Targeted Combination Therapy for Lung Cancer

描述（由申请人提供）：肺癌是美国癌症死亡的主要原因之一，由于缺乏特异性、疗效差和与当前治疗相关的副作用，5年生存率约为15%。非裔美国人、美洲印第安人/阿拉斯加原住民和太平洋岛民的肺癌发病率最高。非小细胞肺癌（non-small cell lung cancer，NSCLC）是肺癌患者中最常见的一种，发病率约为80%. NSCLC具有广泛的分子异质性，这要求同时靶向多种途径。血管内皮生长因子（VEGF）基因过表达（约90%的NSCLC）与生长、存活和血管生成相关。VEGF抗体阻断VEGF的用途由于其非特异性、不良功效和副作用而受到限制。在这条线上，使用VEGF-siRNA（siRNA-V）沉默VEGF将是一种有效的选择，然而，由于非特异性作用、差的细胞渗透性和快速的体内消除，siRNA的临床应用受到阻碍。使用纳米载体进行siRNA-V递送将有助于克服这些问题。此外，发现PI 3 K/mTOR在NSCLC中主要被激活，此外，mTOR抑制导致Akt（细胞存活和增殖的促进剂）的补偿性激活。因此，同时靶向mTOR和Akt沿着VEGF沉默将为更有效的NSCLC治疗铺平道路。PF-04691502（PF 0）是一种强效PI 3 K/mTOR/AKT抑制剂。使用PF 0沿着VEGF沉默靶向mTOR/AKT通路将补充这些生物活性物质对NSCLC的临床潜力。LHRH受体在NSCLC细胞上过表达，而在正常组织上表达受限。我们首次提出开发可生物降解的LHRH受体靶向聚乙二醇化混合纳米载体（HNC），用于同时靶向递送siRNA-V和PF 0（HNC-VP-L）至NSCLC。我们假设，稳定的LHRH受体引导的基于PEG化白蛋白-壳聚糖的混合纳米载体的开发将以靶向方式将协同作用的siRNA-V和PF 0递送至NSCLC肿瘤，并且将导致在较低剂量下抗癌活性的显著改善，同时克服不良反应。我们计划通过以下具体目的来验证我们的假设：目的1：评估siRNA-V和PF 0的联合作用;开发和评估HNC-VP-L;目的2：评估HNC-VP-L在裸鼠中的体内功效;目的3：阐明机制，评估转移和毒理学参数。我们计划利用基于LHRH受体阳性和LHRH受体阴性肿瘤细胞的体外和体内模型（异种移植和正交各向异性）来研究开发的纳米载体的靶向潜力。我们的方法旨在开发一种更有效的治疗NSCLC的治疗方式，以减少肺癌差异的负担。长期目标是将这种新的交付概念推向临床水平。 我们将能够在夏威夷州建立第一个基于纳米载体的校外癌症项目，并通过这个项目培训未被代表的学生。

DESCRIPTION (provided by applicant): Lung cancer is one of the leading causes of cancer deaths in the US with 5 year survival rate of ~15% due to the lack of specificity, poor efficacy, and side effects associated with current therapies. The lung cancer incidences are highest in African Americans, American Indians/Alaska Natives, and Pacific Islanders. The non- small cell lung cancer (NSCLC) is most prevalent (~80% occurrence) among lung cancer patient. NSCLC has wide molecular heterogeneity, which mandates simultaneous targeting of multiple pathways. Vascular endothelial growth factor (VEGF) gene over-expression (in ~90% of NSCLC's) is associated with growth, survival, and angiogenesis. The use of VEGF antibodies to block VEGF has been limited due to their non- specificity, poor efficacy and adverse effects. In this line, silencing VEGF using VEGF-siRNA (siRNA-V) will be an effective option, however, the clinical utility of siRNA has been hampered due to non-specific effect, poor cell permeation and rapid in vivo elimination. The use of nanocarriers for siRNA-V delivery will help to overcome these issues. Furthermore, PI3K/mTOR was found to be predominantly activated in NSCLC, additionally, mTOR inhibition results in compensatory activation of Akt (a promoter of cell survival and proliferation). Hence, simultaneous targeting of mTOR and Akt along with VEGF silencing will pave the way for more effective NSCLC therapy. PF-04691502 (PF0) is a potent PI3K/mTOR/AKT inhibitor. Targeting mTOR/AKT pathway using PF0 along with VEGF silencing will complement the clinical potential of these bioactives against NSCLC. LHRH receptors are over-expressed on NSCLC cells with restricted expression on normal tissues. For the first time, we are herewith proposing the development of biodegradable, LHRH receptor-targeted PEGylated hybrid nanocarrier (HNC) for the simultaneous targeted delivery of siRNA-V and PF0 (HNC-VP-L) to NSCLC. We hypothesize that the development of stable, LHRH receptor-guided PEGylated albumin-chitosan based hybrid nanocarriers will deliver the synergistically-acting siRNA-V and PF0 in a targeted fashion to NSCLC tumors and will result in a significant improvement of anticancer activity, at lower doses, while overcoming adverse effects. We plan to test our hypothesis by following specific aims: Aim 1: To evaluate the combination effect of siRNA-V and PF0; development and evaluation of HNC-VP-L; Aim 2: To evaluate the in vivo efficacy of HNC-VP-L in nude mice; and Aim 3: To elucidate mechanism, evaluate metastasis and toxicological parameters. We plan to utilize LHRH receptor positive and LHRH receptor negative tumor cell based in vitro as well as in vivo models (xenograft and orthotropic) to investigate the targeting potential of developed nan carriers. Our approach aims at developing a more effective treatment modality for the treatment of NSCLC to reduce the burden of lung cancer disparity. The long term goal is to advance this novel delivery concept to the clinic level. We will be able to establish the first nan carrier based extramural cancer program in the state of Hawaii and train the unrepresented students through this project.