Program the Immune System against RAS-driven Cancer

对免疫系统进行编程以对抗 RAS 驱动的癌症

基本信息

  • 批准号:
    10612257
  • 负责人:
  • 金额:
    $ 21.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

Abstract Despite the great progress in recent decades, many types of cancer remain almost fatal. Pancreatic ductal adenocarcinoma (PDAC) is a remarkable example. One of the challenges is that the vast majority (95%) of PDACs are driven by mutations within a gene called KRAS, and these KRAS mutations are notoriously difficult to target with conventional drugs. The first generation of cancer drugs are based on small molecules, the second generation biologics (large biomolecules such as antibodies that specifically bind to cancer cells), and the latest generation cells (engineered to recognize and ablate cancer cells). Here our long-term goal is to demonstrate a new generation of therapeutics, using “circuits” as medicine. Circuits metaphorically refer to collections of biomolecules engineered to regulate each other and process information inside living cells. While conventional analyses output metrics to inform physicians, who then make therapeutic decisions, our circuits close the loop, and will serve as both the analytic and the therapeutic tools. It is a molecular and cellular analysis technology that queries living cells and actuates therapeutic outputs in real time without human intervention. Specifically, we will create circuits to program the immune system and emulate the “abscopal effect”, the occasional observation that distant tumors shrink when local tumors are treated, most likely due to the immune system learning the “signature” of the treated tumors and then extrapolating. We will first create the building blocks for such circuits: sensors that can interrogate whether a cell is in a cancerous state, actuators that can control the signals sent by cells to engage the immune system, and processors that connect the sensors and the actuators. These efforts will benefit from our experience of building circuits exclusively using proteins, which features technical advantages, such as ease of delivery and robustness of functionality in different cellular contexts, compared to more conventional ways of building circuits based on protein-DNA interactions. We will then assemble these building blocks into circuits, and quantify and optimize their operation in cultured cells. Leveraging our expertise in mouse models of PDACs, we will finally test these circuits’ efficacy in vivo. The premise is to program the outputs specifically from cancer cells to mobilize the immune system and then lyse these cells to grant the immune system access to all protein sequences that are uniquely present in cancer. These dead cancer cells will serve essentially as vaccines against other cells that exhibit similar protein sequence profiles. We will achieve this vaccination effect by either mimicking a specific type of cell death known to mobilize the immune system, or program the cancer cells to directly and artificially activate T cells – immune cells responsible for recognizing and ablating cancer cells. The expected outcomes of this proposal are not only preclinical evidence supporting a novel, powerful therapy for KRAS-driven PDAC, but also a proof of principle for the biomedical promise of synthetic biomolecular circuits for other recalcitrant types of cancer and beyond.
摘要 尽管近几十年来取得了很大进展,但许多类型的癌症仍然几乎致命。胰腺 导管腺癌(PDAC)是一个显著的例子。挑战之一是绝大多数(95%) 的PDAC是由一种叫做KRAS的基因突变驱动的,这些KRAS突变是众所周知的困难, to target目标with conventional常规drugs药物.第一代抗癌药物是基于小分子的,第二代是基于小分子的。 第二代生物制剂(大生物分子,如特异性结合癌细胞的抗体),以及最新的 第二代细胞(经工程改造以识别和消融癌细胞)。在这里,我们的长期目标是展示一个 新一代的治疗方法,使用“电路”作为药物。电路隐喻性地指的是 生物分子被设计成相互调节并在活细胞内处理信息。虽然常规 分析输出指标以通知医生,然后医生做出治疗决定,我们的电路闭合回路, 并将作为分析和治疗的工具。它是一种分子和细胞分析技术 在没有人为干预的情况下,在真实的时间内查询活细胞并启动治疗输出。 具体来说,我们将创建电路来编程免疫系统,并模拟“远位效应”, 偶尔观察到远处肿瘤在治疗局部肿瘤时缩小,最可能是由于免疫缺陷, 系统学习被治疗肿瘤的“特征”,然后进行外推。我们将首先创建一个建筑 这些电路的模块:可以询问细胞是否处于癌状态的传感器,可以 控制细胞发出的信号,以吸引免疫系统,以及连接传感器的处理器, 执行器。这些努力将受益于我们专门使用蛋白质构建电路的经验, 具有技术优势,例如易于交付和不同蜂窝网络中的功能的鲁棒性。 与基于蛋白质-DNA相互作用构建电路的更传统的方法相比。我们将 然后将这些构建模块组装成电路,并量化和优化它们在培养细胞中的操作。 利用我们在PDAC小鼠模型方面的专业知识,我们最终将在体内测试这些电路的功效。的 前提是对癌细胞的特异性输出进行编程,以动员免疫系统,然后溶解 这些细胞使免疫系统能够接触到癌症中唯一存在的所有蛋白质序列。 这些死亡的癌细胞将基本上作为疫苗,对抗其他表现出类似蛋白质的细胞。 序列图谱我们将通过模仿已知的特定类型的细胞死亡来实现这种疫苗接种效果 动员免疫系统,或编程癌细胞直接和人工激活T细胞-免疫 负责识别和消除癌细胞的细胞。 该提案的预期结果不仅是临床前证据, 治疗KRAS驱动的PDAC,而且也是合成生物分子的生物医学前景的原理证明。 其他恶性肿瘤及其他疾病的治疗

项目成果

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Xiaojing J Gao其他文献

Xiaojing J Gao的其他文献

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{{ truncateString('Xiaojing J Gao', 18)}}的其他基金

A Novel Class of Synthetic Receptors to Empower the Age of mRNA Therapies
一类新型合成受体将推动 mRNA 治疗时代的到来
  • 批准号:
    10687517
  • 财政年份:
    2023
  • 资助金额:
    $ 21.8万
  • 项目类别:
Cancer Classifiers Based on RNA Sensors in Living Cells
基于活细胞中 RNA 传感器的癌症分类器
  • 批准号:
    10570559
  • 财政年份:
    2022
  • 资助金额:
    $ 21.8万
  • 项目类别:
Cancer Classifiers Based on RNA Sensors in Living Cells
基于活细胞中 RNA 传感器的癌症分类器
  • 批准号:
    10707194
  • 财政年份:
    2022
  • 资助金额:
    $ 21.8万
  • 项目类别:
Synthetic DNA-free Circuits for “Scarless” Programming of Mammalian Cells
用于哺乳动物细胞“无痕”编程的合成无 DNA 电路
  • 批准号:
    10115864
  • 财政年份:
    2020
  • 资助金额:
    $ 21.8万
  • 项目类别:
Synthetic DNA-free Circuits for “Scarless” Programming of Mammalian Cells
用于哺乳动物细胞“无痕”编程的合成无 DNA 电路
  • 批准号:
    10379933
  • 财政年份:
    2020
  • 资助金额:
    $ 21.8万
  • 项目类别:

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  • 批准号:
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    20K17617
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  • 财政年份:
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阐明远隔效应的机制-创新的癌症治疗策略-
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    18H02696
  • 财政年份:
    2018
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    Grant-in-Aid for Scientific Research (B)
The abscopal effect of nanosecond electric pulse tumor ablation and its enhancement for metastatic breast cancer
纳秒电脉冲肿瘤消融及其强化治疗转移性乳腺癌的远隔效应
  • 批准号:
    9756343
  • 财政年份:
    2018
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Consideration of effectiveness of intra-abdominal hyperthermia chemotherapy devised from abscopal effect
从远隔效应角度探讨腹腔热化疗的有效性
  • 批准号:
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  • 财政年份:
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Development of a new cancer treatment method using semiconductor lasers and investigation of the abscopal effect
使用半导体激光器开发新的癌症治疗方法并研究远隔效应
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    18K17222
  • 财政年份:
    2018
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    $ 21.8万
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    Grant-in-Aid for Early-Career Scientists
CT detection of primary and metastatic tumor and their treatment abscopal effect via radiation
原发性和转移性肿瘤的CT检测及其放射治疗远隔效应
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Exploratory Optimization of Organs for Radiotherapy or Cancer Vaccination by Abscopal Effect
通过远隔效应探索性优化放疗或癌症疫苗接种的器官
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