The CARMA3/Bcl10/MALT1 signalosome in osteosarcoma metastasis

 描述(由申请人提供) 骨肉瘤是最常见的骨原发恶性肿瘤，发病高峰在第二个十年。虽然在标准手术切除的基础上增加了化疗方案，患者的预后得到了改善，但几十年来，患者的预后一直停滞不前，而且仍然很差。尽管使用了包括大剂量甲氨蝶呤、顺铂和阿霉素在内的积极化疗，但转移到肺的患者的五年存活率不到30%。很明显，转移是改善患者预后和生存的关键障碍。在这里，我们建议研究骨肉瘤转移发生的分子机制。具体地说，我们将研究由CARMA3、Bcl10和MALT1蛋白组成的细胞内信号复合体在促进骨肉瘤这些过程中的作用，希望找到治疗我们患者的新的治疗方法。我们提出了两个独立的特定目标：第一个目标，我们将研究骨肉瘤肿瘤微环境促进转移的分子机制。然后在第二个目标中，我们将评估MALT1作为治疗转移性骨肉瘤的新的潜在治疗靶点。这项建议的主要调查者是一位正在接受培训的内科科学家，他正在追求专注于 儿童肿瘤学，对肉瘤研究特别感兴趣。拟议的研究计划，以及一个结构良好的培训计划，包括来自儿科肿瘤学、病理学、儿科骨科肿瘤外科和第一阶段临床试验设计领域的有成就的领导者的指导，将奠定基础，使申请者能够启动一项非同寻常的 在儿童癌症研究领域很有前途。

 DESCRIPTION (provided by applicant) Osteosarcoma is the most common primary malignancy of bone, with a peak incidence during the second decade of life. While patient outcomes improved with the addition of a chemotherapy regimen to standard surgical resection, outcomes have been static for decades and remain poor. Patients with metastases, almost always to the lung, have a five year survival rate of less than 30% despite the use of aggressive chemotherapy including high-dose methotrexate, cisplatin, and doxorubicin. It is clear that metastasis is a critical obstacle to the improvement o patient outcomes and survival. Here, we propose to investigate the molecular mechanisms by which osteosarcoma metastasis occurs. Specifically, we will examine the contribution of an intracellular signaling complex comprised of the CARMA3, Bcl10 and MALT1 proteins in promoting these processes in osteosarcoma, with the hopes of identifying novel therapeutic approaches for treating our patients. We propose two independent Specific Aims: In the first aim, we will investigate molecular mechanisms by which the osteosarcoma tumor microenvironment can promote metastasis. Then in the second aim, we will evaluate MALT1 as a new potential therapeutic target for the treatment of metastatic osteosarcoma. The principal investigator of this proposal is a physician scientist in training who is pursuing a career focused on pediatric oncology, with a special interest in sarcoma research. The proposed research plan, along with a well-structured training plan that includes mentoring from accomplished leaders in the fields of pediatric oncology, pathology, pediatric orthopedic oncologic surgery, and phase I clinical trial design, will lay the groundwork to allow this applicant to launch an extraordinarily promising career in childhood cancer research.