Nanoformulated small molecule immunotherapy for SHH medulloblastoma
SHH 髓母细胞瘤的纳米制剂小分子免疫疗法
基本信息
- 批准号:10544532
- 负责人:
- 金额:$ 38.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-01 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAffectAgonistAntibodiesAntineoplastic AgentsBlood - brain barrier anatomyCDK4 geneCTLA4 geneCell ProliferationCell SurvivalCellsChildChildhood Malignant Brain TumorCirculationClinicalCognitive deficitsCombined Modality TherapyDataDevelopmentDiagnosisDisease ProgressionEnvironmentExposure toFlow CytometryFormulationGenetically Engineered MouseGliomaImmuneImmune responseImmune systemImmunotherapyImpairmentImplantIn VitroInfiltrationLeftMacrophageMalignant NeoplasmsMalignant neoplasm of urinary bladderMicellesModalityModelingMusNeoplasmsOperative Surgical ProceduresOutcomePIK3CG genePathway interactionsPatientsPenetrationPharmaceutical PreparationsPhysiologicalPlayPolymersPopulationProto-Oncogene Proteins c-aktRadiation therapyRecurrenceRecurrent diseaseRecurrent tumorReportingRetinoblastoma ProteinRiskRoleSHH geneSurvivorsT cell infiltrationT-LymphocyteTLR7 geneTherapeuticTherapeutic EffectTimeTissuesToxic effectTreatment outcomeTumor PromotionTumor TissueVaccinesaggressive therapyalternative treatmentanti-tumor immune responseblood-brain tumor barrierbrain tissuecancer clinical trialcancer immunotherapycancer therapychemotherapycytokineimmune checkpointimmunological statusimprovedin vivoinhibitorinnovationinterestmTOR Inhibitormedulloblastomamelanomamotor deficitmouse modelnanonanoparticleneoplastic cellnovelnovel therapeuticsprogrammed cell death protein 1resiquimodresponsesmall moleculesynergismtargeted agenttherapy outcometimelinetranscriptometreatment effecttreatment strategytumortumor growthtumor microenvironment
项目摘要
Nanoformulated small molecule immunotherapy for SHH medulloblastoma
M. Sokolsky-Papkov, (PI)
This project focuses on improving therapy of medulloblastomas. Despite aggressive and highly toxic multi-modality
therapy, 30% of the children diagnosed with medulloblastoma will still die from recurrent disease. The survivors have
increased risk for subsequent neoplasms and are often left with severe and lifelong treatment-associated cognitive and motor
deficits. Development of novel modalities that are more effective and safer than the current therapies is paramount in
improving the clinical outcomes in medulloblastomas. Cancer immunotherapy, the utilization of the patients’ own immune
system to treat cancer, has emerged as a powerful new strategy in cancer treatment. A recent study by our collaborator, Dr.
Dolores Hambardzymyan, suggested that SHH medulloblastomas are enriched in TAMs and our data shows that these
TAMs express TLR7/8. An imidazoquinoline drug resiquimod [R848], a Toll-like receptor (TLR) 7 and 8 agonist, is
evaluated as a single agent or adjuvant in combination with vaccines is several oncology clinical trials in patients with
melanoma, bladder cancer, glioma, and other malignancies (ClinicalTrials.gov: NCT00470379, NCT00821652,
NCT00960752, NCT01204684). However, resiquimod is nearly insoluble at neutral physiological pH, and there is no
clinically approved formulation available for its systemic or local intratumoral administration. We have loaded resiquimod
into our ultrahigh-capacity nanoparticle polymeric micelles (PMs) platform. Previously we have utilized this platform to
deliver SMO inhibitor vismodegib, CDK4/6 inhibitor palbociclib and PIK3/AKT/mTor inhibitor Sapanisertib (INK-128).
Delivery in POx PMs reduced toxicity and rendered these agents effective, while free drugs showed no survival benefit in
G-Smo mice-genetically engineered mouse model (GEMM) of SHH medulloblastoma. Unlike cells based or patient derived
implantable models these mice have endogenous tumors which form intact native tumor environment and blood brain barrier
(BBB). Treatment with POx-resiquimod PMs (POx-Res PMs) significantly enhanced infiltration of macrophages into the
tumors decreased tumor cells viability (pRB levels) and prolonged mice survival. This project aims to obtain mechanistic
data to evaluate the effects of POx-res PMs administered systemically (IP) and locally (IT) and determine whether the anti-
neoplastic agents that target SHH pathway can synergize with POx-res PMs to improve treatment outcomes. Specific aims
are: 1. Delineate systemic vs. local effects of POx-res PMs on the tumor immunological status, disease progression, and
therapeutic outcomes in GEMM model of SHH medulloblastoma. 2. Delineate the contributions of immune cell populations
to the therapeutic effect of POx-res PMs and 3. Determine whether the anti-neoplastic agents that target SHH pathway can
synergize with POx-res PMs to improve treatment of SHH driven medulloblastoma.
纳米小分子免疫治疗SHH髓母细胞瘤
M. Sokolsky-Papkov,(PI)
该项目的重点是提高髓母细胞瘤的治疗。尽管有侵略性和高毒性的多模态
尽管如此,30%的被诊断患有髓母细胞瘤的儿童仍然会死于复发性疾病。幸存者
随后发生肿瘤的风险增加,并且通常会留下严重和终身治疗相关的认知和运动功能障碍。
赤字开发比当前疗法更有效、更安全的新疗法至关重要,
改善髓母细胞瘤的临床结局。癌症免疫治疗,利用患者自身免疫
系统治疗癌症,已经成为癌症治疗中一种强大的新策略。我们的合作者最近的一项研究,博士。
Dolores Hambardzymyan提出SHH髓母细胞瘤富含TAM,我们的数据显示这些TAM在SHH髓母细胞瘤中表达。
TAM表达TLR 7/8。一种咪唑并喹啉类药物瑞喹莫特[R848],一种Toll样受体(TLR)7和8激动剂,
作为单一药剂或佐剂与疫苗组合进行评估的是在患有癌症的患者中进行的几项肿瘤学临床试验。
黑素瘤、膀胱癌、神经胶质瘤和其它恶性肿瘤(ClinicalTrials.gov:NCT 00470379,NCT 00821652,
NCT 00960752、NCT 01204684)。然而,瑞喹莫特在中性生理pH下几乎不溶,并且不存在可溶性。
可用于全身或局部肿瘤内给药的临床批准的制剂。我们已经装载了瑞喹莫特
我们的超高容量纳米颗粒聚合物胶束(PMs)平台。此前,我们曾利用该平台
递送SMO抑制剂vismodegib、CDK 4/6抑制剂palbociclib和PIK 3/AKT/mTor抑制剂Sapanisertib(INK-128)。
在POx PM中的递送降低了毒性并使这些药物有效,而游离药物在POx PM中没有显示出存活益处。
SHH髓母细胞瘤的G-Smo小鼠-基因工程小鼠模型(GEMM)。与基于细胞或患者来源的
这些小鼠具有形成完整的天然肿瘤环境和血脑屏障的内源性肿瘤
(BBB)。用POx-瑞喹莫特PM(POx-Res PM)处理显著增强了巨噬细胞向巨噬细胞中的浸润。
肿瘤降低了肿瘤细胞活力(pRB水平)并延长了小鼠存活。该项目旨在获得机械
评估全身(IP)和局部(IT)给予POx-res PM的效果,并确定抗-
靶向SHH途径的肿瘤剂可以与POx-res PM协同作用以改善治疗结果。具体目标
是:1.描述POx-res PM对肿瘤免疫状态、疾病进展和
SHH髓母细胞瘤GEMM模型的治疗结果。2.描述免疫细胞群的贡献
POx-res PMs的治疗效果和3.确定靶向SHH通路的抗肿瘤药物是否可以
与POx-res PM协同改善SHH驱动髓母细胞瘤的治疗。
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)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MARINA SOKOLSKY-PAPKOV其他文献
MARINA SOKOLSKY-PAPKOV的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('MARINA SOKOLSKY-PAPKOV', 18)}}的其他基金
Nanoformulated small molecule immunotherapy for SHH medulloblastoma
SHH 髓母细胞瘤的纳米制剂小分子免疫疗法
- 批准号:
10341773 - 财政年份:2022
- 资助金额:
$ 38.88万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 38.88万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 38.88万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 38.88万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 38.88万 - 项目类别:
Studentship














{{item.name}}会员




