Optical imaging to predict cell-level genetic heterogeneity and treatment sensitivity in colorectal cancer

项目摘要/摘要 在所有癌症中，肿瘤学的一个重要问题是目前缺乏可靠的手段来预测对 针对个别患者的抗癌治疗。特别是在局部晚期直肠癌(LARC)中，众所周知 患者可以从化疗、放射治疗和手术治疗中受益。然而，并不是所有这些 每个患者都可能需要接受治疗。更适用于转移性结直肠癌患者 (CRC)存在多种标准和实验疗法，并有办法预测哪些患者将对 哪种疗法将是一个重大的进步。敏感度测试将防止患者出现不必要的毒性 并允许对那些具有抵抗力的疾病进行升级或替代治疗。一种预测治疗效果的方法 迫切需要作出回应，这就是这项提议的目标。这项建议的长远目标是 利用患者来源的结直肠癌球状培养的光学代谢成像(OMI)预测对 治疗方案。这项提议开发了新的细胞水平成像技术来预测治疗 肿瘤患者自身培养的光学代谢成像(OMI)在个体癌症患者中的反应 肿瘤。由于肿瘤遗传学可以对细胞新陈代谢产生深远影响，因此更好地理解 肿瘤遗传学改变治疗前和治疗后OMI的潜在机制是必要的。在……里面 此外，需要对患者样本中细胞水平的异质性进行评估，以全面预测治疗。 回应。为了询问这些机械查询，我们生成了包括转基因在内的多种工具 具有常见改变基因突变组合的小鼠结直肠癌模型，小鼠结直肠癌球体 培养物、同基因人结直肠癌细胞、患者来源的球状细胞培养物和异种移植。我们的初步数据 表明原发癌和其他肿瘤类型中的OMI可预测小鼠体内的药物反应。我们还有 使用患者派生的CRC球体在试点研究中测试了该平台。 在这项建议中，我们检验了患者来源的球体培养的OMI将预测治疗的假设。 接受化疗和/或放射治疗的结直肠癌患者的反应。具体地说，我们决定如何 球体内个体基因改变对化疗和/或治疗前后OMI的影响 辐射。其次，我们评估了具有复杂分子图谱的CRC球状培养物中的异质性。 在化疗和/或放射治疗前后使用OMI。此外，我们还测试了椭球体是否 应用OMI预测接受局部晚期肿瘤新辅助治疗的患者的临床反应 用于直肠癌和转移性结直肠癌患者的系统治疗。患者将在登记处登记 在开始治疗前的礼仪。OMI预测将与基于临床结果的验证 关于病理学和影像标准。

PROJECT SUMMARY/ABSTRACT Across all cancers a significant problem in oncology is the current lack of reliable means to predict response to anti-cancer treatments for individual patients. Specifically in locally advanced rectal cancer (LARC), it is known that patients can benefit from chemotherapy, radiation, and operative management. However, not all of these therapies may be required for each individual patient. Beyond that for patients with metastatic colorectal cancer (CRC) multiple standard and experimental therapies exist and a way to predict which patients will respond to which therapies would be a major advance. Sensitivity testing would prevent patients from unnecessarytoxicities and allow escalation of or alternative therapies for those with resistant disease. A method to predict treatment response is urgently needed and this is the goal of this proposal. The long-termobjective of this proposal is to utilize optical metabolic imaging (OMI) of patient-derived CRC spheroid cultures to predict sensitivity to therapeutic regimens. This proposal develops novel cellular-level imaging technologies to predict treatment response in individual cancer patients using optical metabolic imaging (OMI) of spheroid cultures from their own tumors. Since tumor genetics can have profound impacts on cellular metabolism, a better understanding of the underlying mechanisms by which tumor genetics alter OMI in the pre- and post-treatment settings is needed. In addition, assessment of cell-level heterogeneity within patient samples is required to fully predict the treatment response. To interrogate these mechanistic inquiries, we have generated multiple tools including transgenic murine CRC models possessing combinations of mutations in commonly altered genes, murine CRC spheroid cultures, isogenic human CRC cells, and patient-derived spheroid cultures and xenografts. Our preliminary data indicate that OMI in primary CRCs and other tumor types predicts in vivo drug response in mice. We have also tested this platform in pilot studies using patient-derived CRC spheroids. In this proposal, we test the hypothesis that OMI of patient-derived spheroid cultures will predict treatment response for patients undergoing chemotherapy and/or radiation for CRC. Specifically, we determine how individual genetic alterations within spheroids impact OMI pre- and post-treatment with chemotherapy and/or radiation. Secondly, we evaluate the heterogeneity within CRC spheroid cultures with complex molecular profiles using OMI pre- and post-treatment with chemotherapy and/or radiation. In addition, we test whether spheroid response using OMI predicts clinical responsein patients undergoing neoadjuvant treatment for locally advanced rectal cancer and for systemic therapies for patients with metastatic CRC. Patients will be enrolled in a registry protocol prior to the initiation of therapy. The OMI predictions will be validated with the clinical outcomes based on pathology and imaging criteria.