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展，但转移性乳腺癌（mBCa）仍然是导致乳腺癌的主要原因之一。 美国女性癌症相关死亡。化疗仍然是治疗的基础 管理 mBCa 的所有分子亚型，蒽环类药物和紫杉烷类药物是两种主要类型 化疗。化疗的一个主要问题是耐药性，包括内在的和获得性的。此外， 免疫疗法对 mBCa 的总体益处仍然有限。仍然需要制定新颖的策略 克服 mBCa 的化疗耐药性和/或免疫疗法的不良反应。 IRhom 蛋白 (iRhom 1 和 iRhom 2) 是菱形膜内蛋白酶的无催化活性亲属，并发挥重要作用 在调节其他膜蛋白的稳定性和运输中发挥作用。 IRhom1 在多种细胞中过表达 包括乳腺癌 (BCa) 在内的癌症类型和 iRhom1 敲除可显着抑制肿瘤 体内生长。我们已经证明 iRhom1 的敲低导致肿瘤细胞对几种 化疗药物包括阿霉素（DOX）和SAHA。我们进一步证明 iRhom1 发挥着 调节肿瘤免疫反应的作用和 iRhom1 的敲除导致肿瘤免疫的改善 微环境。为了促进这些新发现的治疗转化，我们开发了一种新的 纳米载体能够高效地将 iRhom1 siRNA 和化疗药物选择性共递送至 肿瘤。我们还开发了一种生物工程化的 iRhom1 pre-siRNA (pre-siiRhom1)，它被生物转化为 细胞内递送后成熟的 siRNA。我们进一步开发了 DOX-SAHA，一种前药缀合物 促进协同作用的两种药物的共同递送。该应用程序的重点是进一步改进 纳米载体的安全性和肿瘤靶向效率以及整体治疗效果 DOX-SAHA/pre-siiRhom1 的同时递送。还将研究其潜在机制。三个具体目标 将在本提案中予以落实。目标 1 将开发并表征一种改进的纳米载体，用于共同配制 DOX-SAHA 和 pre-siiRhom1。目标2将研究纳米载体的肿瘤靶向效率，以及 DOX-SAHA 和 pre-siiRhom1 在纳米载体中共同配制的 PK 和组织生物分布。目标3将 研究组合的体内治疗功效、潜在机制和毒性特征 小鼠和人类 BCa 模型中的治疗。本研究的成功完成将促进以下领域的发展： 一种新的联合疗法，用于治疗包括 mBCa 在内的不同类型的癌症。