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

集成低成本的纸质设备和个性化 免疫疗法治疗三阴性乳腺癌 摘要 在一名乳腺癌患者与她的临床医生进行初步预约后， 可能的结果是，癌症在一个或多个临床检测中呈阳性 重要的细胞表面“生物标记物”，尤其是雌激素受体(ER)， 孕激素受体(PR)，或HER2。在这种相对较好的情况下，很可能会给患者开处方 个性化治疗，如激素疗法(在ER+和/或PR+癌症的情况下)或使用药物 特异性靶向HER2+细胞(例如，单抗、单抗、赫赛汀™)。这些是个性化的 与化疗鸡尾酒等一般抗癌药物相比，药物的毒性较小。 在一种不同的、相对可怕的情景中，一名患者被告知患有“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，也缺乏HER2。三重 阴性乳腺癌(TNBC)占所有乳腺癌病例的15%-20%，而且不成比例 影响少数族裔人口。如果没有个性化的治疗，这位患者现在只能忍受 使用非靶向和有毒的药物(化疗药物)进行治疗，这些药物带有大量使人衰弱的副作用 效果。通常，需要采取激烈的措施，如乳房切除术，才能完全切除所有组织。 这可能会成为新肿瘤的来源或底物。人口的五年生存结果 HR和/或HER2和TNBC患者的检测阳性也有很大不同。适用于以下患者 区域乳腺癌的HR和/或HER2检测呈阳性，五年生存率约为82-89%，而 TNBC。显然，需要新的技术和方法来瞄准TNBC并为这些患者提供 HR或HER2生物标志物检测呈阳性的患者拥有相同的治疗机会。 在这里，我们提出了一种根本不同的个性化医疗方法，它将 极大地改变了我们对待TNBC的方式，特别是在低收入少数群体中。我们会 进化小蛋白以选择性地结合患者的乳腺癌细胞，而不考虑具体的变化 转移到细胞表面，这是乳腺癌的结果。这些蛋白质将与其他蛋白质融合 在体内提供稳定性的蛋白质，并将抗体从患者的血清中招募到TNBC细胞， 导致它们被有针对性地摧毁。我们将配对我们的TNBC靶向免疫疗法(使用 免疫系统摧毁TNBC细胞)与低成本的纸质平台，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，并允许临床医生选择 会员们应该组成一种综合疗法。该诊断平台还将允许临床医生 在治疗过程中监测鸡尾酒的每个成员(作为癌细胞)的有效性 突变)，并在必要时选择替代成员和/或替代者。 总体而言，这项工作代表着在整合低成本技术方面取得的必要和令人兴奋的进展 TNBC-靶向和个性化药物发现的方法，以及优化和监测 这些免疫治疗鸡尾酒在治疗过程中。

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.