Inhibition of lysosomal flux in carcinogen-induced head and neck cancer
抑制致癌物诱发的头颈癌中的溶酶体通量
基本信息
- 批准号:10993897
- 负责人:
- 金额:$ 24.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Squamous cell carcinoma of the head and neck (SCCHN) is a devastating disease that has a dismal prognosis,
despite aggressive surgical and adjuvant therapy. The average estimated overall survival for patients is
approximately 50% at 5 years (NIDCR.GOV). The high mortality rate demonstrates that current therapeutic
strategies are not adequate. In an effort to improve the outcomes for these patients, genetic analysis of SCCHN
has been used to identify potential novel therapeutic targets. One of the most commonly altered genes in this
malignancy is the calcium activated chloride channel TMEM16A/ANO1. TMEM16A is amplified in 30% of
SCCHN, and overexpression is correlated with poor oncologic outcomes in several cancer types. Our recent
data demonstrates that TMEM16A expression abrogates cisplatin-induced apoptosis. It is therefore likely that
TMEM16A plays a cytoprotective role in cancer cells.
How TMEM16A improves the survival and resistance of cancer cells to therapeutic interventions is unknown.
Sequestration of the cancer drugs and other toxins by the lysosomes followed by their expulsion through the
process of lysosomal exocytosis has emerged as a mechanism that enhances drug resistance of cancer cells.
We find that TMEM16A expression is associated with increased lysosomal acidification, biogenesis and
exocytosis. We propose that TMEM16A over-expressing cells are more efficient in the expulsion of cytotoxic
drugs than wild-type cells. We also postulate that TMEM16A overexpressing tumors are more likely to upregulate
lysosomal flux, and therefore contribute to oncogenesis and resistance to cytotoxic chemotherapy. This is a
groundbreaking concept, since it identifies a new function of a novel ion channel and a new paradigm in cancer
pathology and suggests a new approach to cancer treatment.
During this project, we will identify the mechanism of the TMEM16A-dependent cytoprotective upregulation
of the lysosomal throughput and sequestration/expulsion of cytotoxic drugs. We will test this hypothesis using
human tissues and patient-derived xenograft models. Finally we will test our concepts using the mouse model
of human head and neck tumors and the new approaches specifically aimed at suppressing lysosomal
biogenesis and exocytosis using repurposed antimalarial drugs. The results for these studies can be directly
translated to clinical investigations, by combining anti-lysosomal drugs with conventional cytotoxic agents, noth
of which are FDA-approved agents.
头颈部鳞状细胞癌(SCCHN)是一种预后不良的毁灭性疾病,
尽管进行了积极的手术和辅助治疗。患者的平均估计总生存期为
5年时约为50%(NIDCR.GOV)。高死亡率表明,目前的治疗
战略是不够的。为了改善这些患者的预后,SCCHN的遗传分析
已被用于识别潜在的新的治疗靶点。其中最常见的改变基因之一,
在恶性肿瘤中,钙激活的氯离子通道TMEM 16 A/ANO 1。TMEM 16 A在30%的
SCCHN,并且过表达与几种癌症类型中的不良肿瘤学结果相关。我们最近
数据表明TMEM 16 A表达消除了顺铂诱导的细胞凋亡。因此,
TMEM 16 A在癌细胞中起细胞保护作用。
TMEM 16 A如何提高癌细胞的存活率和对治疗干预的抗性尚不清楚。
通过溶酶体隔离抗癌药物和其他毒素,然后通过
溶酶体胞吐过程已经成为增强癌细胞耐药性的机制。
我们发现TMEM 16 A表达与溶酶体酸化、生物合成和细胞凋亡有关。
胞吐作用我们认为TMEM 16 A过表达的细胞在排出细胞毒性T细胞中更有效。
药物比野生型细胞。我们还假设TMEM 16 A过表达的肿瘤更可能上调TMEM 16 A的表达。
溶酶体流动,因此有助于肿瘤发生和对细胞毒性化疗的抗性。这是一
开创性的概念,因为它确定了一种新的离子通道的新功能和癌症的新模式
并提出了一种新的癌症治疗方法。
在这个项目中,我们将确定TMEM 16 A依赖的细胞保护上调的机制,
的溶酶体吞吐量和螯合/排出的细胞毒性药物。我们将测试这个假设,
人组织和患者来源的异种移植物模型。最后,我们将使用鼠标模型测试我们的概念
以及专门针对抑制溶酶体的新方法
使用重新利用的抗疟药物的生物发生和胞吐作用。这些研究的结果可以直接
将抗溶酶体药物与常规细胞毒性药物结合应用于临床研究,
其中包括FDA批准的药物。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Assessing the learning curve associated with a novel flexible robot in the pre-clinical and clinical setting.
- DOI:10.1007/s00464-021-08445-7
- 发表时间:2022-03
- 期刊:
- 影响因子:0
- 作者:Zhu TS;Godse N;Clayburgh DR;Duvvuri U
- 通讯作者:Duvvuri U
Positive Predictive Value of Neck Imaging Reporting and Data System Categories 3 and 4 Posttreatment FDG-PET/CT in Head and Neck Squamous Cell Carcinoma.
颈部影像报告和数据系统类别 3 和 4 治疗后 FDG-PET/CT 对头颈鳞状细胞癌的阳性预测价值。
- DOI:10.3174/ajnr.a6589
- 发表时间:2020
- 期刊:
- 影响因子:0
- 作者:Wangaryattawanich,P;Branstetter,BF;Ly,JD;Duvvuri,U;Heron,DE;Rath,TJ
- 通讯作者:Rath,TJ
Copper-dependent ATP7B up-regulation drives the resistance of TMEM16A-overexpressing head-and-neck cancer models to platinum toxicity.
- DOI:10.1042/bcj20190591
- 发表时间:2019-12-19
- 期刊:
- 影响因子:0
- 作者:Vyas A;Duvvuri U;Kiselyov K
- 通讯作者:Kiselyov K
Lysosomal inhibition sensitizes TMEM16A-expressing cancer cells to chemotherapy.
- DOI:10.1073/pnas.2100670119
- 发表时间:2022-03-22
- 期刊:
- 影响因子:11.1
- 作者:Vyas A;Gomez-Casal R;Cruz-Rangel S;Villanueva H;Sikora AG;Rajagopalan P;Basu D;Pacheco J;Hammond GRV;Kiselyov K;Duvvuri U
- 通讯作者:Duvvuri U
Response to Neoadjuvant Targeted Therapy in Operable Head and Neck Cancer Confers Survival Benefit.
可手术头颈癌对新辅助靶向治疗的反应可带来生存获益。
- DOI:10.1158/1078-0432.ccr-22-1768
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Mascarella,MarcoA;Olonisakin,TolaniF;Rumde,Purva;Vendra,Varun;Nance,MelonieA;Kim,Seungwon;Kubik,MarkW;Sridharan,ShaumS;Ferris,RobertL;Fenton,MoonJ;Clayburgh,DanielR;Ohr,JamesP;Joyce,SonaliC;Sen,Malabika;Herman,James
- 通讯作者:Herman,James
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UMAMAHESWAR DUVVURI其他文献
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{{ truncateString('UMAMAHESWAR DUVVURI', 18)}}的其他基金
Novel Targets to Treat Head & Neck Cancer in Veterans
治疗头部的新目标
- 批准号:
10512034 - 财政年份:2021
- 资助金额:
$ 24.75万 - 项目类别:
Inhibition of lysosomal flux in carcinogen-induced head and neck cancer
抑制致癌物诱发的头颈癌中的溶酶体通量
- 批准号:
10306375 - 财政年份:2019
- 资助金额:
$ 24.75万 - 项目类别:
Inhibition of lysosomal flux in carcinogen-induced head and neck cancer
抑制致癌物诱发的头颈癌中的溶酶体通量
- 批准号:
10542340 - 财政年份:2019
- 资助金额:
$ 24.75万 - 项目类别:
Novel targets to treat head and neck cancer in Veterans
治疗退伍军人头颈癌的新靶点
- 批准号:
9138391 - 财政年份:2016
- 资助金额:
$ 24.75万 - 项目类别:
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使用标记抗体对基因表达进行定量:基因、HIV 疫苗
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6252184 - 财政年份:1997
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