Nanoparticles-mediated combination therapy for breast cancer

纳米颗粒介导的乳腺癌联合疗法

• 批准号: 10617544
• 负责人: Song Li
• 金额: $ 51.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617544
• 关键词: Anthracycline; Antigen Presentation; Antineoplastic Agents; Apoptosis; Autophagocytosis; BRCA mutations; Biodistribution; Biomedical Engineering; Breast Cancer Model; Breast Cancer Patient; Breast Cancer therapy; Cancer Etiology; Cancer Patient; Carcinoma; Cessation of life; Chemoresistance; Clinic; Combined Modality Therapy; Data; Development; Doxorubicin; Drug resistance; Endoplasmic Reticulum; Endothelium; Enzymes; Epidermal Growth Factor Receptor; HIF1A gene; Homeostasis; Human; Hydrophobicity; Immune response; Immunotherapy; Inflammatory; Knock-out; Ligands; Malignant Neoplasms; Mediating; Membrane; Membrane Proteins; Metabolic Biotransformation; Metalloproteases; Metastatic Neoplasm to the Lung; Metastatic breast cancer; Modeling; Mus; Neoplasm Metastasis; Nucleic Acids; Pathway interactions; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Play; Prodrugs; Prognosis; Proteins; Reporting; Role; Safety; Small Interfering RNA; TNF gene; Therapeutic; Tissues; Toxic effect; Transmembrane Domain; Treatment Efficacy; United States; Vorinostat; Woman; cancer cell; cancer type; chemotherapeutic agent; chemotherapy; cytokine; immunotherapy trials; improved; in vivo; knock-down; lipophilicity; malignant breast neoplasm; molecular subtypes; nanocarrier; nanoparticle; neoplastic cell; new combination therapies; novel; novel strategies; overexpression; p38 Mitogen Activated Protein Kinase; response; rhomboid; small molecule; small molecule inhibitor; targeted delivery; targeted treatment; taxane; therapeutic target; trafficking; transcytosis; translational therapeutics; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor xenograft; tumor-immune system interactions

Abstract Despite recent advances in treatment, metastatic breast cancer (mBCa) remains one of the leading causes of cancer-related deaths in the United States among women. Chemotherapy remains fundamental to the management of all molecular subtypes of mBCa and anthracyclines and taxanes are two major types of chemotherapeutics. One major issue in chemotherapy is drug resistance, both intrinsic and acquired. In addition, the overall benefit of immunotherapy remains limited for mBCa. There is still a need to develop novel strategies to overcome chemoresistance and/or the poor response of immunotherapy in mBCa. IRhom proteins (iRhom 1 and iRhom 2) are catalytically inactive relatives of rhomboid intramembrane proteases and play an important role in regulating the stability and trafficking of other membrane proteins. IRhom1 is overexpressed in several types of cancers including breast cancer (BCa) and knockdown of iRhom1 led to significant inhibition of tumor growth in vivo. We have shown that knockdown of iRhom1 led to sensitization of tumor cells to several chemotherapeutic agents including doxorubicin (DOX) and SAHA. We have further shown that iRhom1 plays a role in modulating tumor immune response and knockout of iRhom1 resulted in an improvement in tumor immune microenvironment. To facilitate the therapeutic translation of these novel findings, we have developed a new nanocarrier that is highly effective in selective codelivery of iRhom1 siRNA and chemotherapeutic agents to tumors. We have also developed a bioengineered iRhom1 pre-siRNA (pre-siiRhom1) that is biotransformed to mature siRNA upon intracellular delivery. We have further developed DOX-SAHA, a prodrug conjugate to facilitate codelivery of the two drugs of synergistic action. This application is focused on further improvement of the safety and the tumor-targeting efficiency of the nanocarrier as well as the overall therapeutic efficacy of codelivery of DOX-SAHA/pre-siiRhom1. The underlying mechanism will also be investigated. Three specific aims will be pursued in this proposal. Aim 1 will develop and characterize an improved nanocarrier for co-formulating DOX-SAHA and pre-siiRhom1. Aim 2 will investigate the tumor-targeting efficiency of the nanocarrier, and the PK and tissue biodistribution of DOX-SAHA and pre-siiRhom1 co-formulated in the nanocarrier. Aim 3 will investigate the in vivo therapeutic efficacy, the underlying mechanism, and the toxicity profile of the combination therapy in murine and human BCa models. Successful completion of this study will lead to the development of a new combination therapy for the treatment of different types of cancers including mBCa.

抽象的 尽管最近在治疗方面取得了进步，但转移性乳腺癌（MBCA）仍然是 在美国，妇女中与癌症有关的死亡。化学疗法仍然是 MBCA和Anthracyclines和tuxanes的所有分子亚型的管理是两种主要类型 化学治疗学。化学疗法的一个主要问题是耐药性和固有性和获得性。此外， MBCA免疫疗法的总体好处仍然有限。仍然需要制定新颖的策略 克服化学抗性和/或MBCA免疫疗法反应不佳。 iRhom蛋白（irhom 1 和irhom 2）是菱形内膜内蛋白酶的催化无活性亲属，并且起着重要的作用 在调节其他膜蛋白的稳定性和运输中的作用。 IRHOM1在几个 包括乳腺癌（BCA）和IRHOM1敲低的癌症类型导致肿瘤的显着抑制 体内生长。我们已经表明，IRHOM1的敲低导致肿瘤细胞对几个 包括阿霉素（DOX）和SAHA在内的化学治疗剂。我们进一步表明irhom1扮演 在调节肿瘤免疫反应和IRHOM1敲除的作用导致肿瘤免疫的改善 微环境。为了促进这些新发现的治疗翻译，我们开发了一个新的 在IRHOM1 siRNA和化学治疗剂的选择性代码传递方面非常有效的纳米载体 肿瘤。我们还开发了一个生物工程的IRHOM1 pre-siRNA（pre-siirhom1），该生物转化为 细胞内递送后成熟的siRNA。我们进一步开发了dox-saha，一种前药结合 促进协同作用的两种药物的代码分子。该应用的重点是进一步改进 纳米载体的安全性和针对性效率以及总体治疗功效 dox-saha/pre-siirhom1的代码。基本机制也将进行研究。三个具体目标 将在此提案中追求。 AIM 1将开发并表征改进的纳米载体以进行合并 dox-saha和pre-siirhom1。 AIM 2将研究纳米载体的肿瘤靶向效率， 在纳米载体中共形成的dox-saha和siirhom1的PK和组织生物分布。目标3意志 研究体内治疗功效，基本机制和组合的毒性特征 鼠和人类BCA模型的治疗。成功完成这项研究将导致 一种新的组合疗法，用于治疗包括MBCA在内的不同类型的癌症。