Novel Therapeutic Targets For Calcineurin Inhibitor-Induced And mTOR-Mediated Can

钙调神经磷酸酶抑制剂诱导和 mTOR 介导的新治疗靶点

• 批准号: 8580854
• 负责人: Soumitro Pal
• 金额: $ 22.84万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580854
• 关键词: Age-Years; Calcineurin; Calcineurin inhibitor; Cancer cell line; Cells; Clear Cell; Data; Development; Down-Regulation; Endothelial Cells; Exploratory/Developmental Grant; Genes; Human; Immunosuppression; Immunosuppressive Agents; In Vitro; Kidney; Kidney Neoplasms; Lead; Lentivirus Vector; Longevity; Malignant Neoplasms; Measures; Mediating; Morphogenesis; Organ; Organ Transplantation; Papillary; Pathway interactions; Patients; Pattern; Phosphorylation; Plasmids; Play; Protein Isoforms; Protein Kinase C; Proto-Oncogenes; Recurrence; Regulation; Renal Cell Carcinoma; Renal carcinoma; Research Proposals; Ribosomal Protein S6 Kinase; Role; S-Phase Fraction; SCID Beige Mouse; Series; Signaling Molecule; Sirolimus; Small Interfering RNA; Solid; Testing; Therapeutic immunosuppression; Toxic effect; Transcriptional Activation; Transplant Recipients; Transplantation; Tumor Tissue; Vascular Endothelial Growth Factors; Xenograft Model; allograft rejection; angiogenesis; base; cancer recurrence; cancer type; clinically significant; human FRAP1 protein; in vivo; inhibitor/antagonist; knock-down; mTOR Inhibitor; migration; new therapeutic target; novel; older patient; prevent; protein expression; public health relevance; ras Proteins; research study; therapeutic target; tumor; tumor growth; tumor progression; tumor xenograft

DESCRIPTION (provided by applicant): Organ transplantation is considered to be the best treatment option for most of the patients having a dysfunctional organ; it provides them a long and healthy lifespan. However, the development/recurrence of cancer is a major and critical problem during post-transplantation period. Renal cancer is one of the major types of cancers in transplant patients. Interestingly, the immunosuppressive agents used in transplant recipients to prevent organ rejection can play a vital role in tumor progression. It has been observed that transplant patients receiving the mTOR inhibitor rapamycin (RAPA) do not develop cancer at the same rate as those receiving other immunosuppressive agents such as calcineurin inhibitors (CNI). We have defined a novel mechanism by which CNIs can activate the proto-oncogene ras and specific isoforms (particularly ?) of protein kinase C (PKC); and they can promote a rapid progression of human renal cancer through the over-expression of vascular endothelial growth factor (VEGF) and VEGF-induced angiogenesis. We have also identified the possible role of a novel molecule CARABIN (an endogenous inhibitor of both calcineurin and Ras) in CNI- induced ras activation, as CNI treatment was found to down-regulate CARABIN. In contrast, we recently observed that RAPA treatment could significantly inhibit CNI-induced and Ras-mediated over-expression of VEGF, and CNI-induced rapid progression of post-transplantation renal cancer. This suggests possible involvement of the mTOR pathway in CNI-induced tumor progression. Presently, it is a challenge for the clinicians to fix a safe but effective immunosuppressive therapy for the transplant patients to inhibit allograft rejection, as well as to prevent cancer development. Thus, new therapeutic targets need to be explored in order to prevent CNI-induced and mTOR-mediated cancers. Our studies suggest a novel cross-talk among CNI-induced signaling molecules and mTOR for the regulation of VEGF expression in renal cancer cells. However, the significance of CARABIN and PKC-? in regulating CNI-induced and mTOR-mediated VEGF over- expression and cancer progression is totally unexplored. Our hypothesis is that the down-regulation of CARABIN and activation of PKC-? plays a major role in CNI-induced and mTOR-mediated renal cancer progression through the over-expression of VEGF. Our Specific Aims will examine: 1) functional significance of CARABIN, PKC-?, and mTOR in CNI-induced VEGF over-expression for the regulation of pathways in renal cancer progression; and 2) the role(s) of CARABIN and PKC-? in CNI-induced and mTOR-mediated renal cancer progression by using an in vivo tumor xenograft model. Together, these studies should explore the specific roles of CARABIN and PKC-? in promoting mTOR-induced and VEGF-mediated renal cancer progression following CNI therapy. We believe that these studies are ideal for the R21 mechanism, as they initiate the exploration for the role of novel molecules in CNI-induced cancers, and they have significant potential to result in high impact findings with clinical significance.

描述(申请人提供)：器官移植被认为是大多数器官功能障碍患者的最佳治疗选择；它为他们提供了长而健康的生命。然而，在移植后阶段，肿瘤的发展/复发是一个主要和关键的问题。肾癌是移植患者的主要癌症类型之一。有趣的是，移植受者用来预防器官排斥反应的免疫抑制剂在肿瘤进展中起着至关重要的作用。已经观察到，接受mTOR抑制剂雷帕霉素(RapA)的移植患者患癌症的速度与接受其他免疫抑制剂(如钙调神经磷酸酶抑制剂(CNI))的患者不同。我们已经定义了一种新的机制，通过CNI可以激活原癌基因ras和特定的异构体(特别是？)它们可以通过过度表达血管内皮生长因子(VEGF)和血管内皮生长因子诱导的血管生成来促进人类肾癌的快速进展。我们还确定了一种新的分子卡拉宾(钙调神经磷酸酶和RAS的内源性抑制剂)在CNI诱导的ras激活中的可能作用，因为CNI治疗被发现下调了卡拉宾的表达。相反，我们最近观察到RAPA治疗可以显著抑制CNI诱导和RAS介导的VEGF的过度表达，以及CNI诱导的移植后肾癌的快速进展。这提示mTOR通路可能参与了CNI诱导的肿瘤进展。目前，临床医生面临的挑战是如何为移植患者确定一种安全而有效的免疫抑制疗法，以抑制同种异体移植排斥反应。 预防癌症的发展。因此，需要探索新的治疗靶点，以预防CNI诱导和mTOR介导的癌症。我们的研究表明，在CNI诱导的信号分子和mTOR之间存在一种新的串扰，用于调节肾癌细胞中血管内皮生长因子的表达。然而，卡拉宾和PKC-？在调控CNI诱导和mTOR介导的血管内皮细胞生长因子过度表达和肿瘤进展方面，目前还完全没有研究。我们的假设是Carabin的下调和PKC-？在CNI诱导和mTOR介导的肾癌进展中起主要作用，其机制是通过过度表达VEGF。我们的具体目标将考察：1)Carabin、PKC-β和mTOR在CNI诱导的血管内皮生长因子过度表达中的功能意义；以及2)Carabin和PKC-？的作用(S)。在CNI诱导和mTOR介导的肾癌进展中使用体内肿瘤异种移植模型。总之，这些研究应该探索Carabin和PKC-？促进CNI治疗后mTOR诱导和血管内皮生长因子介导的肾癌进展。我们认为，这些研究是R21机制的理想选择，因为它们启动了新分子在CNI诱导的癌症中的作用的探索，并且它们具有重大的潜力，可以导致具有临床意义的高影响力的发现。