A novel strategy to overcome drug resistance in cancer

克服癌症耐药性的新策略

基本信息

批准号：
10319166
负责人：
Aimee L Edinger
金额：
$ 23.87万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10319166
关键词：
Address Ally Androgen Receptor Antineoplastic Agents Binding Biochemical Biological Assay Bone Marrow Cancer Control Cancer Patient Cell Death Cell Proliferation Cells Cessation of life Complex Cytotoxic Chemotherapy Data Dependence Dose Drug Kinetics Drug Sensitization Drug resistance Epigenetic Process Exhibits FDA approved Genetic Heterogeneity Genetic Transcription Genetically Engineered Mouse Goals Growth Immunooncology Importins Individual Isogenic transplantation Label Laboratories Ligands Link Malignant Neoplasms Malignant neoplasm of prostate Modeling Mus Mutation Normal Cell Nuclear Nuclear Import Nuclear Pore Nutrient Oncology Organ Organoids Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Pore Proteins Proliferating Property Prostatic Neoplasms Protein Isoforms Protein phosphatase Publishing RNA Splicing Research Resistance Resistance development Safety Signal Pathway Signal Transduction Signaling Molecule Solid Neoplasm Sphingolipids Stress System Testing Therapeutic Thinking Time Toxic effect Tumor Suppressor Proteins Work analog androgen deprivation therapy anti-PD-1 anti-cancer anti-tumor immune response base cancer cell cancer therapy chemoproteomics chemotherapy docetaxel driver mutation drug development evidence base immune checkpoint blockade improved inhibitor innovation intestinal crypt neoplastic cell novel novel strategies novel therapeutic intervention patient subsets pressure prevent prostate cancer cell response single cell sequencing standard of care subcutaneous targeted treatment therapy resistant trafficking transcription factor tumor tumor growth tumor heterogeneity

项目摘要

ABSTRACT The major obstacle to successful cancer therapy is the rapid development of drug resistance. While targeted therapies often extend overall survival in the subset of patients with sensitizing mutations, their effects are short-lived. Patients who initially respond to these drugs generally develop resistance within a few months. Single-cell sequencing of tumors has revealed significant genetic heterogeneity; tumor cells without the sensitizing mutation survive therapy and re-populate the tumor. At the same time, compensatory epigenetic and genetic changes relieve dependence on the targeted pathway, also contributing to resistance. There is thus a critical unmet need for new therapeutic strategies capable of providing more robust cancer control. A robust system continues to function even when an individual component fails. In the context of drug development, a robust therapy would produce parallel, redundant anti-cancer effects, each of which is sufficient to inhibit tumor growth. One approach to achieving such redundancy is to embrace the pleiotropic actions of natural compounds. Endogenous signaling molecules produce coordinated and complex responses by targeting multiple signaling nodes in parallel. For example, endogenous sphingolipids exhibit potent tumor suppressor activity by producing multifaceted and incompletely characterized changes in signaling pathways that trigger proliferative arrest in normal cells and death in cancer cells. SH-BC-893 (893), a synthetic sphingolipid with improved drug properties, retains the anti-neoplastic activity of these natural compounds. In a rigorous, genetically-engineered mouse model for aggressive prostate cancer, 893 reduces autochthonous tumor growth by 82%. In a related subcutaneous isograft model, 893 produces tumor regressions in >50% of mice. 893 is also effective against patient-derived prostate tumor organoids that are resistant to standard-of- care therapies. The major argument against pleiotropic agents has been that toxicity will be unacceptably amplified relative to more specific drugs. However, natural sphingolipids induce quiescence in normal cells as part of an adaptive, homeostatic response to stress. Indeed, 893 does not cause organ toxicity or disrupt the proliferation of normal cells in the bone marrow or intestinal crypts even after 3 months of treatment with the anti-neoplastic dose. Normal cells are more resistant to 893, but 893’s pharmacokinetic properties also likely contribute to its safety margin. Our preliminary data showing that 893 engages multiple, high-value oncology targets results raise the possibility that 893 will be less susceptible to drug resistance and could overcome resistance to FDA-approved therapies. This proposal will test this provocative hypothesis. The expected results would have a significant positive impact by changing thinking in the field and providing a novel therapeutic strategy that would be effective in patients with late-stage, lethal prostate cancers.

抽象的成功癌症治疗的主要障碍是靶向治疗时耐药性的快速发展。治疗通常可以延长具有敏化突变的患者的总体生存期，其效果是最初对这些药物有反应的患者通常会在几个月内产生耐药性。肿瘤的单细胞测序揭示了肿瘤细胞的显着遗传异质性；致敏突变在治疗中存活并重新填充肿瘤，同时，补偿性表观遗传。基因变化减轻了对目标途径的依赖，也有助于抵抗。因此，对能够提供更强有力的癌症控制的新治疗策略的迫切需求尚未得到满足。即使在药物的情况下单个组件发生故障，强大的系统仍能继续发挥作用。发展过程中，一种强有力的疗法会产生并行的、多余的抗癌作用，其中每一个作用都是足以抑制肿瘤生长的一种方法是采用多效性。天然化合物的作用产生协调和复杂的反应。通过并行靶向多个信号传导节点，例如，内源性鞘脂表现出有效的肿瘤作用。通过在信号通路中产生多方面且不完全表征的变化来抑制活性触发正常细胞的增殖停滞和癌细胞的死亡 SH-BC-893 (893)，一种合成的。鞘脂具有改善的药物特性，保留了这些天然化合物的抗肿瘤活性。第893章第893章 893 893 也能有效对抗对标准有抗性的患者来源的前列腺肿瘤类器官。反对多效药物的主要论点是毒性将是不可接受的。然而，天然鞘脂会导致正常细胞静止。事实上，893 不会引起器官毒性或破坏器官功能。即使治疗 3 个月后，骨髓或肠隐窝中的正常细胞仍会增殖正常细胞对 893 的抵抗力更强，但 893 的药代动力学特性也可能如此。我们的初步数据显示 893 涉及多种高价值肿瘤学。第893章 893 对 FDA 批准的疗法的耐药性将测试这一具有挑战性的假设的预期结果。通过改变该领域的思维并提供治疗小说将产生重大的积极影响该策略对晚期致命性前列腺癌患者有效。