Tumor priming sequences combined with novel nanoparticle drug carriers for enhanced therapeutic efficacy in pancreatic cancer: a tripartite USA/Northern Ireland/Republic of Ireland consortium

 描述(申请人提供)：胰腺癌(PACA)发病率很高，通常在确诊时已进入晚期。不考虑治疗，94%的人在两年内死亡。治疗挑战包括肿瘤的遗传异质性，因此“一刀切”的治疗方法是一种令人沮丧的失败。根据患者的癌症生物学进行个性化治疗是必要的。另一个挑战是，肿瘤血液灌注率低限制了有效化疗药物的输送。肿瘤间质细胞与恶性肿瘤细胞合作建立微环境，促进转移、侵袭和治疗耐药，从而构成PACA治疗的另一个靶点。我们假设，一种特定的、顺序的、基于药理学的组合方法将利用这一潜在的脆弱性：首先，将采用“肿瘤启动”步骤来损害血管屏障特性。当血管受损时，将建立一个持久的、肿瘤内的药库，以延长肿瘤细胞的药理暴露，即使屏障重新建立。含有高载药量的纳米药物载体将被用来实现这一目标。使用低传代患者衍生(PDX)肿瘤模型，AIM 1将研究两种不同类型的药物的肿瘤启动特性：一种是基质修改药物，另一种是临床批准的通过诱导肿瘤减压而启动的化疗药物。主要目的是了解(I)导致(Ii)肿瘤启动效应和(Iii)增强纳米颗粒沉积的主要药理效应之间的时间相互关系。特别令人感兴趣的是(Iv)释放肿瘤间质压力在启动效应的暂时开始(和减弱)中的作用。将开发一种新的定量药理学模型，将所有这些组成效应相互关联到一个预测框架中，以便可以使用数学模拟来开发可检验的假说，以确定适当的启动和治疗序列。在目标2中，我们将研究不同的含药纳米粒的有效性；高药物含量的立体稳定脂质体(SSL)和聚乙二醇化聚合物纳米粒将在肿瘤启动方案中被研究其治疗和机制作用。这些配方使我们能够检验这一假设，即药物和载体的综合性质，而不是药物本身的性质，决定了观察到的肿瘤药理效应。在目标3中，我们将测试这一假设，即在肿瘤启动条件下，通过使用肿瘤或间质靶向配体，治疗纳米粒的肿瘤清除(外排)可以减少，从而显著提高疗效。西妥昔单抗-(抗 携带EGFR的纳米颗粒将提供概念验证，因为在PACA中EGFR的表达占主导地位。还将探索新的靶向配体(如抗死亡受体5)。这些研究将提供对“肿瘤启动”现象的全面了解，以使其能够合理设计，并为能够迅速过渡到临床评估的治疗组合和药物提供强有力的理由，PACA是一种几乎一致的致命性癌症。

 DESCRIPTION (provided by applicant): Pancreatic cancer (PaCA) has significant incidence, and is usually advanced at diagnosis. Regardless of treatment, 94% die within 2 yrs. Treatment challenges include tumor genetic heterogeneity, so that "one size fit all" treatment approaches are a dismal failure. Personalizing treatment based on patients' cancer biology is needed. Another challenge is that poor tumor blood perfusion limits delivery of effective chemotherapeutic drugs. Tumor stromal cells collaborate with malignant cells to establish a microenvironment that promotes metastasis, invasion, and treatment resistance, and therefore constitutes an additional target in PaCA treatment. We hypothesize that a specific, sequential, pharmacology-based combination approach will exploit this potential vulnerability: first, a `tumor priming' step will be employed to compromise vascular barrier properties. When vascular compromise is achieved, a persistent, intra-tumor drug depot will be established to extend pharmacological exposure of the tumor cells, even if the barrier is re-established. Nanoparticulate drug carriers containing high drug cargo loads will be employed to achieve this objective. Employing low-passage, patient-derived (PDX) tumor models, Aim 1 will investigate the tumor priming characteristics of two distinct types of agents: a stroma-modifying drug and a clinically-approved chemotherapeutic that primes by inducing tumor decompression. The key objectives are to understand the temporal interrelationships of (i) the primary pharmacological effects that lead to (ii) the tumor priming effect and (iii) enhanced nanoparticle deposition. Of particular interest is (iv) the role of discharging tumor interstitial pressure in the temporal onst (and waning) of the priming effect. A novel, quantitative pharmacological model will be developed to interrelate all these constituent effects into a predictive framework so that mathematical simulation can be used to develop testable hypotheses as to the appropriate priming and therapeutic sequence. In Aim 2 we will investigate distinct drug-containing nanoparticles for their efficacy; high drug-content sterically-stabilized liposomes (SSL) and PEGylated polymeric nanoparticles will be investigated for their therapeutic and mechanistic effects in a tumor- priming regimen. These formulations enable us to test the hypothesis that the aggregate properties of drug and carrier, rather than those of drug alone, determine the tumor pharmacological effects observed. In Aim 3 we will test the hypothesis that under tumor priming conditions, tumor clearance (efflux) of therapeutic nanoparticles can be reduced by employing a tumor- or stroma-targeting ligand, resulting in significant increases in efficacy. Cetuximab- (anti EGFR) bearing nanoparticles will provide proof-of-concept, owing to the predominance of EGFR expression in PaCA. Novel targeting ligands (such as anti-Death Receptor 5) will be explored also. These studies will provide a comprehensive understanding of the `tumor priming' phenomenon to enable their rational design, as well as a strong rationale for therapeutic combinations and agents that could rapidly transition to clinical evaluation in PaCA, a cancer of nearly uniform lethality.