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的一个重大挑战， 21世纪世纪显著的技术进步。多模式无创分子生物学研究进展 和功能成像提供了独特的机会，以扩大我们对癌症的理解， 了解这一点对于开发有效的癌症特异性治疗至关重要。在这次重新提交的报告中， 在肿瘤微环境（TME）中选择了三个相互作用的焦点区域，肿瘤 大环境（TMacE）和治疗诊断学，将在三阴性乳腺癌（TNBC）中进行 和胰腺导管腺癌（PDAC）人肿瘤异种移植物和同基因肿瘤在免疫中的作用 有能力的老鼠在TME焦点中，我们将使用成像来扩展我们对粘着斑的理解 转移级联中的FAK机械转导途径，包括发展PET 成像探针来非侵入性地检测FAK。FAK还在肿瘤免疫抑制中发挥作用。在 我们将扩大我们的努力，了解PDAC诱导的恶病质，导致广泛的 影响器官功能的症状，如肌肉，肝脏，大脑和心脏，引起显著的 发病率肿瘤分泌蛋白组通过影响“宏观环境”而成为该综合征的关键。我们 将专注于表征临床前PDAC异种移植模型中的肿瘤间质液（TIF），以开发 恶病质的生物标志物，并确定潜在的代谢目标，将通过治疗诊断学 专心点在治疗诊断领域，我们将把我们在成像和NP技术方面的努力和专业知识用于 改善TNBC和PDAC中检查点抑制剂的结果。缺乏效应T细胞肿瘤浸润， 已被确定为对这些抑制剂反应不良的主要原因。我们将使用FDA批准的 聚（乳酸-共-乙醇酸）PLGA以产生癌细胞膜（CCM）包被的“免疫体”NP 与粒细胞巨噬细胞集落刺激因子（GM-CSF）包埋，以增加效应T细胞肿瘤 并应用分子影像学技术检测NPs的生物学分布和T细胞的变化 浸润最终，我们希望使用患者自己的癌细胞来合成用于个性化治疗的纳米颗粒。 药由于已知表达FAP-α的癌相关成纤维细胞（CAF）可产生免疫抑制， 抑制性TME，我们将使用与近红外（NIR）染料IR 700偶联的抗FAP-α抗体来检测 CAFS与NIR成像，并消除他们选择性地在肿瘤与PIT。如果表达FAP-α的CAFs的PIT 导致肿瘤中细胞毒性T细胞增加，这可能与 检查点抑制剂治疗。我们将使用基于葡聚糖的生物相容性NP的siRNA递送， 下调FAK和TMacE焦点中鉴定的代谢靶点。我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， 翻译通过R35奖进行的研究，以利于癌症的检测和治疗。

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.