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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：
10609389
负责人：
Aimee L Edinger
金额：
$ 48.08万
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/10609389
关键词：
Address Androgen Receptor Antineoplastic Agents Binding Biochemical Biological Assay Bone Marrow Cancer Control Cancer Patient Cell Proliferation Cell Survival 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 Natural Compound Normal Cell Nuclear Import Nuclear Pore Nutrient Oncology Organ Organoids Outcome Pathway interactions Patients Performance Pharmaceutical Preparations Pore Proteins Predisposition 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 Starvation Stress System Testing Therapeutic Thinking Time Toxic effect Tumor Suppressor Proteins Work access restrictions analog androgen deprivation therapy anti-PD-1 anti-cancer anti-tumor immune response cancer cell cancer therapy chemoproteomics chemotherapy docetaxel driver mutation drug development drug resistance 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 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.

摘要