Enhancing chemotherapeutic efficacy in triple-negative breast cancer via DSTYK silence

通过 DSTYK 沉默增强三阴性乳腺癌的化疗效果

• 批准号: 10657021
• 负责人: Yong Jiang
• 金额: $ 35.5万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-10 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657021
• 关键词: Adjuvant Chemotherapy; Apoptosis; Attenuated; Bax protein; Biochemical; Biological Models; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; CRISPR/Cas technology; Cell Death; Cell Death Inhibition; Cell Survival; Cell model; Cell surface; Cells; Cessation of life; Chemoresistance; Chemotherapy-Oncologic Procedure; Chronic; Clinical; Data; Data Set; Development; Diagnosis; Exhibits; Extracellular Signal Regulated Kinases; Failure; Foundations; In Vitro; Incidence; Inhibition of Apoptosis; Knock-out; Life Expectancy; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Mediating; Methods; Modeling; Mouse Mammary Tumor Virus; Mus; Neoadjuvant Therapy; Neoplasm Metastasis; Pharmaceutical Preparations; Pharmacotherapy; Pre-Clinical Model; Probability; Prognosis; Prognostic Marker; Protein Kinase; Protein Microarray Assay; Proteins; Relapse; Residual state; Resistance; Resistance development; Role; Sampling; Serine; Small Interfering RNA; Statistical Data Interpretation; TACSTD2 gene; Testing; Therapeutic; Therapeutic antibodies; Transgenic Mice; Transgenic Organisms; Treatment Efficacy; Tumor Markers; Tumor Promotion; Woman; chemotherapy; engineered exosomes; exosome; improved; in vivo; inhibitor; insight; malignant breast neoplasm; mortality; mouse model; novel; novel strategies; patient derived xenograft model; personalized chemotherapy; pharmacologic; polyoma middle tumor antigen; pre-clinical; pro-apoptotic protein; therapeutic target; tool; translational study; triple-negative invasive breast carcinoma; tumor

Project Abstract Breast cancer, the most prevalent cancer in women, is responsible for more than 15% of new cancer cases and about 6.9% of all cancer-related death in the US. A major cause of therapeutic failure in breast cancer is the development of resistance to chemotherapy, especially for triple- negative breast cancer (TNBC), a type of breast cancer considered to be more aggressive and have a poorer prognosis than other types of breast cancer. Therefore, how to overcome chemoresistance is the major challenge to improve the life expectancy of TNBC patients. Preliminary data demonstrate that TNBC cells surviving from the chronic treatment of chemotherapeutic drugs show significantly higher expression of a special protein kinase, dual serine/threonine and tyrosine protein kinase (DSTYK), than parental cells without treatment. Additionally, from both in vitro and in vivo results, we found that both the knockout of DSTYK and exosome-mediated DSTYK silence can lead to the apoptosis of chemoresistant cells upon drug treatment. This novel finding suggests that DSTYK exerts a previously unknown and important role in promoting chemoresistance. The objective of this proposal is to elucidate the novel role and the underpinning mechanism of DSTYK in regulating chemoresistance in TNBC cells and further explore the potential of exosome-mediated DSTYK silence in TNBC chemotherapy with preclinical models. We hypothesize that DSTYK is a novel target for chemotherapy to induce TNBC cell death. We will test our hypothesis with three specific aims. In Aim 1, we will investigate the mechanism by which DSTYK promotes chemoresistance in TNBC cells. In Aim 2, we will establish DSTYK as a prognostic biomarker in clinical TNBC. In Aim 3, we will evaluate the therapeutic benefit of DSTYK-siRNA-exosomes in chemotherapy. We engineered exosomes containing siRNA against DSTYK that can specifically target TNBC cells. We found these engineered exosomes can significantly promote tumor regression and inhibit metastasis in both cellular and orthotopic models treated with drugs. Successful completion of the proposed studies will provide fundamental insights into the role of DSTYK in chemoresistance in TNBC cells and will lay the essential foundation for the development of an exosome-mediated strategy targeting DSTYK to significantly improve clinical TNBC chemotherapy.

项目摘要 乳腺癌是女性最常见的癌症，占新发癌症的15%以上 癌症病例和美国所有癌症相关死亡的约6.9%。一个主要的治疗原因 乳腺癌的失败是对化疗产生耐药性，特别是三联化疗， 阴性乳腺癌（TNBC），一种被认为更具侵袭性的乳腺癌， 比其他类型的乳腺癌预后差。因此，如何克服 化学抗性是提高TNBC患者预期寿命的主要挑战。 初步数据表明，TNBC细胞从慢性治疗中存活， 化疗药物表现出显着更高的表达一种特殊的蛋白激酶，双 丝氨酸/苏氨酸和酪氨酸蛋白激酶（DSTYK）的表达。 此外，从体外和体内结果中，我们发现DSTYK的敲除和 外泌体介导的DSTYK沉默可导致化疗耐药细胞的凋亡 治疗这一新的发现表明，DSTYK发挥了以前未知的重要作用， 促进化学抗性的作用。这个建议的目的是阐明新的作用 以及DSTYK调节TNBC细胞中的化学抗性的基础机制， 进一步探索外泌体介导的DSTYK沉默在TNBC化疗中的潜力， 临床前模型。我们假设DSTYK是一种新的化疗靶点， TNBC细胞死亡。我们将用三个具体目标来检验我们的假设。在目标1中，我们将研究 DSTYK促进TNBC细胞中的化学抗性的机制。在目标2中，我们将 建立DSTYK作为临床TNBC预后生物标志物。在目标3中，我们将评估 DSTYK-siRNA-外泌体在化疗中的治疗益处。我们改造了外泌体 含有针对DSTYK的siRNA，其可以特异性靶向TNBC细胞。我们发现这些 工程化的外泌体可以显著促进肿瘤消退并抑制两者的转移。 用药物处理的细胞和原位模型。成功完成拟议的研究 将为DSTYK在TNBC细胞中的化学抗性中的作用提供基本见解， 将为外泌体介导的靶向策略的发展奠定必要的基础 DSTYK显著改善临床TNBC化疗。