P-selectin-Mediated Targeting of PI3K Nanomedicines to the Tumor Microenvironment

摘要 基于患者疾病基因组背景的个性化医学已经成为一种领先的战略 治疗癌症。然而，尽管定制治疗的结果令人振奋，但靶向治疗影响了 在非癌症细胞中同样的信号通路，经常导致剂量限制的“靶向”毒性。这样的一个 例子包括PI3K抑制剂。在头颈部鳞状细胞癌(HNSCC)中，排名第六 在全球癌症中，34%-56%的肿瘤存在PIK3CA突变或扩增，PIK3CA是编码 PI3K的p110α亚基。然而，PI3Kα抑制剂具有显著的毒性特征，这限制了它们的治疗 窗口，特别是对出现顽固性高血糖的患者。使用靶向给药 在这方面，我们已经确定了满足这一需要的战略。PI开发了一种新的纳米颗粒 靶向P-选择素，它允许掺入多种治疗分子，包括 靶向治疗(ShaMay，Sci Transl Med 2016)。我们建立了一个合作研究团队，利用了这一点 靶向在基线或辐射诱导下表达内皮P-选择素的肿瘤的技术(Mizrachi， NAT Commun 2017)。该策略显著提高了治疗指数和存活率，而 将靶向治疗的副作用降至最低。值得注意的是，我们发现PI3K抑制剂，使用我们的 纳米粒载体，导致pS6抑制延长和抗肿瘤效果，同时最小化急性和 高血糖的慢性影响。本项目的目标是在HNSCC的背景下调查 自发表达或诱导表达的P-选择素纳米颗粒介导的PI3K治疗 辐射。这项提案的目标是了解药物的药理、疗效、毒性、 与HNSCC肿瘤微环境的相互作用，以及电离辐射对这些参数的影响。 我们计划追求以下具体目标：1)评估P-选择素介导的肿瘤靶向 微环境。我们将测量纳米颗粒和包裹的药物在肿瘤中的定位。 从器官到细胞层面的微环境。2)通过辐射诱导增强纳米粒子的定位 血管内皮细胞激活。基于我们对辐射诱导的P-选择素表达的理解，我们 假设外照射可增加P-选择素靶向PI3K抑制剂在脑内的定位 由于靶标可获得性的增加，导致肿瘤的扩散。3)评价P-选择素介导的疗效 靶向PI3K抑制剂。我们将评估药物输送机制与治疗之间的关系 回应。我们假设：(I)基于P-选择素的靶向将提高PI3K抑制剂介导的疗效 和肿瘤中的细胞凋亡，(Ii)辐射可以增加抑制物的相对疗效，(Iii) 纳米粒介导的P-选择素靶向将降低PI3K介导的高血糖，以及(Iv) 纳米颗粒递送的治疗组合将提高协同效应，同时减轻 起因于全身应用多种抑制剂。结果将为IND和临床研究提供信息。

SUMMARY Personalized medicine, based on the genomic context of a patient’s disease, has become a leading strategy to treat cancer. However, despite the promising results from customized treatments, targeted therapies affect the same signaling pathways in non-cancerous cells, often leading to dose-limiting, “on-target” toxicities. One such example involves PI3K inhibitors. In head and neck squamous cell carcinoma (HNSCC), the 6th most common cancer worldwide, 34%-56% of tumors harbor mutations or amplifications in PIK3CA, the gene coding for the p110α subunit of PI3K. PI3Kα inhibitors carry a significant toxicity profile, however, that limits their therapeutic window, specifically in patients who develop intractable hyperglycemia. Using a targeted drug delivery approach, we have identified a strategy to address this need. The PI developed a new class of nanoparticles targeted to P-selectin which allows the incorporation of a wide variety of therapeutic molecules, including targeted therapies (Shamay, Sci Transl Med 2016). We built a collaborative research team that employed this technology to target tumors expressing endothelial P-selectin, either at baseline or radiation-induced (Mizrachi, Nat Commun 2017). The strategy effected a significantly improved therapeutic index and survival, while minimizing the side effects of targeted therapeutics. Notably, we found that PI3K inhibitors, targeted using our nanoparticle vehicle, resulted in prolonged pS6 inhibition and anti-tumor efficacy, while minimizing acute and chronic effects of hyperglycemia. The objective of this project is to investigate, in the context of HNSCC, the nanoparticle-mediated delivery of PI3K therapies via P-selectin, expressed spontaneously or induced by radiation. This proposal’s goals are to understand the modulation of drug pharmacology, efficacy, toxicities, interactions with HNSCC tumor microenvironment, and the impact of ionizing radiation on these parameters. We plan to pursue the following specific aims: 1) Assess P-selectin-mediated targeting to the tumor microenvironment. We will measure the localization of the nanoparticle and encapsulated drug in the tumor microenvironment from the organ to cellular levels. 2) Enhance nanoparticle localization via radiation-induced endothelial activation. Based on our understanding of radiation-induced expression of P-selectin, we hypothesize that external beam radiation can increase localization of a P-selectin-targeted PI3K inhibitor in disseminated tumors due to the increased availability of the target. 3) Assess efficacy of P-selectin-mediated targeting of PI3K inhibitors. We will assess the relationship between drug delivery mechanism and treatment response. We hypothesize: (i) that the P-selectin-based targeting will improve PI3K inhibitor-mediated efficacy and apoptosis in tumors, (ii) that radiation may increase the relative efficacy of the inhibitor, (iii) that nanoparticle-mediated P-selectin targeting will mitigate PI3K-mediated hyperglycemia, and (iv) that nanoparticle-delivered therapeutic combinations will improve synergistic effects while attenuating toxicities that arise from systemic administration of multiple inhibitors. The outcomes will inform IND and clinical studies.