Control Issues in Cancer Therapy

本计划的目标有两个方面。首先，我们打算探索应用现有的生物学理论知识来推进癌症治疗事业的可能性;其次，我们打算发展控制理论的基本结果，以解决癌症相关疾病中出现的一些独特问题。这是他在国家癌症研究所资助下担任生物信息学讲师两年期间的教学和研究经验。在培训过程中，这位研究员认识到癌症是由控制系统的B崩溃引起的，该控制系统调节多细胞生物体中的细胞数量，防止肿瘤等不良生长。此外，研究员和合作研究员还认识到，癌症是由控制系统的崩溃引起的。我们坚信，工程文献中经过时间考验的细胞学技术可以得到利用，并进一步发展，以获得癌症治疗的有用指南。我们已经获得了排除干扰的结果，表明了一个明确的方向。特别是，我们与分子生物学家同事迈克尔·比特纳合作，（以前是国家人类基因组研究所（NHGRI），现在是国家基因组研究所（TGEN）），我们开发了一个框架，用于模拟受外部干扰的基因调控网络，干预，并将其用于应用最优控制策略来减缓转移性黑色素瘤的进展，所用的模型是具有外部控制的对象布尔网络（PBN）模型，我们证明了它是受控马尔可夫链的一个特例。这使得应用标准的最优控制技术（如动态规划）成为可能，并使我们能够进行这一概念验证研究。受这一成功和我们丰富经验的激励，在控制理论中，我们已经开始了一项扩展研究，旨在模拟癌细胞系在受到不同剂量电离辐射时的行为。这项研究是与国家癌症研究所（NCI）的阿尔伯特·福纳斯实验室合作进行的，NCI是我们的主要数据来源。使用这些辐射研究的基因表达数据，我们打算建立PBN模型，我们希望这将使我们能够寻找方法，以增加细胞在缺乏称为p53的基因时在辐射时死亡的能力。这是一个合理的控制目标，也具有生物学意义，因为（i）细胞受到辐射会发生DNA损伤;（ii）如果允许DNA损伤的细胞生长，则可能发生癌症;以及（iii）基因p53的功能之一是确保细胞分裂的DNA复制阶段不会发生，除非亲本细胞的受损DNA得到修复。对来自辐射实验的基因表达数据的初步评估已经显示，具有功能性p53的细胞系与具有功能性p53的细胞系之间存在显著差异。因此，我们计划从事的这一行业似乎是一个非常有吸引力的行业。这一建议的提出有助于开创信号处理技术从工程文献到基因组学领域的应用，而另一个合作伙伴对控制领域有着长期的原始贡献。对拟议研究成功的乐观态度部分源于这样一个事实，即P.I.已经与两个合作伙伴进行了成功的合作。此外，让我们的分子生物学家Michael Bittner和Albert Fo nace充分参与到这项研究中，将大大有助于确保研究结果具有生物学意义。我们在癌症治疗方面取得的任何进展，即使是细胞系，使用细胞系的成功干预研究是导致动物研究的先驱，因此，我们B在这项研究中取得的任何重大进展都将不仅影响目前的癌症治疗，而且影响未来几年的癌症治疗，其好处将是挽救更多的生命。

The objectives of the esea ch outlined in this proposal a e two fold.First,we intend to explo e thepossibility of applying existing cont ol theo etic knowledge to advance the cause of cancer therapy;andsecond,we intend to develop fundamental esults in control theo y to address some of the unique p oblemsthat arise in cancer related esearch.The proposed esearch is motivated by the P.I.'s didactic and esearchexperiences du ing his two-year stint as a Bioinformatics T ainee supported by a National Cancer InstituteT aining Grant.In the course of this training,the P.I.has ealized that the disease Cancer is causedby a b eakdown in the control system that egulates the cell numbe s in a multicellula o ganismand p events undesirable g owths such as tumo s from developing.Furthermo e,the P.I.and the co-P.I.'s strongly believe that the time-tested cont ol techniques from the engineering literature could beha nessed,and further developed fo obtaining useful guidelines in cancer therapy.P omising p elimina y esults indicating a clea esea ch direction have already been obtained.Specif-ically,in collabo ation with ou molecula biologist colleague,Michael Bittner (fo merly with the Na-tional Human Genome Resea ch Institute (NHGRI),cur ently with the T anslational Genomics Institute(TGEN)),we developed a f amework for modeling genetic regulatory networks subject to external in-terventions and used it to apply optimal control st ategies to slow down the p ogression of metastaticmelanoma.The pa ticula modeling f amewo k used was the P obabilistic Boolean Netwo k (PBN)modelwith external controls,which we showed to be a special case of a Cont olled Markov Chain.This madeit possible to apply standa d optimal control techniques such as Dynamic P og amming and enabled usto carry out this proof of concept study.Motivated by this success and our extensive experience in Control Theory,we have embarked on anexpanded study aimed at modeling the behaviour of cancer cell lines when they are subjected to variousdoses of ionizing adiation.This study is being carried out in collaboration with Albert Fornace 's labo-ato y at the National Cancer Institute (NCI),which is our prima y data sou ce.Using gene exp essiondata from these adiation studies,we intend to build PBN models that we hope will enable us to look foways to increase the capacity of cells to die upon adiation when they are de .cient in a gene called p53.This is a easonable control objective that also makes biological sense since (i)cells subjected to radiationundergo DNA damage;(ii)if the cell with DNA damage is allowed to eplicate,cancer can esult;and(iii)one of the functions of the gene p53 is to ensure that the DNA eplication stage of cell division doesnot occu unless the damaged DNA of the parent cell is .rst epaired.Ou initial assessment of geneexpression data f om radiation experiments has evealed marked di .erences between the cell lines withfunctional p53 versus those with de .cient p53.Consequently,the line of esea ch that we a e planningto pursue appea s to be a very p omising one.One of the co-P.I.'s of this proposal was instrumental inpioneering the application of signal p ocessing techniques from the engineering literature to the .eld ofgenomics while the other co-P.I.has had a long histo y of o iginal contributions to the Controls .eld.Optimism about the success of the proposed research partially stems from the fact that the P.I.has hadsuccessful esea ch collabo ations with both the co-P.I.'s in the past.In addition,keeping our moleculabiologist collabo ato s Michael Bittner and Albert Fo nace fully involved in the esea ch will go a longway towards ensuring that the esults developed emain biologically meaningful.Any advance that we make in pursuing cancer therapy,even fo cell lines,is bound to have a profoundimpact on society.Successful intervention studies using cell lines are the precursors that lead to subsequentanimal studies and ultimately clinical trials,befo e the pa ticula cancer treatment is approved fo useon the general population.Thus,any signi .cant ground that we b eak in the cou se of this research willimpact cancer treatment not only fo the present time,but also fo years to come.The bene .t will be interms of human lives that are saved down the oad.2