Brian Covello: Radiotherapy Review


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Brian Covello writes a paper on radiotherapy and the DNA damage response associated with radiation.

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The DNA damage response in tumorigenesis and cancer treatment
Jiri Bartek and Jiri Lukas

The DNA damage response pathways can activate cell cycle checkpoints (which can involve p53) to arrest the cell either transiently or permanently (senescence) or they can activate specific DNA repair pathways in response to certain types of DNA damage. Some of the proteins in these pathways are mutated or non-functional in human tumours. This can cause cancer cells to be more reliant on an intact DNA repair pathway or survival, providing a therapeutic window. Inhibition of these intact pathways can selectively target tumour cells and the success of this strategy is illustrated by the progress of poly(ADP-ribose) polymerase (PARP) inhibitors in early phase clinical trials. This Poster highlights how the DNA damage response is thought to protect against tumour progression and the therapeutic rationale for specifically targeting members of the DNA damage response pathways. Some of the drugs that are under development or in clinical trials are also included.

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Brian Covello: Radiotherapy Review

  1. 1. Brian  Covello   Cell  Biology   Review:  “Relevance  and  irrelevance  of  DNA  damage  response  to  radiotherapy”       This  summer  I  will  be  working  under  Dr.  Stephen  Kron  at  the  University  of  Chicago.   As   an   MD/PhD   graduate,   Dr.   Kron   directs   his   research   towards   translation   of   scientific   discoveries   at   the   bench   to   improve   patient   outcomes,   and   his   review   article,   “Review:   Relevance  and  irrelevance  of  DNA  damage  response  to  radiotherapy,”  serves  to  highlight   the  translational  gap  that  currently  exists  between  doctors  and  scientists.  As  a  molecular   geneticist   and   biomolecular   engineer   he   seeks   to   understand   and   improve   targeted   ionizing   radiation   for   treating   human   malignancies.   As   a   doctor,   he   seeks   to   cure   his   patients  of  cancer.    Dr.  Kron  provides  a  brief  historical  background  of  ionizing  radiation,   followed   by   an   in   depth   review   of   the   specific   cellular   mechanisms   that   are   currently   molecular  targets  for  drug  therapies.  Since  the  time  of  this  review  in  2004,  Dr.  Kron  has   analyzed   histones,   chaperone   proteins,   cyclin,   various   tyrosine   kinase   receptors,   and   a   breadth  of  cell  cycle  checkpoints  in  various  model  organisms  in  an  attempt  to  comprehend   the  mechanisms  of  DNA  damage  and  repair.       For   the   past   century,   two   conventional   routes   have   existed   for   treating   cancer   –   radiotherapy  and  chemotherapy,  or  surgery.  With  the  discovery  of  ionizing  radiation  at  the   end   of   the   19th   century,   physicians   sought   to   selectively   target   tumors,   while   leaving   normal   tissue   unscathed.   Within   50   years,   scientists   had   discovered   that   the   target   of   radiation  damage  was  DNA,  yet,  this  scientific  discovery  had  little  effect  on  the  practice  of   physicians,   as   methods   for   assessing   success   of   radiotherapy   never   depended   upon   measurement  of  DNA  damage.       Within  the  realm  of  medicine,  efficient  radiotherapy  relies  heavily  on  the  damage  to   tumor  tissue  as  compared  to  that  of  normal  tissue.  This  ratio  is  called  the  tumor  control  
  2. 2. Brian  Covello   Cell  Biology   probability,   and   different   histological   environments   provide   tumors   with   different   probabilities  of  susceptibility  to  radiotherapy.  In  essence,  therapeutic  indices  are  different   for  different  types  of  cancer.  As  such,  doctors  aim  to  determine  potential  risks  and  benefits   of  radiotherapy  for  each  individual.  Doctors  may  prescribe  radiotherapy  as  a  palliative  or   curative  treatment.  To  this  extent,  doctors  may  adjust  the  radiation  intensity  or  temporal   treatment  schedule.  Without  scientific  input,  doctors  may  do  little  more  than  guesswork   based  off  of  past  and  present  experiences.  To  propel  the  field  of  medicine  and  science,  a   coalition  between  these  disparate  fields  is  a  necessity.       EJ  Hall  et  al.  found  that  the  average  radiotherapy  treatments  that  doctors  prescribe   cause  roughly  40  double  stranded  DNA  breaks  per  diploid  genome,  and  thousands  of  single   strand   breaks   and   base   lesions.   Several   experiments   on   animal   models   have   found   that   normal   tissues   are   better   equipped   to   tolerate   small   repeated   doses   of   radiation,   yet   controversy  surrounding  treatment  schemes  and  radiation  dosage  are  pervasive.  Further   research   in   animal   models   is   required   to   scientifically   assess   the   therapeutic   index   for   cancer.       Several   cellular   mechanisms   are   known   to   synergize   with   radiation,   including   oxidative  damage  and  DNA  interacting  drugs.  TG  Graeber  et  al.  found  that  tumor  hypoxia   led  to  aggressive  forms  of  tumors  that  consisted  of  p53  mutations.  Physicians  attempted  to   utilize  this  research  for  patient  treatments  by  utilizing  various  methods  to  increase  blood   oxygen   levels   including   red   blood   cell   transfusions,   erythropoietin   treatments,   and   hyperbaric  oxygen  inhalation.  Clinical  treatments  with  the  various  methods  yielded  mixed   results,  ultimately  suggesting  complex  mechanisms  of  actions  for  various  tumors.  Medicine   is  in  need  of  more  in  vitro  and  in  vivo  studies  regarding  oxygen  free  radical  damage.  JM  
  3. 3. Brian  Covello   Cell  Biology   Yuhas   et   al.   found   that   free   radical   scavengers   that   reduce   oxidative   damage   increase   radioresistance  in  myriad  tumors.  Due  to  this  discovery,  physicians  are  concerned  with  the   effects  of  thiol  drugs  in  patients  undergoing  radiotherapy.  Again,  no  further  research  has   been   conducted   to   assess   the   validity   of   this   concern.   From   a   scientific   perspective,   nucleoside  analogs  may  serve  as  another  method  to  radio-­‐sensitize  tumor  cells  to  IR,  yet   selective  targeting  to  tumor  cells  is  difficult.  Without  a  scientific  backing,  physicians  found   that   5-­‐flurouracil,   a   nucleoside   analog,   is   effective   in   reducing   rectal,   head,   neck,   esophageal,   and   anal   cancers.   The   efficiency   of   this   drug   has   never   been   tested   experimentally.     With   respect   to   ionizing   radiation,   science   is   primarily   concerned   with   cell   cycle   arrest,   induction   of   stress   responses,   DNA   repair,   and   apoptosis.   Within   these   various   aspects  of  cellular  biology  lies  numerous  potential  for  therapy.  One  approach  to  therapy  is   induction  of  sensitization  to  cancer  cells  through  inhibition  of  repair  mechanisms.  SJ  Collis   et   al.   found   that   siRNA   silencing   of   signaling   proteins   ATM   and   ATR   have   effectively   inhibited   IR-­‐induced   DNA   repair   mechanisms.   AJ   Belenkov   et   al.   sought   to   change   expression  of  Ku70,  Ku86,  and  DNA-­‐PKcs,  proteins  that  participate  in  non-­‐homologous  end   joining   (NHEJ),   a   repair   mechanisms   for   double   stranded   breaks.   Various   experiments   utilized   the   chemotherapeutical   agent   Wortmannin   to   inhibit   the   activation   of   those   proteins  studied  by  AJ  Belenkov.  Scientists  have  also  sensitized  cancer  cells  by  inhibited   RAD51  expression  and  targeting  histone  H2AX.  In  order  for  these  discoveries  to  translate   into   beneficial   molecular   therapies,   scientists   and   physicians   must   develop   methods   for   selective   delivery   to   tumors,   leaving   normal   cells   uninhibited   and   able   to   repair   DNA  
  4. 4. Brian  Covello   Cell  Biology   damage.  To  attain  this  goal,  one  must  exploit  the  cellular  differences  between  cancerous   cells  and  normal  cells.       Compared  to  normal  cells,  tumor  cells  contain  abnormal  G1  checkpoints.  As  such,   molecular   targeting   of   these   checkpoint   mechanisms   provides   hope   for   increased   selectivity   of   therapies.   AJ   Tenzer   et   al.   found   that   targeted   inhibition   of   G2   checkpoint   mechanisms   through   the   drug   pentoxifylline   improved   tumor   response   rates.   This   treatment  allows  cancerous  cells  to  progress  towards  mitosis  at  a  faster  rate,  while  normal   cells   are   protected   due   to   normal   G1   checkpoints.   With   induction   of   mitosis,   the   cancer   cells  invariably  become  disrupted  by  DNA  damage  by  IR.  Physicians  are  currently  running   clinical  trials  to  test  efficacy  of  the  Chk1  inhibitor  UCN-­‐01.       The   consequence   of   IR   induced   DNA   damage   is   cellular   death.   Due   to   this   correlation,   apoptosis   has   been   investigated   extensively.   For   many   years,   scientists   and   doctors   alike   accepted   that   a   positive   correlation   existed   between   apoptosis   and   cancer   without   much   scientific   research.   Common   sense   may   indicate   that   expression   of   anti-­‐ apoptotic  genes  such  as  MDR1  would  serve  to  make  cells  more  resistance  to  IR,  serving  as  a   medicinal  means  to  strengthen  normal  cells  surrounding  cancer.  Yet  research  conducted  by   Ruth  and  Roninson  challenged  this  viewpoint,  and  they  found  that  although  expression  of   anti-­‐apoptotic   genes   resulted   in   reduced   apoptosis,   the   concomitant   increase   in   cells   undergoing   mitosis   followed   by   cellular   death   through   DNA   damage   by   IR   invalidated   expression  of  anti-­‐apoptotic  genes  as  a  valid  protection  against  IR.  Similarly,  BG  Wouters  et   al.   sought   to   increase   apoptotic   genes   in   cancer   cells   and   found   that   cells   became   more   resistant   to   IR   than   normal   cells.   More   research   is   needed   to   discover   the   underlying   mechanisms  of  these  experiments.    
  5. 5. Brian  Covello   Cell  Biology   The  plasma  membrane  plays  a  critical  role  in  cellular  apoptosis.  The  accumulation  of   phosphatidylserine   on   the   outer   surface   of   the   plasma   membrane   marks   the   cell   for   phagocytosis  by  macrophages.  These  corresponding  signaling  pathway  are  also  a  molecular   therapy   target.   SM   Huang   et   al.   inhibited   the   epidermal   growth   factor   receptor   (EGFR),   whose  induction  by  IR  causes  the  cell  to  resist  apoptosis.  These  molecular  therapies  tend  to   be   cell-­‐type   dependent,   as   such,   the   tumor   microenvironment   must   be   considered.   The   microenvironments   greatly   complicate   the   design   of   therapeutics,   and   this   complexity   necessitates  personalized  medicine.       Tumors  are  also  markedly  distinct  from  normal  cells  due  to  enhanced  angiogenesis   and  microvasculature  formation  required  for  support  of  a  bulk  mass  of  cells.  O’Reilly  and   Folkman   sought   to   inhibit   angiogenesis   through   angiostatin   treatment,   and   the   research   group   found   increased   therapeutic   index   for   the   combined   treatment.   Specifically,   Dr.   Kron’s  laboratory  engineered  a  viral  vector  carrying  the  tumor  necrosis  factor  alpha.  This   vector   had   a   promoter   that   is   only   induced   upon   exposure   to   ionizing   radiation.   Thus,   injection  of  this  vector  into  the  tumor  site  allowed  release  of  an  apoptotic  that  controlled   through  exposure  to  radiation.  Clinical  trials  are  currently  taking  place  and  have  thus  far   proven  to  be  a  highly  effective  therapy.     The  gap  between  scientific  discoveries  and  medicinal  therapies  must  be  filled  for   cancer  therapeutics  to  progress.  As  a  researcher,  I  look  forward  to  working  with  Dr.  Kron   to   design   a   project   that   aims   to   control   inducible   and   selective   genetic   therapies   that   enhance  normal  cellular  response  to  ionizing  radiation  and  decrease  tumor  resistance  to   radiation.  It  is  research  such  as  this  that  truly  motivates  and  inspires  me,  for  I  believe  the   summit  of  intellect  is  the  application  of  knowledge  to  improve  the  wellbeing  of  our  society.