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（由申请人提供）：对于大多数患有功能失调器官的患者而言，器官移植被认为是最好的治疗选择；它为他们提供了长期健康的寿命。但是，在移植后期，癌症的发展/复发是一个重大且关键的问题。肾脏癌是移植患者中主要类型的癌症之一。有趣的是，用于防止器官排斥的移植受者中使用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）的移植患者不会以与接受其他免疫抑制剂（如钙调蛋白抑制剂（CNI））相同的癌症患癌症。我们定义了一种新型机制，CNIS可以通过该机制激活蛋白激酶C（PKC）的原始癌RAS和特定的同工型（尤其是？）；它们可以通过过度表达血管内皮生长因子（VEGF）和VEGF诱导的血管生成来促进人类肾癌的快速发展。我们还确定了新型分子卡拉宾（钙调蛋白和Ras的内源性抑制剂）在CNI诱导的RAS激活中的可能作用，因为发现CNI处理可下调carabin。相比之下，我们最近观察到，RAPA治疗可以显着抑制CNI诱导的VEGF和RAS介导的过表达，而CNI诱导的移植后肾脏肾癌的快速发展。这表明MTOR途径可能参与CNI诱导的肿瘤进展。目前，对于临床医生而言，要为移植患者抑制同种异体移植的抑制以及对移植患者进行安全但有效的免疫抑制治疗是一个挑战 预防癌症发展。因此，需要探索新的治疗靶标，以防止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之间进行了新的串扰，以调节肾脏癌细胞中VEGF的表达。但是，carabin和pkc-的意义？在调节CNI诱导和MTOR介导的VEGF表达和癌症进展时，完全没有探索。我们的假设是carabin的下调和PKC-的激活？通过VEGF的过表达，在CNI诱导和MTOR介导的肾癌进展中起着重要作用。我们的具体目的将研究：1）Carabin，PKC-？和MTOR在CNI诱导的VEGF过表达中的功能显着性，以调节肾脏癌进展中的途径； 2）Carabin和Pkc-的作用？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。这些研究共同探讨了Carabin和PKC-的特定作用？ CNI治疗后促进MTOR诱导和VEGF介导的肾脏癌进展。我们认为，这些研究是R21机制的理想选择，因为它们启动了对CNI诱导的癌症中新分子作用的探索，并且它们具有具有临床意义的高影响结果的巨大潜力。