A novel strategy to overcome drug resistance in cancer

克服癌症耐药性的新策略

• 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
• 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

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 癌症治疗成功的主要障碍是耐药性的迅速发展。虽然有针对性 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 短暂的。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显着的遗传异质性；肿瘤细胞没有 敏化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。有 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。一个 即使单个组件发生故障，强大的系统也能继续运行。在毒品的背景下 发展过程中，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。实现这种冗余的一种方法是采用多效性 天然化合物的作用。内源信号分子产生协调且复杂的反应 通过并行定位多个信令节点。例如，内源性鞘脂表现出强效的肿瘤作用 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 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。在一个 第893章 肿瘤生长82%。第893章 50%以上的肿瘤消退 老鼠。第893章 护理疗法。反对多效剂的主要论点是毒性将是不可接受的 相对于更具体的药物而言被放大。然而，天然鞘脂会导致正常细胞静止 对压力的适应性、稳态反应的一部分。事实上，893 不会引起器官毒性或破坏 即使治疗 3 个月后，骨髓或肠隐窝中的正常细胞仍会增殖 抗肿瘤剂量。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 有助于其安全边际。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 批准的疗法产生耐药性。该提案将检验这一具有争议性的假设。预期结果 通过改变该领域的思维并提供新的治疗方法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。