Combination therapy to inhibit neuroblastoma growth

描述(申请人提供)：抑制神经母细胞瘤生长的综合疗法神经母细胞瘤是最常见的儿童实体肿瘤，起源于交感神经系统。神经母细胞瘤表现出临床和生物学上的异质性，与某些基因异常有关。晚期IV型神经母细胞瘤对所有传统治疗方法都难以奏效，且预后不佳。儿童高危IV期神经母细胞瘤的治愈率保持在20%，这为更好地了解可以靶向治疗这种疾病的分子机制提供了令人信服的理由。放射治疗仍然是控制恶性肿瘤和良性肿瘤的治疗方式的主要组成部分。在残留或复发的良性肿瘤患者中，人们越来越担心放射相关的副作用，即使在放射外科等高度精确的治疗下也可能发生这些副作用。尽管有一定的治疗效果，但最近的证据表明，辐射可能通过激活与肿瘤侵袭、血管生成和转移有关的几条途径，在体外和体内促进癌细胞的恶性行为。辐射的另一个后果是肿瘤往往对辐射产生抵抗力。越来越多的晚期后遗症长期幸存者强调了新的治疗方法的必要性。肿瘤的生长和血管生成发生在细胞外基质(ECM)的背景下，ECM的水平和沉积在一定程度上由富含半胱氨酸的酸性分泌蛋白(SPARC)控制，SPARC是一种基质糖蛋白。SPARC调节细胞与细胞外基质的相互作用，在正常细胞中具有不同的作用，其中许多已被证明与肿瘤的发生有关。正如我们和其他人所指出的那样，正常脑中SPARC的相对表达水平随着恶变的发生而降低。我们的初步研究表明，与亲本细胞和EV转基因细胞相比，SPARC过表达抑制了神经母细胞瘤细胞的增殖、迁移、血管生成和肿瘤生长。我们还提供了SPARC可作为放射治疗的增敏剂。我们假设SPARC的调节与辐射的结合以及这些治疗的抗癌效果将被确定。本提案的具体目的如下：在具体目标1中，我们将在体外和体内模型中评价p-SPARC和辐射单独和联合对神经母细胞瘤细胞迁移和侵袭的影响。在具体目标2中，我们将确定p-SPARC和辐射单独和联合对神经母细胞瘤细胞生长、增殖、黏附和凋亡的影响。在具体目标3中，我们将确定p-SPARC和辐射单独和联合对神经母细胞瘤细胞与体外和体内微环境相互作用的影响，以及p-SPARC和辐射单独和联合对体外和体内血管生成的影响。这种体外基础科学实验和体内翻译研究的结合，将为开发一种新的治疗神经母细胞瘤的方法提供基础，这些肿瘤对传统的放射治疗无效。 公共卫生相关性：神经母细胞瘤占所有青少年癌症的10%。一岁以上儿童的晚期神经母细胞瘤在目前的治疗方案下很大程度上是无法治愈的。然而，越来越多的长期存活者从这种治疗中获得了二次效应，这突显了开发新的治疗方法的必要性。这项建议代表了一项综合分析，以确定SPARC表达与放射治疗相结合治疗神经母细胞瘤的疗效。

DESCRIPTION (provided by applicant): Combination therapy to inhibit neuroblastoma growth Neuroblastoma is the most common pediatric solid tumor that arises from the sympathetic nervous system. Neuroblastoma tumors exhibit clinical and biological heterogeneity associated with certain genetic aberrations. Advanced state IV neuroblastoma is refractory to all conventional therapeutic modalities and is associated with a dismal prognosis. The cure rate of children with high-risk stage IV neuroblastoma remains at <20%, providing a compelling reasons to better understand the molecular mechanisms that can be targeted to treat this disease. Radiotherapy remains a major component of treatment modalities for controlling both malignant and benign tumors. In patients with residual or recurring benign tumors, there is increasing concern about radiation-related side effects that may occur even with highly accurate therapies such as radiosurgery. Despite some therapeutic effect, recent evidence has shown that irradiation may promote malignant behaviors of cancer cells both in vitro and in vivo by activating several pathways involved in tumor invasiveness, angiogenesis and metastasis. Another consequence of radiation is that tumors often become resistant to radiation. An increasing number of long-term survivors with late sequelae highlight the need for novel therapeutic approaches. Tumor growth and angiogenesis occur in the context of the extracellular matrix (ECM), the levels and deposition of which are controlled in part by secreted protein, acidic and rich in cysteine (SPARC), a matricellular glycoprotein. SPARC modulates cellular interaction with the ECM and has diverse roles in normal cells, many of which have been shown to contribute to tumorigenesis. The relative levels of SPARC expression in normal brain decreased with malignant transformation, as indicated by our group and others. Our preliminary studies demonstrated that over-expression of SPARC inhibited neuroblastoma cell proliferation, migration, angiogenesis and tumor growth in vivo compared to parental and EV- transfected cells. We also provided that SPARC may act as a sensitizer to radiotherapy. We hypothesize that modulation of SPARC combined with radiation and the anticancer effects of these treatments will be determined. The specific aims of this proposal are as follows: In Specific Aim 1, we will evaluate the effects of the p-SPARC and radiation, alone and in combination, on neuroblastoma cell migration and invasion in both in vitro and in vivo models. In Specific Aim 2, we will determine the effects of p-SPARC and radiation, alone and in combination, on neuroblastoma cell growth, proliferation, adhesion and apoptosis. In Specific Aim 3, we will determine the effect of p-SPARC and radiation, alone and in combination, on neuroblastoma cell interactions with the microenvironment of both in vitro and in vivo and the effect of p-SPARC and radiation, alone and in combination, on angiogenesis both in vitro and in vivo. This combination of in vitro basic science experiments and translational in vivo studies will provide the basis for development of a new therapeutic approach to neuroblastoma tumors which are resistant to conventional radiotherapy. PUBLIC HEALTH RELEVANCE: Neuroblastoma accounts for 10% of all juvenile cancers. Advanced stage neuroblastoma in children over one-year old is largely incurable using current treatment protocols. However, an increasing number of long-term survivals with secondary effects from this treatment highlighted the need for development of novel therapeutic approaches. This proposal represents a comprehensive analysis to determine the therapeutic benefit of SPARC expression in combination with radiation for the treatment of neuroblastoma.