Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
使用纤连蛋白组装的有效抑制剂对肿瘤微环境进行直接治疗干预
基本信息
- 批准号:10409814
- 负责人:
- 金额:$ 20.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:ArchitectureAutomobile DrivingBinding ProteinsBiochemicalBiological AvailabilityBiologyBiophysicsBreastBreast Cancer DetectionBreast Cancer ModelBreast Cancer PatientBreast Cancer TreatmentCellsClinical DataClinical TreatmentClinical TrialsCollagenCollagen FiberCollagen FibrilCuesDataDepositionDiseaseDisease ProgressionEnzymesExtracellular MatrixFiberFibronectinsFibrosisFutureGoalsHeart DiseasesImmuneImmune EvasionImmune responseImmunosuppressionImmunotherapyInfiltrationInflammationInflammatoryInnovative TherapyKidney DiseasesLightLinkMalignant NeoplasmsMammary NeoplasmsMechanicsNeoadjuvant TherapyNeoplasm Circulating CellsNeoplasm MetastasisPathologicPatient-Focused OutcomesPatientsPeptidesPharmaceutical PreparationsPharmacologyPlayPre-Clinical ModelPrimary NeoplasmProteomicsRegulationRenal TissueResearchResistanceSafetySignal PathwaySignal TransductionSpecificityStreptococcus pyogenesStructureTestingTherapeuticTherapeutic AgentsTherapeutic InterventionTreatment EfficacyTumor Cell InvasionTumor stageTumor-associated macrophagesVascular DiseasesWorkadvanced breast canceralternative treatmentanti-PD-L1 therapybasebreast cancer progressioncancer therapychemotherapycyclooxygenase 2drug developmenteffective therapyimmune checkpoint blockadein vivoinfiltrating duct carcinomainhibitorinterestmalignant breast neoplasmnanodrugnovelpre-clinicalprofibrotic cytokineprognosticprognostic signaturerecruitstandard of caresuccesstherapeutic candidatetherapeutic targettranslational potentialtreatment strategytumortumor growthtumor microenvironmenttumor progression
项目摘要
PROJECT SUMMARY
Among the hallmarks of cancer, the extracellular matrix contributes to the regulation of each of the hallmark
principles underlying tumor progression. Importantly, extracellular matrix stiffness and fiber organization
enhance overall breast cancer progression and are associated with poor patient outcome. Biophysical and
biochemical cues from fibrillar matrix stiffness have emerged as key regulators of steps in the metastatic
cascade, including increased tumor cell invasion, inflammatory signaling, circulating tumor cells, and metastatic
outgrowth. Moreover, emerging studies demonstrate that biophysical cues from the ECM impact tumor intrinsic
and extrinsic factors implicated in immunotherapy resistance. Taken together, this data suggests that stromal
matrix stiffness may be one of the underlying mechanisms driving immunosuppression in the breast tumor
microenvironment. Despite the growing evidence that biophysical cues play a key role in disease progression
and the mounting interest in therapeutically targeting tumor ECM, there has yet to be an effective therapy directly
targeting the stromal matrix in breast cancer. Therefore, we propose to develop a therapeutically useful agent to
directly disrupt extracellular matrix assembly, deposition, and organization within the primary and metastatic
tumor microenvironments for the clinical treatment of breast cancer. We hypothesize that directly targeting
FN assembly with PEGylated-FUD will subsequently reduce tumor fibrosis by inhibiting collagen
deposition and fiber alignment resulting in decreased tumor growth and metastatic progression. We
further hypothesize that reduced fibronectin and collagen deposition will limit mechanical activation of pro-tumor
inflammation resulting in enhanced therapeutic efficacy in combination with immune checkpoint blockade. We
will test our hypothesis in the following aims: Aim 1: Determine the efficacy of PEGylated FUD as an anti-cancer
therapy in pre-clinical models of breast cancer. Aim 2. Evaluate the impact of PEGylated-FUD on
immunosuppressive signaling to enhance anti-PD-L1 therapy for treatment of metastatic disease.
项目摘要
在癌症的特征中,细胞外基质有助于调节每一个特征
肿瘤进展的基本原则。重要的是,细胞外基质硬度和纤维组织
增加乳腺癌的整体进展,并与患者预后不良相关。生物物理和
来自纤维状基质硬度的生物化学线索已经成为转移性肿瘤发生步骤的关键调节因子。
级联反应,包括增加的肿瘤细胞侵袭、炎性信号传导、循环肿瘤细胞和转移性肿瘤细胞。
结果此外,新兴的研究表明,来自ECM的生物物理线索影响肿瘤内在的细胞因子。
以及与免疫疗法抗性有关的外在因素。总之,这些数据表明,基质
基质硬度可能是乳腺肿瘤免疫抑制的潜在机制之一
微环境尽管越来越多的证据表明生物物理学线索在疾病进展中起着关键作用
以及对治疗靶向肿瘤ECM的兴趣越来越大,还没有直接有效的治疗方法
靶向乳腺癌中的基质。因此,我们建议开发一种治疗上有用的药剂,
直接破坏原发性和转移性肿瘤内的细胞外基质组装、沉积和组织,
乳腺癌临床治疗的肿瘤微环境。我们假设直接瞄准
FN与PEG化FUD的组装随后将通过抑制胶原蛋白而减少肿瘤纤维化
沉积和纤维排列导致肿瘤生长和转移进展减少。我们
进一步假设减少的纤连蛋白和胶原沉积将限制促肿瘤的机械活化
炎症导致与免疫检查点阻断组合的增强的治疗功效。我们
目的1:确定PEG化FUD作为抗癌药物的功效
乳腺癌的临床前模型的治疗。目标二。评价聚乙二醇化FUD对
免疫抑制信号传导以增强用于治疗转移性疾病的抗PD-L1疗法。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Glen S. Kwon其他文献
Polymeric micelle nanocarriers in cancer research
- DOI:
10.1007/s11705-016-1582-2 - 发表时间:
2016-08-21 - 期刊:
- 影响因子:4.500
- 作者:
Dae Hwan Shin;Yu Tong Tam;Glen S. Kwon - 通讯作者:
Glen S. Kwon
Polymeric Micelles for Multi-Drug Delivery in Cancer
- DOI:
10.1208/s12249-014-0251-3 - 发表时间:
2014-12-11 - 期刊:
- 影响因子:4.000
- 作者:
Hyunah Cho;Tsz Chung Lai;Keishiro Tomoda;Glen S. Kwon - 通讯作者:
Glen S. Kwon
Soluble Self-Assembled Block Copolymers for Drug Delivery
- DOI:
10.1023/a:1011991617857 - 发表时间:
1999-01-01 - 期刊:
- 影响因子:4.300
- 作者:
Glen S. Kwon;Teruo Okano - 通讯作者:
Teruo Okano
Production of paclitaxel-loaded PEG-emb/em-PLA micelles using PEG for drug loading and freeze-drying
使用聚乙二醇进行药物负载和冷冻干燥来生产紫杉醇负载的聚乙二醇-乳化/包埋-聚乳酸微球
- DOI:
10.1016/j.jconrel.2022.08.032 - 发表时间:
2022-10-01 - 期刊:
- 影响因子:11.500
- 作者:
Morteza Rasoulianboroujeni;Lauren Repp;Hye Jin Lee;Glen S. Kwon - 通讯作者:
Glen S. Kwon
Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(ε-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity
- DOI:
10.1007/s11095-007-9451-9 - 发表时间:
2007-10-03 - 期刊:
- 影响因子:4.300
- 作者:
M. Laird Forrest;Jaime A. Yáñez;Connie M. Remsberg;Yusuke Ohgami;Glen S. Kwon;Neal M. Davies - 通讯作者:
Neal M. Davies
Glen S. Kwon的其他文献
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{{ truncateString('Glen S. Kwon', 18)}}的其他基金
Direct therapeutic intervention of the tumor microenvironment with a potent inhibitor of fibronectin assembly
使用纤连蛋白组装的有效抑制剂对肿瘤微环境进行直接治疗干预
- 批准号:
10199263 - 财政年份:2021
- 资助金额:
$ 20.92万 - 项目类别:
Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy
用于联合治疗的寡(乳酸)n-前药纳米药物
- 批准号:
10371257 - 财政年份:2021
- 资助金额:
$ 20.92万 - 项目类别:
Oligo(lactic acid)n-Prodrug Nanomedicines for Combination Therapy
用于联合治疗的寡聚(乳酸)n-前药纳米药物
- 批准号:
10597075 - 财政年份:2021
- 资助金额:
$ 20.92万 - 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
- 批准号:
8497027 - 财政年份:2013
- 资助金额:
$ 20.92万 - 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
- 批准号:
8605161 - 财政年份:2013
- 资助金额:
$ 20.92万 - 项目类别:
Co-Delivery of Antifungal Agents: Toxicity and Efficacy in Invasive Candidiasis
抗真菌药物的联合给药:侵袭性念珠菌病的毒性和功效
- 批准号:
8786047 - 财政年份:2013
- 资助金额:
$ 20.92万 - 项目类别:
Tri-modal Polymeric Micelles for 'See & Treat' Applications in Surgical Oncology
用于“See”的三峰聚合物胶束
- 批准号:
8298518 - 财政年份:2011
- 资助金额:
$ 20.92万 - 项目类别:
Tri-modal Polymeric Micelles for 'See & Treat' Applications in Surgical Oncology
用于“See”的三峰聚合物胶束
- 批准号:
8175145 - 财政年份:2011
- 资助金额:
$ 20.92万 - 项目类别:
BIOSPECIFIC POLYMER ENZYME CONJUGATES FOR DRUG DELIVERY
用于药物输送的生物特异性聚合物酶缀合物
- 批准号:
6262537 - 财政年份:2001
- 资助金额:
$ 20.92万 - 项目类别:
BIOSPECIFIC POLYMER ENZYME CONJUGATES FOR DRUG DELIVERY
用于药物输送的生物特异性聚合物酶缀合物
- 批准号:
6489389 - 财政年份:2001
- 资助金额:
$ 20.92万 - 项目类别:
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