Nanosystems Biology Cancer Center

纳米系统生物学癌症中心

• 批准号: 9753711
• 负责人: James R. Heath
• 金额: $ 199.77万
• 依托单位: INSTITUTE FOR SYSTEMS BIOLOGY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753711
• 关键词: Address; Area; Biological; Biological Assay; Biopsy; Blood - brain barrier anatomy; Cancer Biology; Cancer Center; Cancer Patient; Cancer Research Project; Cell Communication; Cells; Chemistry; Clinic; Clinical; Clinical Oncology; Cloning; Collaborations; Combination immunotherapy; Combined Modality Therapy; Communities; Comprehensive Cancer Center; Data; Development; Diagnostic; Discipline; Disease remission; Drug Delivery Systems; Drug Targeting; Drug usage; Engineering; Ensure; Epitopes; Equilibrium; Exhibits; Faculty; Funding; Gases; Generations; Genetic; Goals; Health; Human; Immune; Immune system; Immunologic Monitoring; Immunotherapy; Individual; Infusion procedures; Institution; Intracranial Neoplasms; Kinetics; Label; Lead; Lesion; Libraries; Ligands; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mentors; Modeling; Modernization; Molecular; Mus; Nanotechnology; Oncoproteins; Operative Surgical Procedures; PD-1 blockade; Patients; Pharmaceutical Preparations; Phase; Physicians; Point Mutation; Population; Protac; Proteins; Proteolysis; Radiation; Recording of previous events; Records; Research; Research Personnel; Resistance; Resources; Running; Science; Scientific Advances and Accomplishments; Scientist; Sorting - Cell Movement; Structure; T-Cell Receptor; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Training and Education; Translating; Translations; Tumor Antigens; Ultrasonography; Universities; base; cancer care; cancer cell; cancer immunotherapy; cancer therapy; cellular imaging; chemotherapy; chimeric antigen receptor; clinical care; clinical translation; combination cancer therapy; combinatorial; contrast imaging; design; effective therapy; engineered T cells; exome; fighting; frontier; high resolution imaging; imaging modality; immunotherapy trials; improved; in vitro Assay; in vivo; in vivo imaging; individual patient; inhibitor/antagonist; invention; medical schools; melanoma; microorganism; mutant; nanomedicine; nanoparticle; nanoparticle delivery; nanosystems; nanotherapeutic; nanotherapy; nanovesicle; neoantigens; neoplastic cell; new combination therapies; news; novel; oncology; patient population; phase III trial; professor; programs; protein metabolite; public health relevance; response; senior faculty; success; targeted treatment; therapeutic nanoparticles; therapy design; tool; tumor; tumor microenvironment

 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.

 描述（由申请人提供）：我们建议纳米系统生物学癌症中心（NSBCC）作为加州理工学院和加州大学洛杉矶分校格芬医学院之间的合作，开发纳米技术，以应对组合癌症治疗的挑战。四个科学项目由两个核心资源和一个行政结构支持，旨在促进癌症生物学，临床肿瘤学以及基础和工程科学前沿的跨大学互动。通过利用我们各自机构，琼森综合癌症中心和商业合作伙伴的大力支持，我们将加州理工学院世界一流的物理，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教师包括四名临床研究人员，5名助理教授和来自两个校区的几名高级研究人员，由Jim Heath（加州理工学院）领导，Michael Phelps（加州大学洛杉矶分校）共同领导。Heath和Phelps在建立跨学科的领先癌症研究项目方面有着良好的记录，并有效地转化为临床和市场。 我们的项目平衡了发现与翻译。两个项目涉及纳米治疗，两个涉及纳米技术工具的开发，用于指导癌症免疫治疗和靶向治疗组合的选择。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着成功（部分由我们的研究人员的黑色素瘤试验驱动）带到更大的患者群体中。 在项目1，我们提出了纳米颗粒（NP）载体，旨在提供治疗和治疗组合，以充分参与跨越完整血脑屏障（BBB）的肿瘤。该项目建立在最初的有希望的结果，并从NSBCC的历史提供NP治疗进入I期和II期（很快III期）试验。项目。1采取的指导（以及一个新的面板的人源性颅内肿瘤模型）从项目。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>200种蛋白质和代谢物，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3个加州理工学院的发明。第一种是表位靶向PCC试剂（Heath），其是可以开发以靶向含有单一激活点突变的癌蛋白的合成配体。我们靶向癌蛋白AktE 17 K和KrasG 12 D。KrasG 12 D是人类癌症中最主要的癌蛋白，也被认为是不可治疗的。这些靶向配体与蛋白水解靶向嵌合分子（protacs; Deshaies）组合，该嵌合分子利用天然细胞机制来标记蛋白质以进行破坏。PCC Agent-protacs通过适应NP化学物质被递送到细胞中，该NP化学物质首先由Davis开发并在临床上翻译。仅靶向突变蛋白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发展成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，用于肿瘤新抗原特异性T细胞群的~60重分选，其可以直接应用于新鲜活检肿瘤。这有助于识别那些在肿瘤内克隆性扩增的T细胞，并允许我们识别肿瘤抗原，T细胞受体α/β序列（用于克隆）和T细胞的功能活性。该技术应用于Project 3 PI Ribas最近进行的免疫治疗试验中的一组匹配患者肿瘤活检，并应为治疗目前对PD-1阻断表现出短暂阳性反应的患者群体提供指导，并帮助为甚至没有表现出短暂反应的患者制定治疗方案。在项目3中，我们还提出了一种新的体内成像纳米技术，用于肿瘤模型中T细胞输注的动力学跟踪。该技术利用某些微生物产生充气纳米囊泡的遗传能力，并产生一种图像对比机制，该机制将适用于TCR或嵌合抗原受体（CAR）工程化T细胞，用于使用超声或超极化129 μ M MRI的高分辨率成像模式将T细胞浸润成像到小鼠肿瘤模型中。这为我们提供了在体内测试由体外测定产生的假设的能力。所有项目都提供了重要的初步数据。