Interplay between tumor and microenvironment in bone metastasis
骨转移中肿瘤与微环境的相互作用
基本信息
- 批准号:10590697
- 负责人:
- 金额:$ 46.15万
- 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:2021-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdherenceAgeAndrogensAnimal ModelAntigensAutophagocytosisBone Marrow CellsCancer EtiologyCell CommunicationCellular immunotherapyCessation of lifeClinicClinicalComplicationComprehensionDataDevelopmentDiagnosisDiseaseEngineeringEnvironmentGenesGoalsHormonesHumanIL24 geneImmuneImmunosuppressionImmunotherapeutic agentImmunotherapyInduction of ApoptosisInsulin-Like Growth-Factor-Binding ProteinsInterleukin-24InvadedLesionMalignant Bone NeoplasmMalignant NeoplasmsMalignant neoplasm of prostateMediatingMelanoma CellMetastatic Neoplasm to the BoneMetastatic Prostate CancerModalityModelingMolecularMolecular TargetMorbidity - disease rateNeoplasm MetastasisOrganPathogenicityPatientsPhenotypePositioning AttributePre-Clinical ModelProceduresProcessPropertyProstate Cancer therapyProteinsReagentResearchResearch ProposalsRoleSTAT3 geneSchemeSignal TransductionSiteSolidT cell therapyT-Cell Immunologic SpecificityT-LymphocyteTechnologyTestingTherapeuticTherapeutic AgentsToxic effectTranslatingTumor ImmunityUp-RegulationWorkadvanced prostate cancerangiogenesisanti-canceranti-cancer therapeuticantiangiogenesis therapyanticancer activityanticancer researchbonecancer cellcancer diagnosiscarcinogenesiscombinatorialconventional therapycurative treatmentscytokineeffective therapyefficacy evaluationengineered T cellsimmune checkpoint blockadeimmunoregulationimprovedinhibitorinnovative technologiesinsightmalemelanomamenmetastatic processmolecular targeted therapiesmortalitymouse modelmultidisciplinaryneoplastic cellnext generationnovelnovel therapeuticspharmacologicpre-clinicalprogramspromoterprostate cancer cellprostate cancer metastasisprostate cancer modelprostate cancer progressionrational designreceptorrelapse preventionskeletalsmall moleculesmall molecule inhibitorsubtraction hybridizationsuccesssynergismtargeted treatmenttherapeutic targettreatment strategytumortumor microenvironment
项目摘要
Prostate cancer (CaP) is the most commonly diagnosed cancer and the second leading cause of cancer
death in men over the age of fifty. Bone is the primary site of metastasis in patients whose CaP progresses
beyond organ confinement. The absence of curative therapies for metastatic CaP emphasizes the imperative to
develop innovative technologies for target-specific delivery of therapeutic agents as well as novel treatment
strategies that are efficacious with minimal toxicity. Our investigative team seeks to address different aspects of
CaP bone metastasis through a highly integrated and focused research effort that will enhance our
comprehension of the mechanisms underlying CaP progression and improve therapeutic strategies to eradicate
bone metastases and prevent relapse. Our early work using a subtraction hybridization screen identified two
unique genes, i.e., melanoma differentiation associated gene-9 (mda-9) and mda-7/IL-24 from terminally
differentiating human melanoma cells. Subsequent research established MDA-9 as a key promoter of cancer
invasion and metastasis, whereas MDA-7/IL-24 was recognized as a broad-spectrum anti-cancer therapeutic.
Using a newly developed syngeneic pre-clinical model of CaP bone metastasis, we will investigate the interplay
between CaP bone metastases and the bone niche orchestrated by MDA-9 and evaluate therapeutic activity of
‘first-in-class’ small molecule inhibitor of MDA-9 (i.e., PDZ1i) for targeting both metastatic CaP cells and the bone
niche. By exploiting the exquisite ability and high efficiency of T cells to locate and destroy disseminated cancer
cells, especially those in normally inaccessible sites, i.e., bone, we will engineer CaP-reactive T cells to produce
MDA-7/IL-24, a unique cancer-selective apoptosis-inducing cytokine, for improved capacity to attack potentially
antigenically heterogenous bone metastases. Last, based on the ability of PDZ1i to reprogram the immune niche
in the tumor microenvironment, we will combine engineered T cells producing next-generation MDA-7/IL-24
(“Superkine MDA-7/IL-24“, “S7M”), having enhanced secretion and stability, with MDA-9-targeted therapy for
synergistic elimination of CaP bone lesions. We anticipate that the insights garnered from these studies will
enable a more precise molecular understanding of bone metastasis development for target discovery, rational
design of improved cellular immunotherapy, and combinatorial treatment modalities optimized to achieve a
maximum therapeutic potential. Successful completion of this multidisciplinary, synergistic research program will
provide a rapid path to translate these technologies and strategies into the clinic to safely and effectively manage
this most common skeletal complication of CaP.
前列腺癌(CaP)是最常诊断的癌症,也是第二大癌症原因
50岁以上的男性死亡。骨是CaP进展患者转移的主要部位
超越了器官限制转移性CaP的治愈性疗法的缺乏强调了
开发创新技术,用于治疗剂的靶向特异性递送以及新型治疗
有效且毒性最小的策略。我们的调查小组寻求解决不同方面的问题,
通过高度整合和集中的研究工作,CaP骨转移,这将提高我们的
了解CaP进展的潜在机制,并改善治疗策略,
骨转移和防止复发。我们早期的工作使用减法杂交筛选确定了两个
独特的基因,即,黑色素瘤分化相关基因9(mda-9)和mda-7/IL-24
分化人类黑色素瘤细胞随后的研究确定MDA-9是癌症的关键启动子
而MDA-7/IL-24被认为是一种广谱的抗癌治疗剂。
我们将使用一个新开发的同基因的CaP骨转移临床前模型,
之间的钙磷骨转移和骨龛编排的MDA-9和评估的治疗活性
MDA-9的“一流”小分子抑制剂(即,PDZ 1 i)用于靶向转移性CaP细胞和骨
利基通过利用T细胞的精确能力和高效率来定位和摧毁扩散的癌症,
细胞,特别是那些在正常情况下不可接近的部位,即,我们将设计CaP反应性T细胞,
MDA-7/IL-24,一种独特的癌症选择性凋亡诱导细胞因子,用于提高潜在的攻击能力
抗原性异种骨转移最后,基于PDZ 1 i重编程免疫生态位的能力,
在肿瘤微环境中,我们将联合收割机工程化T细胞产生下一代MDA-7/IL-24
(“Superkine MDA-7/IL-24”,“S7 M”),其具有增强的分泌和稳定性,与MDA-9靶向疗法用于
协同消除CaP骨损伤。我们预计,从这些研究中获得的见解将
能够更精确地从分子水平了解骨转移的发展,
设计改进的细胞免疫疗法和优化的组合治疗方式,以实现
最大的治疗潜力。成功完成这一多学科,协同研究计划将
提供了一条快速的途径,将这些技术和策略转化为临床,以安全有效地管理
最常见的骨骼并发症
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)
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PAUL B FISHER其他文献
PAUL B FISHER的其他文献
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{{ truncateString('PAUL B FISHER', 18)}}的其他基金
Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma
肝细胞癌的新型靶向组合疗法
- 批准号:
10532827 - 财政年份:2022
- 资助金额:
$ 46.15万 - 项目类别:
Interplay between tumor and microenvironment in bone metastasis
骨转移中肿瘤与微环境的相互作用
- 批准号:
10197281 - 财政年份:2021
- 资助金额:
$ 46.15万 - 项目类别:
Interplay between tumor and microenvironment in bone metastasis
骨转移中肿瘤与微环境的相互作用
- 批准号:
10339465 - 财政年份:2021
- 资助金额:
$ 46.15万 - 项目类别:
Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma
肝细胞癌的新型靶向组合疗法
- 批准号:
10063980 - 财政年份:2019
- 资助金额:
$ 46.15万 - 项目类别:
Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma
肝细胞癌的新型靶向组合疗法
- 批准号:
10299601 - 财政年份:2019
- 资助金额:
$ 46.15万 - 项目类别:
Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma
肝细胞癌的新型靶向组合疗法
- 批准号:
10737864 - 财政年份:2019
- 资助金额:
$ 46.15万 - 项目类别:
Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma
肝细胞癌的新型靶向组合疗法
- 批准号:
10747553 - 财政年份:2019
- 资助金额:
$ 46.15万 - 项目类别:
Novel Targeted Combinatorial Therapy for Hepatocellular Carcinoma
肝细胞癌的新型靶向组合疗法
- 批准号:
10521269 - 财政年份:2019
- 资助金额:
$ 46.15万 - 项目类别:
New transgenic animal model to study pancreatic cancer
研究胰腺癌的新转基因动物模型
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8991487 - 财政年份:2015
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$ 46.15万 - 项目类别:
New transgenic animal model to study pancreatic cancer
研究胰腺癌的新转基因动物模型
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8808340 - 财政年份:2015
- 资助金额:
$ 46.15万 - 项目类别:
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