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Development of synthetic sphingolipids for prostate cancer therapy

开发用于前列腺癌治疗的合成鞘脂

基本信息

批准号：
10269032
负责人：
Alison Nicole McCracken
金额：
$ 98.94万
依托单位：
SIEGE PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-24 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10269032
关键词：
Address Amino Acids Androgen Receptor Antigens Benchmarking Bone Marrow Cancer Patient Canis familiaris Cardiovascular system Cause of Death Cell Nucleus Cells Characteristics Clinical Research Clinical Trials Design Combined Modality Therapy Cross Presentation Cytotoxic Chemotherapy Data Dendritic Cells Development Dose Dose-Limiting Drug Kinetics Drug Sensitization Drug resistance Effectiveness Evaluation FDA approved Fasting Funding Genes Genetic Transcription Genetically Engineered Mouse Glucose Goals Government Growth Immunologics Immunotherapy Importins In Vitro In complete remission Lead Lipids Malignant Neoplasms Malignant neoplasm of prostate Maximum Tolerated Dose Measures Modeling Morbidity - disease rate Mus Normal Cell Normal tissue morphology Nuclear Nuclear Import Nutrient Oncogenic Oncology Oral Organoids Outcome Patients Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Phase I Clinical Trials Population Pre-Clinical Model Proliferating Prostate Prostate Cancer therapy Prostate-Specific Antigen Protein Phosphatase 2A Regulatory Subunit PR53 Protocols documentation Rattus Recurrence Resistance Risk Safety Signal Transduction Sphingolipids Stress Structure-Activity Relationship Telemetry Testing Therapeutic Index Toxic effect Toxicology Tumor Volume Tumor stage Work addiction anticancer activity cancer cell cancer therapy chemotherapy clinical application efficacy evaluation first-in-human in vivo innovation mortality neoplastic cell novel patient derived xenograft model patient population pharmacodynamic biomarker phase I trial prevent prostate cancer model response risk minimization standard of care targeted agent therapy resistant trafficking tumor tumor growth tumor metabolism tumor-immune system interactions

项目摘要

PROJECT SUMMARY The objective of this project is to develop the synthetic sphingolipid SGE-893 (893) into an FDA-approved cancer therapy, with the ultimate goal of reducing mortality and morbidity rates in end-stage, drug-resistant prostate cancer. 893 shows promising pharmacological characteristics and potent anti-cancer activity in pre-clinical models while sparing normal tissues. 893 and related molecules have a novel mechanism of action, simultaneously engaging two validated oncology targets. This dual-target approach is deadly to cancer cells and predicted to reduce the risk of resistance. Despite its pleiotropic actions, 893 is well-tolerated by normal proliferating cells. Thus, 893 shows potential as a single-agent therapy that could produce a durable response even in hard-to-treat cancers like late-stage prostate, for which systemic chemotherapy remains the standard- of-care (SOC) and high recurrence and mortality rates are driven by resistance. As 893’s mechanism of action further suggests that it could sensitize drug-resistant tumors to FDA-approved agents, 893 may have additional clinical applications as a component of combination therapy. With key de-risking studies completed, we are proposing a Direct-to-Phase II approach. The objectives of Aim 1 are to extend the Target Product Profile by evaluating efficacy in combination with FDA-approved agents and to validate pharmacodynamics markers that can be used to measure target engagement in a phase 1 trial. Aim 2 proposes toxicology studies required for an IND application. The expected results would become part of a strong portfolio demonstrating acceptable toxicity to share with the FDA. Were it to be approved for patient use, this innovative molecule would become a first-in- class compound, offering hope and reducing mortality in PC patients whose tumors fail to respond to or become resistant to SOC.

项目总结