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耐药性的快速发展。有针对性的疗法通常会扩大具有敏化突变患者子集的总体生存，其影响是短暂的。最初对这些药物做出反应的患者通常会在几个月内发展出抗药性。肿瘤的单细胞测序显示出明显的遗传异质性。肿瘤细胞没有敏化突变在疗法中生存并重新填充肿瘤。同时，补偿性表观遗传遗传变化缓解了对靶向途径的依赖，也有助于阻力。有因此，对能够提供更强大癌症控制的新治疗策略的批判性未满足。一个即使单个组件失败，稳健的系统仍会继续运行。在毒品的背景下开发，一种健壮的疗法会产生平行的，多余的抗癌作用，每种疗法是足以抑制肿瘤生长。实现这种冗余的一种方法是拥抱多效性天然化合物的作用。内源信号分子产生了协调和复杂的响应通过并联靶向多个信号节点。例如，内源性鞘脂暴露有效肿瘤通过产生多方面和未完全表征信号通路的变化来抑制活性这会触发正常细胞中的增生剂停滞，并在癌细胞中死亡。 SH-BC-893（893），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。在严格的，遗传工程的小鼠模型，用于侵略性前列腺癌，893减少了自围候肿瘤生长增长了82％。在相关的皮下同类移植模型中，893在> 50％以上产生肿瘤回归老鼠。 893还有效地抵抗患者衍生的前列腺肿瘤类器官，这些器官耐药性护理疗法。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放大。然而，天然鞘脂会在正常细胞中诱导静止自适应，稳态反应的一部分。确实，893不会引起器官毒性或破坏即使经过3个月的治疗，骨髓或肠道隐窝中正常细胞的增殖抗塑性剂量。正常细胞对893的耐药性更大，但是893的药代动力学特性也可能具有对其安全利润的贡献。我们的初步数据表明893与多个高价值肿瘤学参与目标结果增加了893的可能性，即耐药性不太容易受到耐药的影响对FDA批准的疗法的抗性。该建议将检验这一挑衅性假设。预期结果通过改变现场思维并提供新颖的疗法，将产生重大的积极影响对晚期致死前列腺的患者有效的策略。