Lipid-based Cancer Therapeutics

基于脂质的癌症治疗

• 批准号: 10065270
• 负责人: Johannes Morstein
• 金额: $ 3.24万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-11 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065270
• 关键词: Antineoplastic Agents; Biological; Biology; Cancer Biology; Cell Culture Techniques; Cell membrane; Chemistry; Clinical; Clinical Trials; Complement; Conceptions; Development; Doxorubicin Hydrochloride Liposome; Encapsulated; Enzymes; Goals; Human; In Vitro; Interdisciplinary Study; Ion Channel; KRAS2 gene; Knowledge; Light; Lipids; Malignant Neoplasms; Medicine; Membrane Proteins; Mutate; Oncogenes; Optics; Pharmaceutical Preparations; Pharmacology; Postdoctoral Fellow; Property; RNA; Research; Research Project Grants; Signal Transduction; Small RNA; Structure; Surface; System; Tail; Therapeutic; base; cancer immunotherapy; cancer therapy; clinical efficacy; design; improved; innovation; lipid metabolism; lipid nanoparticle; nanotherapy; novel; novel strategies; pharmacophore; receptor; small molecule; therapeutic RNA

Project Summary Significant progress in human cancer therapy in the last decade has been driven by conceptionally new approaches to targeting cancer, including cancer immunotherapy, cancer nanotherapy, or new types of biologics and small molecules. Both my dissertation and postdoc research will be focused on the development of fundamentally new approaches to targeting cancer. My dissertation research is focused on the development of photoswitchable lipids for the optical control of lipid metabolism and function. In addition to targeting specific receptors, ion-channels, or enzymes, light-induced structural changes in a lipid nanoparticle (LNP) could serve as trigger for the release of encapsulated drugs. Triggered release could markedly improve the efficacy of clinically approved LNP-based cancer therapeutics, which include Doxil/Caelyx, DaunoXome, Myocet, Lipo-Dox, or Marqibo. I seek to design and synthesize photoswitchable lipids for `photoactivable lipid nanoparticles', herein termed paLNPs, that allow for effective light- triggered release of encapsulated cancer drugs. Two complementary approaches will be developed for small molecule drugs and RNA-based therapeutics and the pharmacological properties of paLNPs will be systematically investigated in vitro and in cell culture. In my postdoctoral research I seek to use my acquired knowledge in chemistry, lipid-biology, and medicine to develop lipid-drug conjugates for biological targets that function at plasma-membrane signaling hotspots. The initial target will be the mutated oncogene KRAS G12C, which is ideally suited for this new approach. Conjugating selective covalent modifier of this oncogene with a lipid will attach an additional lipid tail to the surface of KRAS that could largely alter its membrane-protein interaction and in the best case completely inhibit its function. This could markedly increase the efficacy of the covalent pharmacophores currently in clinical trials. I seek to synthesize and systematically study these lipid-drug conjugates in vitro and in cell culture.

项目摘要 在过去的十年中，人类癌症治疗的重大进展是由概念上新的 靶向癌症的方法，包括癌症免疫疗法、癌症纳米疗法或新型生物制剂 和小分子。我的论文和博士后研究都将集中在发展 治疗癌症的全新方法。 我的学位论文研究的重点是光开关脂质的光学控制的发展 代谢和功能。除了靶向特定的受体、离子通道或酶之外，光诱导的 脂质纳米颗粒（LNP）中的结构变化可以作为释放包封药物的触发器。 触发释放可以显著提高临床批准的基于LNP的癌症治疗剂的功效， 其包括Doxil/Caelyx、DaunoXome、Myocet、Lipo-Dox或Marqibo。我试图设计和合成 用于“光活化脂质纳米颗粒”的光可转换脂质，本文称为paLNP，其允许有效的光- 引发了包裹的抗癌药物的释放。将为小型企业开发两种互补的方法， 分子药物和基于RNA的治疗方法以及paLNPs的药理学特性将是 在体外和细胞培养中进行了系统研究。 在我的博士后研究中，我试图利用我在化学，脂质生物学和医学方面获得的知识， 开发用于在质膜信号传导热点处起作用的生物靶标的脂质-药物缀合物。的 最初的目标将是突变的癌基因KRAS G12 C，它非常适合这种新方法。缀合 该癌基因与脂质的选择性共价修饰剂将使额外的脂质尾附着到KRAS的表面 这可以在很大程度上改变其膜蛋白相互作用，并在最好的情况下完全抑制其功能。这 可以显著增加目前在临床试验中的共价药效团的功效。我寻求 合成并在体外和细胞培养中系统地研究这些脂质-药物缀合物。

项目成果

Photoswitchable Isoprenoid Lipids Enable Optical Control of Peptide Lipidation.

• DOI: 10.1021/acschembio.2c00645
• 发表时间: 2022-10-21
• 期刊: ACS CHEMICAL BIOLOGY
• 影响因子: 4
• 作者: Morstein, Johannes;Bader, Taysir;Cardillo, Ariana L.;Schackmann, Julian;Ashok, Sudhat;Hougland, James L.;Hrycyna, Christine A.;Trauner, Dirk H.;Distefano, Mark D.
• 通讯作者: Distefano, Mark D.

A Photohormone for Light-Dependent Control of PPARα in Live Cells.

用于活细胞中 PPARα 光依赖性控制的光激素。

• DOI: 10.1021/acs.jmedchem.1c00810
• 发表时间: 2021
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Willems,Sabine;Morstein,Johannes;Hinnah,Konstantin;Trauner,Dirk;Merk,Daniel
• 通讯作者: Merk,Daniel

Postsynthetic Photocontrol of Giant Liposomes via Fusion-Based Photolipid Doping.

• DOI: 10.1021/acs.langmuir.2c01685
• 发表时间: 2022-10-04
• 期刊: LANGMUIR
• 影响因子: 3.9
• 作者: Pritzl, Stefanie D.;Morstein, Johannes;Kahler, Sophia;Konrad, David B.;Trauner, Dirk;Lohmuller, Theobald
• 通讯作者: Lohmuller, Theobald

Chemoselective Covalent Modification of K-Ras(G12R) with a Small Molecule Electrophile.

• DOI: 10.1021/jacs.2c05377
• 发表时间: 2022-09-07
• 期刊: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
• 影响因子: 15
• 作者: Zhang, Ziyang;Morstein, Johannes;Ecker, Andrew K.;Guiley, Keelan Z.;Shokat, Kevan M.
• 通讯作者: Shokat, Kevan M.