Augmenting Quadruple Negative Breast Cancer Treatment by ADRM1 Inhibitor Up284

ADRM1 抑制剂 Up284 增强四阴性乳腺癌治疗

基本信息

批准号：
10809409
负责人：
Balasubramanyam Karanam
金额：
$ 37.49万
依托单位：
TUSKEGEE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-07 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10809409
关键词：
4T1 Address Affect African American African American population African ancestry Androgen Receptor Antibodies Antitumor Response Apoptosis Binding Biological Biological Assay Biological Markers Biomedical Research Biotinylation Blood Bortezomib Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line CRISPR/Cas technology Cell Line Cells Chemistry Cisplatin Clinic Clinical Combination immunotherapy Data Deubiquitination Development Disease Disparity Dose Drug Kinetics Drug Targeting ERBB2 gene Exhibits Genomics Goals Growth Growth Factor Receptors Histologic Hormone Receptor Human Immune checkpoint inhibitor Immunotherapy In Vitro Knock-out Label Lead Licensing Lymphoid Malignant Neoplasms Mammary Neoplasms Measures Medical Metabolic Modeling Molecular Weight Monoclonal Antibodies Morbidity - disease rate Mus Myelogenous Neoplasm Metastasis Neutropenia Normal Cell Nude Mice Organoids Outcome PD-1 inhibitors Paclitaxel Patient Selection Patients Peptides Peritoneal Pharmaceutical Preparations Pharmacodynamics Phenotype Population Predisposition Prognosis Property Proteasome Inhibition Proteasome Inhibitor Proteins Race Research Resistance Safety Sampling Signal Pathway Signal Transduction Solid Solid Neoplasm Specimen Streptavidin Structure System Therapeutic Thrombocytopenia Tissue Microarray Tissues Toxic effect Treatment Efficacy Ubiquitin Universities Venous aggressive breast cancer anti-PD-L1 anti-tumor immune response anticancer activity biomarker development biomarker selection cancer cell cancer subtypes chemotherapeutic agent chemotherapy cohort design disparity reduction effective therapy efficacy validation endoplasmic reticulum stress health disparity improved inhibitor inhibitor therapy insight malignant breast neoplasm misfolded protein mortality mouse model multicatalytic endopeptidase complex novel particle programmed cell death ligand 1 protein aggregation racial disparity receptor receptor expression response small molecule small molecule inhibitor standard of care synergism therapeutic lead compound three dimensional cell culture treatment response triple-negative invasive breast carcinoma tumor tumor growth tumor progression tumor xenograft ubiquitin isopeptidase

项目摘要

Project Summary This proposal aims to develop QNBC as the lead indication for our ADRM1 inhibitor, Up284, and support biomarker development to select QNBC patients for ADRM1 inhibitor therapy. It addresses critical questions for the development of effective and safe treatments for QNBC and the reduction of the disparity in breast cancer outcomes. Quadruple negative breast cancer (QNBC) is a subtype of breast cancer that does not express the hormone receptors ER and PR, the growth factor receptor HER2, and the androgen receptor AR. QNBC has the poorest prognosis among breast cancer subtypes and disproportionately affects African Americans. Currently, there is no standard-of-care treatment for QNBC, and there is an urgent need to develop effective and safe treatments and biomarkers to address this unmet medical need and the disparity in breast cancer outcomes. Our research team has recently found that elevated expression of proteasome subunit ADRM1 is associated with both African American race and lower survival in QNBC patients. Our collaborator Up Therapeutics developed an inhibitor called Up284 that targets ADRM1. While QNBC and triple negative breast cancer (TNBC) cell lines show evidence of greater vulnerability to proteasome inhibitors, approved 20S proteasome inhibitors like bortezomib have proven ineffective against solid tumors due to their partial proteasome inhibition, inability to achieve therapeutic doses, and poor pharmacokinetic properties. Up284 is a novel small molecule designed to overcome these limitations. Its structure is a non-peptide spiro compound with improved drug access and favorable pharmacokinetic properties to solid tumors compared to peptide-based 20S inhibitors. Up284 also blocks substrate recognition and deubiquitination, providing full proteasome inhibition and avoiding key toxicities like thrombocytopenia and neutropenia. In vitro studies show that Up284 has broad anticancer activity, including against QNBC lines and patient-derived organoids. It has a promising safety profile and pharmacodynamics and can control syngeneic and xenograft tumors. By inhibiting proteasome ubiquitin receptor ADRM1 function and its associated deubiquitinase activity, Up284 triggers more rapid accumulation and increased molecular weight polyubiquitinated protein aggregates than 20S inhibitors. These toxic misfolded protein aggregates produce unresolved ER stress and activate the canonical Unfolded Protein Response (UPR) signaling cascade, leading to more rapid apoptosis than 20S inhibitors. We plan to examine ADRM1 and ER stress markers' expression in diverse QNBC patient samples and validate sensitivity to Up284 to develop a biomarker for selecting patients for better therapeutic efficacy and safety. We also will validate the synergy of Up284 efficacy in combination with in-clinic chemotherapeutic agents used to treat TNBC to improve therapeutic response and block the emergence of resistance. Finally, we will assess Up284's potential to induce antitumor immune response in combination with checkpoint inhibitors, notably with anti-PDL1 or anti-PD1 inhibitors.

项目概要该提案旨在开发 QNBC 作为我们的 ADRM1 抑制剂 Up284 的主要适应症，并支持生物标志物开发，以选择 QNBC 患者接受 ADRM1 抑制剂治疗。它解决了开发有效且安全的 QNBC 治疗方法的关键问题，减少乳腺癌结果的差异。四阴性乳腺癌 (QNBC) 是不表达乳腺癌的一种亚型激素受体 ER 和 PR、生长因子受体 HER2 和雄激素受体AR。 QNBC 在乳腺癌亚型中预后最差，对非裔美国人的影响尤为严重。目前，尚无标准护理治疗对于 QNBC，迫切需要开发有效且安全的治疗方法和生物标志物解决这一未满足的医疗需求和乳腺癌结果的差异。我们的研究研究小组最近发现，蛋白酶体亚基 ADRM1 的表达升高与非洲裔美国人种族和 QNBC 患者的生存率较低。我们的合作者向上 Therapeutics 开发了一种名为 Up284 的抑制剂，其靶向 ADRM1。而 QNBC 和 Triple 阴性乳腺癌 (TNBC) 细胞系显示出更容易受到蛋白酶体抑制剂，已批准的 20S 蛋白酶体抑制剂（如硼替佐米）已被证明由于其部分蛋白酶体抑制作用，无法有效对抗实体瘤治疗剂量和药代动力学特性较差。 Up284是一种新型小分子旨在克服这些限制。其结构是一种非肽螺环化合物与实体瘤相比，改善了药物的可及性和有利的药代动力学特性基于肽的 20S 抑制剂。 Up284 还阻断底物识别和去泛素化，提供全面的蛋白酶体抑制并避免关键毒性，如血小板减少症和中性粒细胞减少症。体外研究表明 Up284 具有广泛的抗癌活性，包括 QNBC 系和源自患者的类器官。它具有良好的安全性和药效学，可以控制同基因和异种移植肿瘤。通过抑制蛋白酶体泛素受体 ADRM1 功能及其相关的去泛素酶活性， Up284 触发更快速的积累并增加多聚泛素化的分子量蛋白质聚集性优于 20S 抑制剂。这些有毒的错误折叠蛋白质聚集体会产生未解决的内质网应激并激活经典的未折叠蛋白反应 (UPR) 信号级联反应，导致比 20S 抑制剂更快的细胞凋亡。我们计划检查 ADRM1 和 ER 应激标记物在不同 QNBC 患者样本中的表达并验证其敏感性 Up284 开发一种生物标志物，用于选择患者以获得更好的治疗效果和安全。我们还将验证Up284功效与临床相结合的协同作用用于治疗 TNBC 的化疗药物可改善治疗反应并阻断阻力的出现。最后，我们将评估 Up284 诱导抗肿瘤免疫的潜力与检查点抑制剂联合使用的反应，特别是与抗 PDL1 或抗 PD1 联合使用抑制剂。