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

总结 基于患者疾病的基因组背景的个性化医疗已成为一种领先的策略， 治疗癌症然而，尽管定制治疗的结果很有希望，但靶向治疗会影响患者的预后。 在非癌细胞中具有相同的信号传导途径，通常导致剂量限制性的“靶向”毒性。一个这样 实例涉及PI 3 K抑制剂。在头颈部鳞状细胞癌（HNSCC）中， 在世界范围内的癌症中，34%-56%的肿瘤在PIK 3CA中具有突变或扩增，PIK 3CA是编码 PI 3 K的p110α亚基。然而，PI 3 K α抑制剂具有显著的毒性特征，这限制了它们的治疗效果。 窗口，特别是在顽固性高血糖症患者中。使用靶向药物输送 我们已经确定了一项战略来满足这一需求。PI开发了一种新的纳米粒子 靶向P-选择素，其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， 靶向表达内皮P-选择素的肿瘤的技术，无论是在基线还是辐射诱导的（Mizrachi， Nat Commun 2017）。该策略显著改善了治疗指数和生存率， 最小化靶向治疗的副作用。值得注意的是，我们发现PI 3 K抑制剂，靶向使用我们的 纳米颗粒载体，导致延长的pS 6抑制和抗肿瘤功效，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 纳米颗粒介导的通过P-选择素的PI 3 K疗法的递送，所述P-选择素自发表达或由 辐射该提案的目标是了解药物药理学、功效、毒性的调节， 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性 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 微环境从器官到细胞水平。2)通过辐射诱导增强纳米颗粒定位 内皮激活基于我们对辐射诱导的P-选择素表达的理解，我们 假设外部射线照射可以增加P-选择素靶向PI 3 K抑制剂在 扩散的肿瘤由于增加的可用性的目标。3)评估P-选择素介导的 靶向PI 3 K抑制剂。我们将评估药物传递机制和治疗之间的关系 反应我们假设：（i）基于P-选择素的靶向将改善PI 3 K通道介导的功效 和肿瘤中的细胞凋亡，（ii）辐射可以增加抑制剂的相对功效，（iii） 纳米颗粒介导的P-选择素靶向将减轻PI 3 K介导的高血糖症，和（iv） 纳米颗粒递送的治疗组合将改善协同效应， 由多种抑制剂的全身给药引起。这些结果将为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.