Cancer Therapeutics through Theory and Experiment: From Cell Lines to Canine Tumors Grown on the Back of Mice

通过理论和实验进行癌症治疗:从细胞系到小鼠背部生长的犬肿瘤

基本信息

项目摘要

The number of cells in an adult multicellular organism such as a human being is under very tight control and, under normal circumstances, there is a balance between new cell production and cell death. Roughly speaking, cancer results when there is excessive cell division or reduced cell death due to some malfunctioning in the cell number control system. A possible approach to cancer therapy is to quickly and robustly induce the death of cancer cells, and earlier work has used an engineering approach to explain the rationale behind the dramatically successful induction of human cancer cell death by a therapeutic molecule. The goal here is to extend these results to the domain of canine cancers by first modeling them and then conducting therapeutic experiments on canine tumors grown on the backs of mice. Since the work is driven by the goal of improving cancer treatment, the potential societal benefits of this project could be enormous. The project will be carried out at the Center for Bioinformatics and Genomic Systems Engineering (CBGSE) at Texas A & M University, where widespread dissemination of the research results, imparting truly interdisciplinary hands-on education to graduate students, and beneficially targeting minorities and minority institutions, are top priorities. The malfunctioning of the cell-cycle control system, an essential characteristic of cancer, can be attributed to different signaling breakdowns at many different locations in a signaling pathway. As a result, a proper design of cancer therapy should first attempt to identify the location and type of malfunction in the pathway and then arrive at a drug combination that is particularly well suited for it. Unfortunately, with the notable exception of the recent attempts at targeted immunotherapy, most of the approaches to cancer therapy do not follow such a systematic procedure. Thus, for most of cancers, there is a critical need for precisely identifying the failure point(s) in the pathway, hopefully leading to a more targeted therapy with a better likelihood of success. Many of the cancer therapies to date have mostly focused on blocking the pathways essential to cell proliferation. However, often, even if the drugs are initially successful in treating the cancer, the success is usually short lived as the cancer cell can activate some other pathways not targeted by the drug. An alternative approach to treat cancer would be to use drugs that are capable of inducing cell death. Chemotherapeutic drugs targeting cell death also display drug resistance which occurs when the cancer cells figure out mechanisms to evade the cell death inducing activity of the drug. If, however, one could identify molecules along the cell death pathway that can play a decisive role in ensuring cell death, regardless of the upstream signaling breakdown(s), then targeting such molecules with drugs would provide a robust strategy for treating cancer. In very recent work, the research team has utilized mathematical modeling and experimentation to demonstrate remarkable success in achieving robust cell killing for human breast cancer, pancreatic cancer and melanoma cell lines. This was done via the modulation of a gene called STAT3 using drug combination cocktails containing Cryptotanshinone, a traditional Chinese herb derivative. Motivated by this preliminary success, the goal here is to carry out similar modeling for osteosarcoma and demonstrate therapeutic success on cell lines and mice implanted canine cancer xenografts in a veterinarian's lab. Success with the latter is likely to move the results closer to the domain of drug development for clinical applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
成年多细胞生物体(如人类)的细胞数量受到非常严格的控制,在正常情况下,新细胞产生和细胞死亡之间存在平衡。粗略地说,当细胞数量控制系统出现故障而导致细胞过度分裂或细胞死亡减少时,就会产生癌症。 癌症治疗的一种可能方法是快速而有力地诱导癌细胞死亡,早期的工作已经使用工程方法来解释治疗分子显着成功诱导人类癌细胞死亡背后的原理。这里的目标是将这些结果扩展到犬类癌症领域,首先对它们进行建模,然后对在小鼠背部生长的犬类肿瘤进行治疗实验。由于这项工作是由改善癌症治疗的目标驱动的,因此该项目的潜在社会效益可能是巨大的。该项目将在得克萨斯州农工大学的生物信息学和基因组系统工程中心(CBGSE)进行,在那里,研究成果的广泛传播,向研究生提供真正的跨学科实践教育,并有益地针对少数民族和少数民族机构,是首要任务。细胞周期控制系统的故障是癌症的一个基本特征,可以归因于信号通路中许多不同位置的不同信号传导故障。因此,一个适当的癌症治疗设计应该首先尝试确定的位置和类型的故障的途径,然后在一个药物组合,是特别适合它。不幸的是,与最近的尝试在靶向免疫治疗显着的例外,大多数癌症治疗的方法不遵循这样一个系统的程序。因此,对于大多数癌症来说,迫切需要精确识别途径中的失败点,希望能够导致具有更大成功可能性的更具靶向的治疗。迄今为止,许多癌症疗法主要集中在阻断细胞增殖所必需的途径上。然而,通常情况下,即使药物最初成功治疗癌症,成功通常是短暂的,因为癌细胞可以激活药物不靶向的其他途径。治疗癌症的另一种方法是使用能够诱导细胞死亡的药物。靶向细胞死亡的化疗药物也显示出耐药性,当癌细胞找到逃避药物诱导细胞死亡的机制时,就会出现耐药性。然而,如果人们能够鉴定出沿着细胞死亡途径的分子,这些分子可以在确保细胞死亡中起决定性作用,而不管上游信号传导的破坏,那么用药物靶向这些分子将提供治疗癌症的强大策略。在最近的工作中,研究小组利用数学建模和实验证明了在实现对人类乳腺癌,胰腺癌和黑色素瘤细胞系的强大细胞杀伤方面取得了显着的成功。这是通过使用含有隐丹参酮(一种传统中药衍生物)的药物组合鸡尾酒来调节一种名为STAT3的基因来完成的。受这一初步成功的激励,这里的目标是对骨肉瘤进行类似的建模,并在兽医实验室中证明细胞系和小鼠移植犬癌异种移植物的治疗成功。后者的成功可能会使结果更接近临床应用的药物开发领域。该奖项反映了NSF的法定使命,并通过使用基金会的知识价值和更广泛的影响审查标准进行评估,被认为值得支持。

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)
Network modeling and inference of peroxisome proliferator-activated receptor pathway in high fat diet-linked obesity
高脂饮食相关肥胖中过氧化物酶体增殖物激活受体途径的网络建模和推断
  • DOI:
    10.1016/j.jtbi.2021.110647
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    2
  • 作者:
    Vundavilli, Haswanth;Tripathi, Lokesh P.;Datta, Aniruddha;Mizuguchi, Kenji
  • 通讯作者:
    Mizuguchi, Kenji
In Silico Modeling of the Induction of Apoptosis by Cryptotanshinone in Osteosarcoma Cell Lines
  • DOI:
    10.1109/tcbb.2020.3037318
  • 发表时间:
    2020-11
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Radhika Saraf;A. Datta;Chao Sima;Jianping Hua;Rosana Lopes;M. Bittner;T. Miller;H. Wilson-Robles
  • 通讯作者:
    Radhika Saraf;A. Datta;Chao Sima;Jianping Hua;Rosana Lopes;M. Bittner;T. Miller;H. Wilson-Robles
Anti-tumor effects of cryptotanshinone (C19H20O3) in human osteosarcoma cell lines
  • DOI:
    10.1016/j.biopha.2022.112993
  • 发表时间:
    2022-06-01
  • 期刊:
  • 影响因子:
    7.5
  • 作者:
    Vundavilli, Haswanth;Datta, Aniruddha;Wilson-Robles, Heather M.
  • 通讯作者:
    Wilson-Robles, Heather M.
Image Processing Pipeline to Compute Homologous Recombination Score
计算同源重组分数的图像处理管道
  • DOI:
    10.1145/3535694.3535704
  • 发表时间:
    2022
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Vundavilli, Haswanth;Tumiati, Manuela;Hautaniemi, Sampsa;Datta, Aniruddha;Kauppi, Liisa
  • 通讯作者:
    Kauppi, Liisa
Drug Target Identification in Triple Negative Breast Cancer Stem Cell Pathways: A Computational Study of Gene Regulatory Pathways Using Boolean Networks
  • DOI:
    10.1109/access.2023.3283291
  • 发表时间:
    2023-01-01
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Lahiri,Aditya;Vundavilli,Haswanth;Datta,Aniruddha
  • 通讯作者:
    Datta,Aniruddha
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Aniruddha Datta其他文献

Robust and Optimal PID Controller Design
  • DOI:
    10.1016/s1474-6670(17)42581-x
  • 发表时间:
    1997-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    Ming-tzu Ho;Aniruddha Datta;L.H. Keel;S.P. Bhattacharyya
  • 通讯作者:
    S.P. Bhattacharyya
In Vitro Flowering and High Xanthotoxin in Ammi majus L.
  • DOI:
    10.1007/bf03262956
  • 发表时间:
    2012-12-30
  • 期刊:
  • 影响因子:
    1.500
  • 作者:
    Madhumati Purohit;Deepshikha Pande;Aniruddha Datta;Prem S. Srivastava
  • 通讯作者:
    Prem S. Srivastava
An addition to the endemic Indian radiation of Eutropis: Phylogenetic position of Eutropis dissimilis Hallowell (Squamata: Scincidae).
印度地方性辐射Eutropis的补充:Eutropis dissimilis Hallowell(有鳞目:Scincidae)的系统发育位置。
  • DOI:
    10.11646/zootaxa.4027.1.9
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0.9
  • 作者:
    Aniruddha Datta;V. Deepak;Chinta Sidharthan;A. J. Barley;K. Karanth
  • 通讯作者:
    K. Karanth
Phylogeny of endemic skinks of the genus Lygosoma (Squamata: Scincidae) from India suggests an in situ radiation
印度石龙子属(Squamata:Scincidae)地方性石龙子的系统发育表明存在原位辐射
  • DOI:
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Aniruddha Datta;Mewa Singh;K. Karanth
  • 通讯作者:
    K. Karanth
Anti-tumor effects of cryptotanshinone (Csub19/subHsub20/subOsub3/sub) in human osteosarcoma cell lines
隐丹参酮(C₁₉H₂₀O₃)在人骨肉瘤细胞系中的抗肿瘤作用
  • DOI:
    10.1016/j.biopha.2022.112993
  • 发表时间:
    2022-06-01
  • 期刊:
  • 影响因子:
    7.500
  • 作者:
    Haswanth Vundavilli;Aniruddha Datta;Chao Sima;Jianping Hua;Rosana Lopes;Michael Bittner;Tasha Miller;Heather M. Wilson-Robles
  • 通讯作者:
    Heather M. Wilson-Robles

Aniruddha Datta的其他文献

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{{ truncateString('Aniruddha Datta', 18)}}的其他基金

I-Corps: Model-driven precision oncology for cancer therapy design
I-Corps:用于癌症治疗设计的模型驱动的精准肿瘤学
  • 批准号:
    2136215
  • 财政年份:
    2021
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Identification of Drug Targets and Their Validation in Cancer Therapy Design
癌症治疗设计中药物靶标的识别及其验证
  • 批准号:
    1609236
  • 财政年份:
    2016
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Exploiting The Heterogeneous Composition Of Tumor Tissue And The Altered Metabolism Of Tumor Cells For Cancer Therapy Design
利用肿瘤组织的异质组成和肿瘤细胞代谢的改变进行癌症治疗设计
  • 批准号:
    1404314
  • 财政年份:
    2014
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Student Travel Award Support for GENSIPS'13
对 GENSIPS13 的学生旅行奖支持
  • 批准号:
    1342663
  • 财政年份:
    2013
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Cancer Therapy Design Based on Pathway Information
基于通路信息的癌症治疗设计
  • 批准号:
    1068628
  • 财政年份:
    2011
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Modeling and Control in Cancer Genomics
癌症基因组学的建模和控制
  • 批准号:
    0701531
  • 财政年份:
    2007
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Control Issues in Cancer Therapy
癌症治疗中的控制问题
  • 批准号:
    0355227
  • 财政年份:
    2004
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Controller Synthesis Subject to Structure and Order Constraints
受结构和阶次约束的控制器综合
  • 批准号:
    9903488
  • 财政年份:
    1999
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Robust Adaptive Control Based on Kharitonov Theory and Its Extensions
基于Kharitonov理论及其扩展的鲁棒自适应控制
  • 批准号:
    9417004
  • 财政年份:
    1995
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant
Robustness Quantification and Performance Improvement in Adaptive Control Systems
自适应控制系统的鲁棒性量化和性能改进
  • 批准号:
    9210726
  • 财政年份:
    1992
  • 资助金额:
    $ 42.49万
  • 项目类别:
    Standard Grant

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重新思考重新利用:开发冷冻凝胶技术,通过为期一年的局部重新利用治疗方法来解决胶质母细胞瘤复发问题
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通过使用芯片上的母胎界面开发基于细胞外囊泡的早产疗法
  • 批准号:
    10434794
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通过个性化电路读写疗法产生有弹性的状态
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