Cancer and Oncogenes Bioscience in the 21st

Century Linda  Lowe-­‐Krentz  September  24,  2014  

Ø People  

Ø Becoming  Cancer  

Ø Gene?c  Defects  

Ø Drugs  

Our  friends  and  family  

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Incidence  of  cancer  

Other  similar  data  

Weinberg, the Biology of Cancer

mice

Muta?ons  collected    

Ø Original  hypothesis  –  2  muta?ons,  one  in  signaling  and  one  in  the  nucleus.  

Ø Sta?s?cal  analysis  says  more  like  5  or  6  muta?ons  are  probably  important  for  most  cancer  in  humans.  

Ø Typically  at  least  one  muta?on  is  in  a  cell  growth  pathway.  

More  numbers    

Ø The  5  year  survival  rate  is  now  about  66%  for  all  cancer.  

Ø Overall  death  rates  from  cancer  are  con?nuing  to  decline  at  somewhere  between  1%  and  2%  per  year.  

Ø The  most  progress  has  been  made  in  the  most  common  forms  of  cancer.  

Ø But,  overall  deaths  from  cancer  will  likely  not  con?nue  to  drop  –  why?  

Abili?es  acquired  Ø Grow  rapidly  Ø Dissociate  from  neighboring  cells  Ø Invade  adjacent  ?ssue  Ø Recruit  vasculature  and  invade  blood  vessels  or  lympha?c  system  

Ø Escape  immune  system  Ø Arrest  in  a  new  loca?on  Ø Get  into  target  ?ssue  Ø Proliferate  in  new  loca?on  

Normal Dysplasia

Pre-malignant,

appear abnormal

Carcinoma

Increased cell proliferation

Additional possible changes here include decreased ability to catch mistakes

Malignant

Epithelial to mesenchymal transition.

Cells are able to change characteristics and gain the ability to migrate across barriers or through membranes.

Vascular  differences  

Cancer  Evolu?on  http://scienceblog.cancerresearchuk.org/2012/08/03/the-queen-in-the-hive-scientists-find-more-evidence-for-cancer-stem-cells/

Not  like  classic  evolu?on  

Intes&nal  cells  

From  stem  cell  to  death  in  a  very  short  ?me  span.      

One  example  pathway  

Normal Epithelium Hyperplastic epithelium APC  Less  Me  of  DNA  

Early Adenoma KRas Intermediate Adenoma Smad4  

Late Adenoma p53   Carcinoma Invasion  and  Metastasis  

Oxida?ve  damage  outcomes  

But  repair  enzymes  fix  most  problems  

Ø If  you  cannot  fix  the  all  of  the  DNA  damage,  mistakes  accumulate  more  rapidly  and  cancer  usually  starts  earlier.  

Ø An  example  when  repair  is  not  complete  is  individuals  with  Li-­‐Fraumeni  syndrome  whose  cells  do  not  recognize  damage  (faulty  p53).  

Ø Another  example  is  Xeroderma  Pigmentosum,  where  pa?ents  cannot  repair  UV  damage  and  get  skin  cancer  more  rapidly  than  most  people  –  with  much  less  exposure  

Growth  factors  and  the  cell  cycle  

Together these pathways control a complicated set of events that result in a balance of proteins and other factors leading to cell growth and division.

Mitogens (Accelerators)

SCF  is  over  produced  

In many Small Cell Lung Carcinoma patients, lots of SCF (stem cell factor) is produced and the cells also contain the growth factor receptor for this molecule. Therefore, continuous growth signaling occurs.

Ras  signaling  and  cancer  

Many mistakes in this pathway have been identified.

Akt  

(Adds phosphate)

(Removes phosphate)

Types  of  genes  that  get  mutated  Ø Oncogenes  –  gain  of  func?on  (accelerators)  

Ø Hybrid  proteins  that  change  func?on  Ø Over-­‐produc?on  of  a  protein  Ø Ac?vity  increases  Ø CANCER  ONLY  NEEDS  ONE  BAD  COPY  

Ø Suppressor  –  loss  of  func?on  (brakes)  Ø They  can’t  stop  growth  Ø USUALLY  YOU  LOSE  BOTH  GENES  if  there  is  a  defect  leading  to  cancer  

Massive  changes  in  the  nucleus  

Translocations, duplications, deletions

Early  Chemotherapy  

•  Targets  –  rapidly  growing  cells.  

Drug  An?bodies  •  An?bodies  against  growth  factor  receptors  or  mutated  overac?ve  forms  of  the  receptors.  

R

ü Antibodies might recruit the immune system ü Antibodies might block ligand binding to remaining receptors ü Antibodies might block receptor function

Small  molecule  drugs  

•  Small  molecule  inhibitors.  

•  Some  of  these  small  molecule  drugs  are  ini?ally  effec?ve,  but  cancer  cells  can  some?mes  acquire  muta?ons  that  make  them  less  effec?ve  over  ?me.    Some  cancer  cells  make  pumps  to  dump  the  drugs  back  out.  

Long  term  goals  

•  Ul?mately,  targe?ng  the  stem  cells  that  are  cancerous  rather  than  only  the  most  rapidly  growing  cells  will  be  important.  

•  Development  of  specific  drugs  based  on  specific  cancer  situa?ons  is  also  con?nuing  (personalized  medicine).  

•  hgp://www.cancer.gov/  

What  we  discussed.  

Ø It  takes  mul?ple  muta?ons  to  get  cancer.  Ø The  collec?on  of  muta?ons  is  more  rapid  and  complex  than  in  typical  evolu?on.  

Ø Muta?ons  in  oncogenes  and  suppressors  both  play  roles.  

Ø Cancer  cell  development  progresses  over  ?me,  and  cancer  stem  cells  may  remain.  

Ø Treatments  are  becoming  more  specialized.