Molecular Imaging and Theranostics of Cancer

实现癌症治愈，甚至控制，仍然是卫生保健领域一项尚未回答的重大挑战，尽管 21世纪令人瞩目的技术进步。多模式非侵入性分子研究进展 和功能成像正在提供独特的机会来扩大我们对癌症的理解，以及 了解这一点对于开发有效的癌症特异性治疗方法至关重要。在这份重新提交的文件中，我 在肿瘤微环境(TME)内选择了三个相互作用的焦点区域，肿瘤 将在三阴性乳腺癌(TNBC)中进行的宏观环境(TMacE)和基因治疗 和胰腺导管腺癌(PDAC)人肿瘤移植瘤和同源肿瘤的免疫 有能力的老鼠。在TME焦点中，我们将使用成像来扩展我们对焦点粘连的理解 包括发展中的PET在内的转移级联中的激酶(FAK)机械转导途径 无创性检测FAK的成像探头。FAK也在肿瘤免疫抑制中发挥作用。在 TMacE Focus我们将进一步努力了解PDAC引起的广泛范围的恶病质 影响肌肉、肝脏、大脑和心脏等器官功能的症状，引起显著的 发病率。肿瘤分泌组通过影响“大环境”而控制着这种综合征的关键。我们 将重点研究肿瘤间质液(TIF)在临床前PDAC异种移植模型中的开发 恶病质的生物标志物，并确定潜在的代谢靶点，将通过Theranostic 全神贯注。在Theranostic Focus，我们将把我们在成像和NP技术方面的努力和专业知识引导到 改善TNBC和PDAC中检查点抑制剂的治疗结果。缺乏效应性T细胞肿瘤侵袭 已被确定为对这些抑制剂反应不佳的主要原因。我们将使用FDA批准的 聚乳酸-羟基乙酸共聚物制备包被免疫小体的癌细胞膜纳米粒 粒细胞巨噬细胞集落刺激因子(GM-CSF)包埋增加效应T细胞瘤 并应用分子成像技术检测NPs的生物分布和T细胞的变化 渗透。最终，我们希望使用患者自己的癌细胞来合成个性化的NPs 医药。由于表达FAP-α的肿瘤相关成纤维细胞(CAF)被认为可以产生一种免疫 抑制TME，我们将使用抗FAP-α抗体与近红外染料IR700偶联来检测 对CAF进行近红外成像，并在有PIT的肿瘤中选择性地清除它们。表达CAF的FAP-α的IF pIT 结果在肿瘤中细胞毒性T细胞的增加，这可能有重要的应用与 检查点抑制剂治疗。我们将使用基于葡聚糖的生物相容纳米粒的siRNA传递来 下调FAK和TMacE焦点中确定的代谢目标。我已经建立了一个强大的网络 包括临床肿瘤学家、放射科医生、病理学家和外科医生在内的合作者将确保 通过R35奖项进行的研究的翻译，以利于癌症检测和治疗。

Achieving cancer cure, or even control, continues to be a major unanswered challenge in health care despite the remarkable technological advances of the 21st century. Advances in multi-modal noninvasive molecular and functional imaging are providing unique opportunities to expand our understanding of cancer, an understanding that is critical to developing effective and cancer specific treatments. In this resubmission I have chosen three interactive focus areas within the tumor microenvironment (TME), the tumor macroenvironment (TMacE), and Theranostics, that will be pursued in triple negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) human tumor xenografts and syngeneic tumors in immune competent mice. In the TME focus, we will use imaging to expand our understanding of the focal adhesion kinase (FAK) mechanotransduction pathway in the metastatic cascade that will include developing PET imaging probes to detect FAK noninvasively. FAK also plays a role in tumor immune suppression. In the TMacE focus we will expand our efforts in understanding PDAC induced cachexia that results in a wide range of symptoms affecting the function of organs such as muscle, liver, brain, and heart, causing significant morbidity. The tumor secretome holds the key to this syndrome by influencing the `macroenvironment'. We will focus on characterizing the tumor interstitial fluid (TIF) in preclinical PDAC xenograft models to develop biomarkers of cachexia and identify potential metabolic targets that will be pursued through the Theranostic focus. In the Theranostic focus we will direct our efforts and expertise in imaging and NP technology to improve the outcome of checkpoint inhibitors in TNBC and PDAC. Lack of effector T-cell tumor infiltration has been identified as a major cause of the poor response to these inhibitors. We will use FDA approved poly(lactic-co-glycolic acid) PLGA to create cancer cell membrane (CCM) coated `immunosome' NPs embedded with granulocyte macrophage colony-stimulating factor (GM-CSF) to increase effector T cell tumor infiltration, and apply molecular imaging to detect the biodistribution of the NPs and the changes in T cell infiltration. Ultimately we want to use the patients own cancer cells to synthesize the NPs for personalized medicine. Since FAP-α expressing cancer associated fibroblasts (CAFs) are known to create an immune suppressive TME, we will use anti-FAP-α antibody conjugated to the near infrared (NIR) dye IR700 to detect CAFS with NIR imaging and eliminate them selectively in the tumor with PIT. If PIT of FAP-α expressing CAFs results in increased cytotoxic T cells in tumors, this may have significant applications in combination with checkpoint inhibitor treatment. We will use siRNA delivery with dextran based biocompatible NPs to downregulate FAK, and metabolic targets identified in the TMacE focus. I have built a strong network of collaborators that include clinical oncologists, radiologists, pathologists and surgeons that will ensure the rapid translation of the research conducted through the R35 award to benefit cancer detection and treatment.