Nanosystems Biology Cancer Center

 描述(由申请人提供)：我们建议成立纳米系统生物学癌症中心(NSBCC)，作为加州理工大学和加州大学洛杉矶分校格芬医学院的合作项目，以开发纳米技术，以应对癌症组合疗法中的挑战。四个科学项目得到两个核心资源和一个行政结构的支持，该结构旨在促进跨大学在癌症生物学、临床肿瘤学以及基础和工程科学前沿的互动。通过利用我们各自机构、Jonsson综合癌症中心和商业合作伙伴的大力支持，我们将加州理工大学的世界级物理、生物和工程科学与加州大学洛杉矶分校的尖端癌症生物学和癌症临床护理相结合。NSBCC的教职员工包括来自两个校区的四名临床研究人员、五名助理教授和几名高级研究人员，由加州理工学院的吉姆·希思领导，加州大学洛杉矶分校的迈克尔·菲尔普斯联合领导。希思和菲尔普斯在建立领先的癌症研究项目方面有着良好的记录，这些项目涉及多个学科，并有效地转化为临床和市场。我们的项目平衡了发现和翻译。两个项目涉及纳米疗法，两个项目涉及开发纳米技术工具，以指导癌症免疫疗法和靶向疗法组合的选择。我们专注于脑癌和黑色素瘤，这使我们能够利用当前资金周期的势头。然而，我们寻求广泛适用的技术。这一点尤其适用于免疫治疗的情况，其中的挑战是将该领域最近取得的显著成功(部分是由我们的研究人员的黑色素瘤试验推动的)带给更多的患者群体。在项目中。1，我们提出了纳米颗粒(NP)载体，旨在提供治疗方法和治疗组合，以完全结合位于完整血脑屏障(BBB)上的肿瘤。该项目建立在最初有希望的结果和NSBCC将NP治疗药物输送到第一阶段和第二阶段(即将进入第三阶段)试验的历史基础上。项目。1从项目中获得指导(以及一组新的人源性颅内肿瘤模型)。4，我们提出了纳米技术和微技术工具来定量分析从GBM肿瘤分离的单个癌细胞中的&gt；200蛋白质和代谢物，目的是了解这些细胞对靶向单一疗法的动态反应。这些反应总是会导致某种形式的耐药性，我们试图解码这些反应，以确定有效的治疗组合。对于项目2，我们建议整合加州理工学院的3项发明。第一种是表位靶向PCC试剂(Heath)，这是一种合成配体，可以开发成针对包含单个激活点突变的癌蛋白。我们的目标是癌蛋白AktE17K和KrasG12D。KrasG12D是人类癌症中最主要的癌蛋白，也被认为是不可用药的。这些靶向配体与蛋白质降解靶向嵌合分子(Protas；Deshaies)结合在一起，这些嵌合分子利用自然的细胞机制来标记要销毁的蛋白质。PCC试剂通过调整由Davis最先开发和临床翻译的NP化学物质进入细胞。仅以突变蛋白为靶点可以为靶向抑制剂打开治疗窗口，从而实现新的治疗组合。在项目3中，我们转向癌症免疫治疗，将我们强大的免疫监测工具套件演变为了解肿瘤微环境中免疫细胞/肿瘤细胞相互作用的平台。特别是，在肿瘤外显子组分析的指导下，我们构建了基于纳米技术的文库，用于对肿瘤新抗原特异性T细胞群进行~60-plex分类，可直接应用于新鲜的活检肿瘤。这有助于识别在肿瘤内克隆性扩张的T细胞，并使我们能够识别肿瘤抗原、T细胞受体α/β序列(用于克隆)和T细胞的功能活性。这项技术应用于Project 3 Pi Ribas最近进行的免疫治疗试验中的一组匹配的患者肿瘤活检组织，应该为治疗那些目前对PD-1阻断表现出短暂的、阳性反应的患者组提供指导，并帮助为甚至没有表现出短暂反应的患者制定治疗思路。在项目3中，我们还提出了一种新的体内成像纳米技术，用于动态跟踪肿瘤模型中T细胞的输注。这项技术利用了某些微生物产生充气纳米囊泡的遗传能力，并产生了一种图像对比机制，这种机制将适用于TCR或嵌合抗原受体(CAR)工程T细胞，使用超声波或超极化129Xe MRI的高分辨率成像方式，对T细胞渗透到小鼠肿瘤模型中进行成像。这为我们提供了在体内测试体外测试产生的假说的能力。对于所有项目，都提供了重要的初步数据。

 DESCRIPTION (provided by applicant): We propose the NanoSystems Biology Cancer Center (NSBCC) as a collaboration between Caltech and the UCLA Geffen School of Medicine, to develop nanotechnologies for addressing challenges in combinatorial cancer therapies. Four scientific Projects are supported by two Core Resources and an Administrative structure designed to promote cross-university interactions at the frontiers of cancer biology, clinical oncology, and the basic and engineering sciences. By leveraging strong support from our respective institutions, the Jonsson Comprehensive Cancer Center, and commercial partners, we integrate world-class physical, biological and engineering sciences at Caltech with cutting edge cancer biology and cancer clinical care at UCLA. The NSBCC faculty include four clinical researchers, 5 assistant professors, and several senior researchers from both campuses, and is led by led by Jim Heath (Caltech) and co-led by Michael Phelps (UCLA). Heath and Phelps have track records of building leading cancer research programs that draw across disciplines, with effective translation into the clinic and marketplace. Our Projects balance discovery with translation. Two Projects involve nanotherapies, and two involve the development of nanotech tools for guiding the selection of combination both cancer immunotherapy and targeted therapy treatments. We focus on brain cancers and melanoma, which allows us to take advantage of momentum from the current funding cycle. However, we seek broadly applicable technologies. This holds especially for the case of immunotherapy, where the challenge is to bring the remarkable recent successes in the field (partly driven by our investigator's melanoma trials) to larger patient populations. In Proj. 1, we propose nanoparticle (NP) vehicles designed to deliver therapies and therapy combinations to fully engage a tumor that lies across an intact blood brain barrier (BBB). This project builds upon initial promising results, and from an NSBCC history of delivering NP therapeutics into Phase I and Phase II (and soon Phase III) trials. Proj. 1 takes guidance (as well as a novel panel of human-derived intracranial tumor models) from Proj. 4, where we propose nanotech and microtech tools to quantitatively assay for >200 proteins and metabolites from single cancer cells separated from a GBM tumor, with the goal of understanding the dynamical responses of those cells to targeted monotherapies. Those responses invariably lead to some form of resistance, and we seek to decode those responses to identify effective therapy combinations. For Project 2 we propose to integrate 3 Caltech inventions. The first are epitope targeted PCC Agents (Heath), which are synthetic ligands that can be developed to target oncoproteins containing single activating point mutations. We target the oncoproteins AktE17K and KrasG12D. KrasG12D is the most dominant oncoprotein in human cancer, and also considered undruggable. These targeting ligands are combined with proteolysis-targeting chimeric molecules (protacs; Deshaies) that exploit the natural cellular machinery to label a protein for destruction. The PCC Agent-protacs are delivered into cells by adapting NP chemistries that were first developed and clinically translated by Davis. Targeting just the mutant protein can open up the therapeutic window for targeted inhibitors, thus enabling new therapy combinations. In Project 3, we turn to cancer immunotherapy by evolving our powerful suite of immune monitoring tools into platforms for understanding immune cell/tumor cell interactions within the tumor microenvironment. In particular, guided by exome analysis of the tumor, we construct nanotechnology-based libraries for a ~60-plex sorting of tumor neoantigen specific T cell populations that can be applied directly to fresh biopsied tumors. This helps identify those T cells that have clonally expande within the tumor, and permits us to identify the tumor antigen, the T Cell receptor α/β sequence (for cloning), and the functional activity of the T cell. This technology is applied a set of matched patient tumor biopsies from recent immunotherapy trials run by Project 3 PI Ribas, and should provide guidance for treating those patient groups that currently exhibit transient, positive responses to PD-1 blockade, as well as helping to frame treatment ideas for patients that do not exhibit even transient responses. In Project 3, we also propose a novel in vivo imaging nanotechnology for the kinetic tracking of T cell infusions in tumor models. The technology draws from the genetic ability of certain microorganisms to generate gas- filled nanovesicles, and yields an image contrast mechanism that will be adapted to TCR- or chimeric antigen receptor (CAR)-engineered T cells for imaging T cell infiltrates into mouse tumor models, using the high resolution imaging modalities of ultrasound or hyperpolarized 129Xe MRI. This provides us with the ability to test, in vivo, hypotheses generated from the in vitro assays. For all projects, significant preliminary data is provided.