Nanotechnology enabled targeting of p53 deficiency in human cancer
纳米技术能够靶向人类癌症中的 p53 缺陷
基本信息
- 批准号:9307738
- 负责人:
- 金额:$ 35.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-07-08 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:AlginatesAllelesAlpha CellAmanitaAmanitinsAmino AcidsAntibodiesAntineoplastic AgentsBiodistributionCD44 geneCancer PatientCatalytic DomainCell Adhesion MoleculesCellsClinicClinicalColorectalColorectal CancerComplexCyclic PeptidesDataDoseDrug resistanceEncapsulatedEnsureEpithelial CellsEssential GenesFluorouracilGene DosageGenesGenomicsHumanHydrogelsHydrophobicityIn VitroMalignant NeoplasmsMalignant neoplasm of ovaryMalignant neoplasm of pancreasMalignant neoplasm of prostateMediatingMedicineMicrocapsules drug delivery systemMorbidity - disease rateMutationNanotechnologyNatureNormal CellOperative Surgical ProceduresPOLR2A genePermeabilityProtein p53Public HealthPublishingRNA Polymerase IIRegimenResearchResistanceSignal TransductionStem cellsTP53 geneTechnologyTestingTranslatingTumor InitiatorsTumor Suppressor ProteinsTumorigenicityVariantWaterbasecancer cellcancer therapyenzyme pathwayexperiencefight againsthydrophilicityimprovedin vivomalignant breast neoplasmminiaturizemortalitymouse modelmutantnanoparticlenovelnovel strategiesoverexpressionoxaliplatinresistance mechanismstemstem-like cellsystemic toxicitytargeted deliverytargeted treatmentthree dimensional cell culturetumortumorigenic
项目摘要
Project Summary/Abstract
There has been little change in mortality rate of human colorectal cancer (CRC) in the past decades and
the treatment options available for CRC are still very limited today. In CRC and most other human cancers, the
tumor suppressor TP53 gene is frequently inactivated by mutation or deletion. Consequently, tremendous
effort has been made to restore the p53 activity for cancer therapy. However, no p53-based therapy has been
successfully translated into clinical cancer treatment due to the complexity of p53 signaling.
Therefore, instead of restoring the p53 activity, identifying vulnerabilities conferred by TP53 deletion or
mutation is a novel strategy for fighting against the p53 deficiency in human cancer. In a recent study
published in Nature, we confirmed that genomic deletion of TP53 is frequently accompanied by the partial loss
of neighboring essential genes and cancer cells with hemizygous TP53 deletion are remarkably vulnerable to
further suppression of such neighboring essential genes. We revealed that POLR2A is such an essential gene
that is often partially co-deleted with TP53 in human cancers. Such hemizygous loss of TP53/POLR2A occurs
in 53, 60, and 41% of colorectal, breast, and pancreatic cancers, respectively.
The POLR2A activity is specifically inhibited by α-Amanitin (Ama), a cyclic peptide of 8 amino acids found
in the mushroom Amanita phalloides. We demonstrate that low doses of Ama conjugated with anti-epithelial
cell adhesion molecule (EpCAM) antibody for targeting CRC can result in much enhanced tumor regression in
murine models of human CRC with hemizygous deletion of POLR2A without evident systemic toxicity.
However, a small fraction of CRC cells are found to be resistant to Ama in a dose-dependent manner.
These drug-resistant cells are often called cancer stem-like cells (CSCs) or tumor initiating cells (TICs). A
common feature of the CSCs in many cancers (e.g., CRC together with breast and pancreatic cancers) is that
they overexpress the variant CD44. Our preliminary data show that the Ama-resistant CRC cells are indeed
enriched with CD44, but not EpCAM. Moreover, our studies show that human breast and prostate CSCs can
be effectively destroyed in vitro and in vivo using anticancer agent-laden nanoparticles that target the variant
CD44 (but not the normal or non-variant CD44 on normal stem cells) with no evident systemic toxicity.
Here, we hypothesize that targeted delivery of Ama and/or clinically used anticancer drugs to the variant
CD44+ cancer cells with nanoparticles can overcome their drug resistance. We will test this hypothesis with two
specific aims: 1, to determine the mechanisms of resistance to the Ama-based POLR2A-targted therapy of
human CRCs with hemizygous loss of TP53 and 2, to determine if the combined therapy of Ama and clinically
used anticancer drugs co-delivered with the variant CD44-targeting nanoparticles can overcome the drug
resistance of human CRCs. It is expected that this project may result in a novel approach to targeting TP53
and could have a major impact on the treatment of colorectal and other cancers harboring TP53 deficiency.
项目摘要/摘要
在过去的几十年里,人类结直肠癌(CRC)的死亡率几乎没有变化,而且
目前,结直肠癌可供选择的治疗方法仍然非常有限。在结直肠癌和大多数其他人类癌症中,
肿瘤抑制基因TP53常因突变或缺失而失活。因此,巨大的
人们已经努力恢复用于癌症治疗的P53活性。然而,目前还没有基于p53的治疗方法
由于P53信号的复杂性,成功地将其转化为临床癌症治疗。
因此,不是恢复P53的活性,而是识别由TP53缺失或
突变是对抗人类癌症中P53缺失的一种新策略。在最近的一项研究中
发表在《自然》杂志上,我们证实了TP53的基因组缺失经常伴随着部分缺失
邻近的必需基因和具有半合子TP53缺失的癌细胞非常容易受到
进一步抑制这种邻近的必要基因。我们揭示了POLR2A是一个如此重要的基因
在人类癌症中,该基因经常与TP53部分共缺失。这种TP53/POLR2A基因的半合子缺失
在结直肠癌、乳腺癌和胰腺癌中分别为53%、60%和41%。
α-Amanitin(Ama)是一种由8个氨基酸组成的环肽,它特异性地抑制POLR2a的活性
在蘑菇鹅膏菌中。我们证明了低剂量的AMA与抗上皮细胞抗体结合
靶向CRC的细胞黏附分子(EpCAM)抗体可显著增强肿瘤的消退
POLR2A半合子缺失且无明显全身毒性的人结直肠癌小鼠模型。
然而,一小部分结直肠癌细胞被发现以剂量依赖的方式对Ama产生耐药。
这些耐药细胞通常被称为癌症干细胞(CSCs)或肿瘤起始细胞(TICs)。一个
许多癌症(例如,结直肠癌以及乳腺癌和胰腺癌)中CSCs的共同特征是
它们过度表达CD44变异体。我们的初步数据显示,耐阿莫西林的CRC细胞确实是
富含CD44,但不含EPCAM。此外,我们的研究表明,人类的乳腺和前列腺干细胞可以
在体外和体内使用针对该变体的抗癌剂载药纳米粒有效地摧毁
CD44(但不是正常干细胞上的正常或非变异的CD44),没有明显的全身毒性。
这里,我们假设靶向递送AMA和/或临床上使用的抗癌药物给变异体
带有纳米颗粒的CD44+癌细胞可以克服其耐药性。我们将用两个例子来检验这一假设
具体目的:1、确定抗癌基因POLR2A靶向治疗的耐药机制
Tp53和Tp2基因半合子缺失的人肾细胞癌患者的临床研究
使用的抗癌药物与变种的CD44靶向纳米颗粒一起传递可以克服这种药物
人卵巢癌的耐药性。预计这一项目可能会产生一种针对TP53的新方法
并可能对结直肠癌和其他携带TP53缺陷的癌症的治疗产生重大影响。
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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Xiaoming He其他文献
Xiaoming He的其他文献
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{{ truncateString('Xiaoming He', 18)}}的其他基金
Multiscale hydrogel biomaterials-enabled 3D modeling of cancer drug resistance
基于多尺度水凝胶生物材料的癌症耐药性 3D 建模
- 批准号:
10639167 - 财政年份:2023
- 资助金额:
$ 35.91万 - 项目类别:
Nanotechnology for targeted therapy and fundamental understanding oftherapeutic resistance in triple negative breast cancer
用于靶向治疗的纳米技术和对三阴性乳腺癌治疗耐药性的基本了解
- 批准号:
10593921 - 财政年份:2020
- 资助金额:
$ 35.91万 - 项目类别:
Nanotechnology for targeted therapy and fundamental understanding oftherapeutic resistance in triple negative breast cancer
用于靶向治疗的纳米技术和对三阴性乳腺癌治疗耐药性的基本了解
- 批准号:
10376777 - 财政年份:2020
- 资助金额:
$ 35.91万 - 项目类别:
Nanotechnology enabled targeting of p53 deficiency in human cancer
纳米技术能够靶向人类癌症中的 p53 缺陷
- 批准号:
10063652 - 财政年份:2018
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Investigate the mechanisms underlying microRNA-146a activity in regulation of foreign body response to biomaterials
研究 microRNA-146a 活性调节生物材料异物反应的机制
- 批准号:
10522163 - 财政年份:2017
- 资助金额:
$ 35.91万 - 项目类别:
Investigate the mechanisms underlying microRNA-146a activity in regulation of foreign body response to biomaterials
研究 microRNA-146a 活性调节生物材料异物反应的机制
- 批准号:
10641032 - 财政年份:2017
- 资助金额:
$ 35.91万 - 项目类别:
Nanotechnology enabled targeting of p53 deficiency in human cancer
纳米技术能够靶向人类癌症中的 p53 缺陷
- 批准号:
9193391 - 财政年份:2016
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Microencapsulation of oocytes for low-CPA (cryoprotectant) vitrification
用于低 CPA(冷冻保护剂)玻璃化冷冻的卵母细胞微囊化
- 批准号:
8050447 - 财政年份:2011
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$ 35.91万 - 项目类别:
Microencapsulation of oocytes for low-CPA (cryoprotectant) vitrification
用于低 CPA(冷冻保护剂)玻璃化冷冻的卵母细胞微囊化
- 批准号:
8325224 - 财政年份:2011
- 资助金额:
$ 35.91万 - 项目类别:
Microencapsulation of oocytes for low-CPA (cryoprotectant) vitrification
用于低 CPA(冷冻保护剂)玻璃化冷冻的卵母细胞微囊化
- 批准号:
8600270 - 财政年份:2011
- 资助金额:
$ 35.91万 - 项目类别:
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