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

肿瘤启动序列与新型纳米颗粒药物载体相结合，增强胰腺癌的治疗效果：美国/北爱尔兰/爱尔兰共和国三方联盟

• 批准号: 9765180
• 负责人: Martin Clynes
• 金额: $ 41.65万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765180
• 关键词: Address; Affinity; Blood; Blood Vessels; Blood flow; Cancer Biology; Cancer Patient; Cetuximab; Characteristics; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Complex; Data; Death Receptor 5; Deposition; Development; Diagnosis; Disease; Disease Progression; Drug Carriers; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Drug Transport; Encapsulated; Enzymes; Epidermal Growth Factor Receptor; Exposure to; FDA approved; Failure; Formulation; Funding; Genetic Heterogeneity; Human; Hyaluronidase; Incidence; Individual; Inhibition of Apoptosis; Intercellular Fluid; Investigation; Ireland; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mathematics; Mediating; Metabolic Clearance Rate; Modeling; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Northern Ireland; Operative Surgical Procedures; Paclitaxel; Patients; Penetration; Perfusion; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Polymers; Property; Regimen; Research; Role; SHH gene; Sterically Stabilized Liposome; Stream; Stromal Cells; Stromal Neoplasm; System; Testing; Therapeutic; Treatment Efficacy; Tumor-Derived; Twin Multiple Birth; Work; base; blood perfusion; cancer cell; cancer therapy; chemotherapy; clinically relevant; cytotoxicity; density; design; drug release kinetics; improved; improved outcome; ineffective therapies; inhibitor/antagonist; interest; interstitial; models and simulation; nanoparticle; nanoparticle delivery; nanoparticle drug; nanoparticulate; neoplastic cell; novel; novel strategies; overexpression; personalized medicine; poly(lactide); preclinical study; pressure; programs; prototype; public health relevance; receptor; research clinical testing; response; restoration; simulation; smoothened signaling pathway; systemic toxicity; taxane; therapeutic nanoparticles; therapy outcome; therapy resistant; tumor

 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.

 描述（由申请人提供）：胰腺癌（PaCA）具有显著的发病率，并且通常在诊断时是晚期的。无论治疗如何，94%的患者在2年内死亡。治疗挑战包括肿瘤遗传异质性，因此“一刀切”的治疗方法是一个令人沮丧的失败。需要根据患者的癌症生物学进行个性化治疗。另一个挑战是肿瘤血液灌注差限制了有效化疗药物的递送。肿瘤基质细胞与恶性细胞合作建立促进转移、侵袭和治疗抗性的微环境，因此构成PaCA治疗中的额外靶标。我们假设，一个特定的，顺序的，基于药理学的组合方法将利用这种潜在的脆弱性：首先，一个“肿瘤引发”的步骤将被用来损害血管屏障特性。当血管受损时，即使屏障重建，也将建立持久的肿瘤内药物储库以延长肿瘤细胞的药理学暴露。含有高载药量的纳米颗粒药物载体将用于实现该目标。采用低传代、患者源性（PDX）肿瘤模型，目标1将研究两种不同类型药物的肿瘤引发特征：基质修饰药物和临床批准的通过诱导肿瘤减压引发的化疗药物。主要目的是了解（i）导致（ii）肿瘤引发效应的主要药理学作用和（iii）增强的纳米颗粒沉积的时间相互关系。特别令人感兴趣的是（iv）在启动效应的时间onst（和减弱）中放电肿瘤间质压力的作用。将开发一种新的定量药理学模型，将所有这些成分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验证的假设，以确定适当的启动和治疗顺序。在目标2中，我们将研究不同的含药物纳米颗粒的功效;将研究高药物含量的空间稳定脂质体（SSL）和PEG化聚合物纳米颗粒在肿瘤引发方案中的治疗和机制作用。这些制剂使我们能够检验这样的假设，即药物和载体的聚集性质，而不是单独药物的聚集性质，决定了观察到的肿瘤药理学作用。在目标3中，我们将测试以下假设：在肿瘤引发条件下，治疗性纳米颗粒的肿瘤清除（流出）可以通过采用肿瘤或基质靶向配体来减少，从而导致功效显著增加。西妥昔单抗-（抗 携带EGFR的纳米颗粒将提供概念验证，这是由于EGFR在PaCA中的表达占优势。新的靶向配体（如抗死亡受体5）也将被探索。这些研究将提供对“肿瘤引发”现象的全面理解，以使其合理设计，以及治疗组合和药物的有力依据，这些组合和药物可以快速过渡到PaCA（一种几乎一致致死率的癌症）的临床评价。

项目成果

Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer.

• DOI: 10.1038/s41416-020-01046-6
• 发表时间: 2020-11
• 期刊: British journal of cancer
• 影响因子: 8.8
• 作者: Greene MK;Chen T;Robinson E;Straubinger NL;Minx C;Chan DKW;Wang J;Burrows JF;Van Schaeybroeck S;Baker JR;Caddick S;Longley DB;Mager DE;Straubinger RM;Chudasama V;Scott CJ
• 通讯作者: Scott CJ

Cluster Gauss-Newton and CellNOpt Parameter Estimation in a Small Protein Signaling Network of Vorinostat and Bortezomib Pharmacodynamics.

• DOI: 10.1208/s12248-021-00640-7
• 发表时间: 2021-10-07
• 期刊: The AAPS journal
• 作者: Niu J;Nguyen VA;Ghasemi M;Chen T;Mager DE
• 通讯作者: Mager DE

Pharmacodynamic modeling of synergistic birinapant/paclitaxel interactions in pancreatic cancer cells.

• DOI: 10.1186/s12885-020-07398-9
• 发表时间: 2020-10-23
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Niu J;Wang X;Qu J;Mager DE;Straubinger RM
• 通讯作者: Straubinger RM

Physiologically-based pharmacokinetic and pharmacodynamic models for gemcitabine and birinapant in pancreatic cancer xenografts.

• DOI: 10.1007/s10928-018-9603-z
• 发表时间: 2018-10
• 期刊: Journal of pharmacokinetics and pharmacodynamics
• 影响因子: 2.5
• 作者: Zhu X;Trueman S;Straubinger RM;Jusko WJ
• 通讯作者: Jusko WJ