Control Issues in Cancer Therapy

Texas A&M Engineering Experiment Station, College Station TX

Investigators

Abstract

The objectives of the esea ch outlined in this proposal a e two fold.First,we intend to explo e the possibility of applying existing cont ol theo etic knowledge to advance the cause of cancer therapy;and second,we intend to develop fundamental esults in control theo y to address some of the unique p oblems that arise in cancer related esearch.The proposed esearch is motivated by the P.I.'s didactic and esearch experiences du ing his two-year stint as a Bioinformatics T ainee supported by a National Cancer Institute T aining Grant.In the course of this training,the P.I.has ealized that the disease Cancer is caused by a b eakdown in the control system that egulates the cell numbe s in a multicellula o ganism and 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 be ha 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 metastatic melanoma.The pa ticula modeling f amewo k used was the P obabilistic Boolean Netwo k (PBN)model with external controls,which we showed to be a special case of a Cont olled Markov Chain.This made it possible to apply standa d optimal control techniques such as Dynamic P og amming and enabled us to carry out this proof of concept study. Motivated by this success and our extensive experience in Control Theory,we have embarked on an expanded study aimed at modeling the behaviour of cancer cell lines when they are subjected to various doses 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 ession data from these adiation studies,we intend to build PBN models that we hope will enable us to look fo ways 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 radiation undergo 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 does not occu unless the damaged DNA of the parent cell is .rst epaired.Ou initial assessment of gene expression data f om radiation experiments has evealed marked di .erences between the cell lines with functional p53 versus those with de .cient p53.Consequently,the line of esea ch that we a e planning to pursue appea s to be a very p omising one.One of the co-P.I.'s of this proposal was instrumental in pioneering the application of signal p ocessing techniques from the engineering literature to the .eld of genomics 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 had successful esea ch collabo ations with both the co-P.I.'s in the past.In addition,keeping our molecula biologist collabo ato s Michael Bittner and Albert Fo nace fully involved in the esea ch will go a long way 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 profound impact on society.Successful intervention studies using cell lines are the precursors that lead to subsequent animal studies and ultimately clinical trials,befo e the pa ticula cancer treatment is approved fo use on the general population.Thus,any signi .cant ground that we b eak in the cou se of this research will impact cancer treatment not only fo the present time,but also fo years to come.The bene .t will be in terms of human lives that are saved down the oad. 2