞，而不论特定变化乳腺癌导致的细胞表面。这些蛋白质将融合到其他提供体内稳定性的蛋白质，并募集从患者血清到TNBC细胞的抗体，导致其目标破坏。我们将配对我们的TNBC靶向免疫疗法（使用的药物使用低成本纸张平台破坏TNBC单元的免疫系统，该平台将允许简单，可访问和常规评估我们的TNBC靶向蛋白，并允许临床医生选择哪个成员应构成组合疗法。诊断平台还将允许临床医生监测鸡尾酒在治疗过程中的有效性（如癌细胞突变），并在必要时选择替代成员和/或替换。总的来说，这项工作代表了低成本整合的必要而令人兴奋的进步针对TNBC靶向和个性化的药物发现的方法，以及对在治疗过程中，这些免疫治疗鸡尾酒。