Targeting Cathepsin L: A Novel Strategy to Impede Prostate and Breast Cancer Meta

靶向组织蛋白酶 L：阻止前列腺癌和乳腺癌转移的新策略

• 批准号: 8583124
• 负责人: DIETMAR W SIEMANN
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583124
• 关键词: Acidosis; Address; Basement membrane; Bone Matrix; Bone Pain; Bone Resorption; Bone Tissue; Breast; Breast Cancer Cell; Cancer Patient; Cancer Prognosis; Cathepsin L; Cathepsins; Cells; Clinic; Clinical; Coupled; Cysteine Protease; Development; Disease; Disseminated Malignant Neoplasm; Distant; E-Cadherin; Excision; Exocytosis; Extracellular Matrix; Extracellular Matrix Degradation; Failure; Fostering; Future; Goals; Growth; Growth Factor; Human; Hypercalcemia; Hypoxia; Image; In Vitro; Incidence; Investigation; Lead; Local Therapy; Malignant neoplasm of prostate; Mammary Neoplasms; Mediating; Metastatic Lesion; Metastatic Neoplasm to the Bone; Modeling; Molecular; Morbidity - disease rate; Mus; Neoplasm Metastasis; Nerve compression syndrome; Operative Surgical Procedures; Osteoclasts; Outcome; Oxygen; Oxygen measurement, partial pressure, arterial; Pathological fracture; Patients; Peptide Hydrolases; Phenotype; Play; Primary Neoplasm; Process; Proteolysis; Quality of life; Radiation therapy; Relapse; Risk; Rodent; Role; Route; Secondary to; Site; Skeleton; Solid Neoplasm; Source; Spinal Cord; Spinal nerve structure; Stem cells; System; Therapeutic; Transplantation; Treatment outcome; Tumor Angiogenesis; Tumor Cell Invasion; angiogenesis; base; bone; cancer cell; cancer therapy; cancer type; cathepsin K; cell motility; cytokine; deprivation; design; extracellular; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; metastatic process; mortality; neoplastic cell; neovascularization; new therapeutic target; non-invasive monitor; novel; novel strategies; novel therapeutics; outcome forecast; pre-clinical; prognostic; prostate cancer model; public health relevance; response; skeletal; small molecule; soft tissue; therapeutic target; treatment strategy; tumor; tumor microenvironment; vasculogenesis

DESCRIPTION (provided by applicant): Metastasis remains the major cause of therapeutic failure, poor prognosis and high mortality in breast and prostate cancer patients treated with surgery or radiotherapy. Novel approaches to reduce metastatic incidences and improve overall survival of cancer patients clearly are needed. The current proposal is focused on therapeutically targeting a key player in the metastatic cascade; the cysteine protease cathepsin L (CTSL). CTSL is over-expressed and hyper-activated in primary tumors and metastatic lesions in many cancer types, including breast and prostate cancer. Its over-activation correlates with tumor invasiveness and tumor grade, yielding a poor patient prognosis. CTSL initiates migratory and invasive processes through direct degradation of E-Cadherin, extracellular matrix, and basement membrane components. Cathepsins also critically contribute to the process by which metastatic tumor cells in the skeleton stimulate osteoclast-mediated bone resorption; a source of significant morbidity in prostate and breast cancer patients. CTSL may therefore provide a unique target in the metastatic process. The goal of the present proposal is to explore the anti-metastatic potential of CTSL inhibition using a small molecule targeting approach in human (MBA-MB-231, PC-3ML) and rodent (TRAMP) breast and prostate cancer models. Aim 1 will assess the impact of selective small molecule CTSL inhibitors on key functional steps associated with tumor cell dissemination including ECM degradation, cell motility, and cell invasion. In Aim 2 the effect of hypoxic and acidic tumor microenvironments, as commonly occur in solid tumors, on CTSL release, activity, and response to small molecule inhibition will be assessed. Aim 3 will examine whether cathepsin targeting can inhibit bone resorption; a key process leading to skeletal morbidity in cancer patients. Aim 4 will evaluate the in vivo anti-metastatic potential of CTSL targeting using both molecular suppression and selective therapeutic inhibition of CTSL. First, a known number of MDA-MB- 231 or PC-3ML cells will be injected via the intracardiac route and the efficacy of CTSL inhibitors (KGP94 or KGP207) will be determined by (i) non-invasive monitoring of the metastatic burden using an in vivo imaging system, and (ii) quantifying the number of bone metastases. Second, select studies will evaluate the effect of CTSL interference on the spread of cancer cells from primary tumors to secondary sites in (i) mice undergoing surgical removal of orthotopically transplanted breast tumors and (ii) the spontaneous prostate cancer metastasis TRAMP model. Finally, Aim 5 will address the role of CTSL and its inhibition to tumor induced angiogenesis and vasculogenesis, key contributors to metastasis. The successful completion of the proposed studies will provide evidence that CTSL is a potential therapeutic target for novel anti-metastatic cancer therapies. Preclinical investigations of approaches targeting the spread of cancer cells may ultimately provide clinical benefit by enabling the development of future treatment regimes designed to enhance outcomes of existing surgical interventions and radiotherapy treatments for advanced breast and prostate cancer patients.

描述（由申请人提供）：乳腺癌和前列腺癌患者手术或放疗治疗失败、预后差和死亡率高的主要原因是转移。显然需要新的方法来减少转移发生率和提高癌症患者的总体生存率。目前的建议集中在治疗上靶向转移级联中的一个关键角色；半胱氨酸蛋白酶组织蛋白酶L （CTSL）CTSL在包括乳腺癌和前列腺癌在内的许多癌症类型的原发肿瘤和转移性病变中过度表达和过度激活。它的过度激活与肿瘤侵袭性和肿瘤分级相关，导致患者预后不良。CTSL通过直接降解E-Cadherin、细胞外基质和基底膜组分，启动迁移和侵袭过程。组织蛋白酶还在骨骼转移性肿瘤细胞刺激破骨细胞介导的骨吸收的过程中发挥重要作用；前列腺癌和乳腺癌患者发病率的重要来源。因此，CTSL可能在转移过程中提供一个独特的靶点。本研究的目的是利用小分子靶向方法在人（MBA-MB-231, PC-3ML）和啮齿动物（TRAMP）乳腺癌和前列腺癌模型中探索CTSL抑制的抗转移潜力。目的1将评估选择性小分子CTSL抑制剂对与肿瘤细胞传播相关的关键功能步骤的影响，包括ECM降解、细胞运动和细胞侵袭。在Aim 2中，将评估实体肿瘤中常见的缺氧和酸性肿瘤微环境对CTSL释放、活性和对小分子抑制的反应的影响。目的3将检验组织蛋白酶靶向是否能抑制骨吸收；导致癌症患者骨骼发病率的关键过程。目标4将评估