Validation of a novel 3D culture platform for TNBC treatment selection

验证用于 TNBC 治疗选择的新型 3D 培养平台

• 批准号: 10540094
• 负责人: David Gallup
• 金额: $ 64.42万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540094
• 关键词: 3-Dimensional; Address; Adriamycin PFS; Architecture; Biological Assay; Biotechnology; Breast Cancer Patient; Breast Cancer Treatment; Businesses; Cancer Center; Cancer Diagnostics; Cancer Patient; Carboplatin; Cells; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Data; Clinical Research; Clinical Trials; Cyclophosphamide; Data; Diagnostic tests; Doxorubicin; Engineering; Evaluation; Genomics; Goals; Immuno-Chemotherapy; Immunotherapy; Individual; Industrialization; Legal patent; Malignant Neoplasms; Measures; Mechanics; Methodist Church; Methods; Modeling; Molecular Profiling; Mutation; Neoadjuvant Therapy; Oncology; Organoids; Outcome; Paclitaxel; Patient Care; Patient Care Team; Patient-derived xenograft models of breast cancer; Patients; Pharmaceutical Preparations; Physicians; Prospective Studies; Reagent; Reporting; Research; Research Institute; Resolution; Retrospective Studies; Scientist; Selection for Treatments; Serum; Slice; Solid; Solid Neoplasm; System; T-Cell Activation; Testing; Time; Tissues; Translating; Tumor Biology; Tumor Tissue; Validation; anti-PD-L1; anti-PD-L1 therapy; anticancer research; base; cancer care; cancer diagnosis; chemotherapy; clinical care; clinical practice; clinical translation; clinically actionable; cost; design; diagnostic assay; drug sensitivity; evidence base; genomic profiles; improved; in vivo; individual patient; malignant breast neoplasm; metastatic colorectal; mouse model; novel; patient derived xenograft model; patient response; pembrolizumab; personalized care; personalized medicine; precision drugs; precision medicine; product development; prospective; resistance mechanism; responders and non-responders; response; standard of care; targeted treatment; taxane; three dimensional cell culture; tissue culture; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor immunology; tumor microenvironment

PROJECT SUMMARY The goal of this academic [Houston Methodist Research Institute (HMRI) and MD Anderson Cancer Center (MDACC)] and industrial (EMPIRI) collaborative project is to validate a novel, functional cancer diagnostic assay for clinical translation to improve and personalize the care of triple-negative breast cancer (TNBC) patients. The study will validate a novel 3D tumor tissue culture method (E-slices) invented by MPI Kyuson Yun (HMRI) and licensed to EMPIRI, Inc., a biotech startup co-founded by Dr. Yun and Dave Gallup (MPI). Together with Dr. Naoto Ueno (MPI, MDACC), a renowned physician-scientist specializing in TNBC research and patient care, the team will validate the predictive accuracy of E-slices for individual TNBC patient responses to recently approved chemoimmunotherapy for early TNBC patient care. The need for personalized medicine in oncology is widely accepted but translating this important concept into clinical practice has been challenging. Currently, the dominant platform for precision medicine utilizes genomics/sequencing-based assays to measure the expression and/or mutational profiles and then infer responses to targeted therapies; however, this approach benefits <10% of patients with profiled tumors. Recognizing the inherent limitations of these inference-based methods, functional assays (e.g., organoids, PDX models) have been developed, but these approaches have numerous limitations including high cost and time required to establish the models, low “take rates”, and destruction of the native tumor microenvironment (TME). To overcome these challenges, EMPIRI developed a novel 3D ex vivo tumor culture method (E-slices) that enables rapid, personalized drug sensitivity testing in intact patient tumor tissues. E-slices retain the native TME and tissue architecture and are cultured in serum-free defined media, overcoming the limitations of other approaches. In addition, E-slices can be generated from any solid tumor and used for testing responses to chemotherapy, targeted therapy, and immunotherapy. Importantly, E-slice accuracy has been validated in a clinical setting for metastatic colorectal cancer to accurately predict individual patient treatment responses and detect inter-patient differences to the same treatments in 4-12 days, paving the way for near evidence-based personalized treatment selections. The team will: (i) determine whether E-slices predict patient responses to SOC NAC: doxorubicin (Adriamycin) plus cyclophosphamide) in a retrospective study, (ii) measure chemoimmunotherapy (Pembrolizumab plus paclitaxel + carboplatin) responses in humanized PDX slices from known responders and non-responders; and (ii) evaluate the clinical utility of E-slices in predicting TNBC patient responses to newly approved standard of care chemoimmunotherapy in a prospective study. Successful completion of this project will provide the necessary data to apply E-slices as the first functional cancer diagnostic test specifically designed to inform TNBC patient care.

项目摘要 休斯顿卫理公会研究所（HMRI）和MD安德森癌症研究所的目标是 中心（MDACC）]和工业（EMPIRI）的合作项目是验证一种新型的功能性癌症 用于临床转化的诊断测定，以改善和个性化三阴性乳腺癌的护理 （TNBC）患者。该研究将验证MPI发明的新型3D肿瘤组织培养方法（E切片） Kyuson Yun（HMRI）并授权给EMPIRI，Inc.，由云博士和戴夫·盖洛普共同创立的生物技术创业公司 （MPI）。与专门研究TNBC的著名医学科学家Naoto Ueno博士（MPI，MDACC）一起 研究和患者护理，该团队将验证E-slices对个体TNBC患者的预测准确性 对最近批准的用于早期TNBC患者护理的化学免疫疗法的反应。 在肿瘤学中，个性化医疗的需求被广泛接受，但翻译这一重要概念 临床实践是一个挑战。目前，精准医疗的主导平台利用 基于基因组学/测序的测定，以测量表达和/或突变谱，然后推断 靶向治疗的反应;然而，这种方法使<10%的具有轮廓肿瘤的患者受益。 认识到这些基于推理的方法的固有局限性，功能测定（例如，类器官，PDX 模型），但这些方法具有许多限制，包括高成本和时间 建立模型所需的低“获取率”和天然肿瘤微环境（TME）的破坏。 为了克服这些挑战，EMPIRI开发了一种新的3D离体肿瘤培养方法（E切片）。 这使得能够在完整的患者肿瘤组织中进行快速、个性化的药物敏感性测试。E切片保留了 天然TME和组织结构，并在无血清的限定培养基中培养，克服了 其他方法。此外，E切片可以从任何实体瘤产生，并用于测试对以下的反应： 化疗、靶向治疗和免疫治疗。重要的是，E切片准确性已在 转移性结直肠癌的临床环境，以准确预测个体患者的治疗反应， 在4-12天内检测相同治疗的患者间差异，为近循证医学铺平道路。 个性化的治疗选择。该小组将：（i）确定E切片是否预测患者对以下问题的反应： SOC NAC：回顾性研究中的多柔比星（阿霉素）+环磷酰胺），（ii）测量 来自人源化PDX切片中的化学免疫疗法（派姆单抗加紫杉醇+卡铂）应答 已知的响应者和非响应者;以及（ii）评估E切片在预测TNBC患者中的临床效用 在一项前瞻性研究中，对新批准的标准护理化学免疫疗法的反应。成功 该项目的完成将提供必要的数据，以应用电子切片作为第一个功能性癌症诊断 测试专门设计用于告知TNBC患者护理。