Part  2:  Cancer  Therapies,    Present  and  Future  

Adrianna  San  Roman  Leah  Liu  

Clare  Malone  

Objec?ves  

• Most  cancer  therapies  aBack  general  features  common  to  all  cancers  

•  New  cancer  therapies  aBack  specific  features  or  muta?ons  found  in  individual  cancers    

Unlimited  and  Uncontrolled  Replica?on  

Normal  Cell  

Cancer  Cell  

Tumor  

General  vs.  Specific  Features  of  Cancer  Cells  

Uncontrolled  cell  division  and  DNA  replica?on  

Specific  DNA  muta?on  

DNA  replica?on  occurs  during  each    cell  division  

DNA  replica?on  occurs  during  each    cell  division  

Ac?vely  dividing  cell  

DNA  

Cell  division  

Chemotherapy:  chemicals  that  kill  fast-­‐dividing  cells  

Chemotherapy  agents  cover  DNA  

Cell  division  is  blocked  

cell  death  and  tumor  shrinkage  

Most  cells  in  the  body  do  not  divide  frequently  

Therapeu?c  Window:  • Medicine  dosages  that  are  both  safe  and  effec?ve  

Increasing  Dose  

Benefit  

Smaller  Therapeu?c  Window:  effec?ve  dose  is  close  to  toxic  dose  

Increasing  Dose  

Benefit  

Nausea  

Drowsiness  

Blood  clots  

Chemotherapy  causes  side  effects  

Inflamma?on  of  the  diges?ve  tract,  nausea,  diarrhea  

hBp://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm  

Hair  loss  

Fewer  blood  cells,  suppressed  immune  system  (bone  marrow)  

Chemotherapy  has  a  small  therapeu?c  window  

Why  are  the  bone  marrow,  hair,  and  diges?ve  tract  affected?  

•  Chemotherapy  aBacks  ANY  fast-­‐dividing  cells  

Blood  cells  in  bone  marrow   Hair  follicle   Intes?nal  cells  

How  effec?ve  is  chemotherapy?  

• What  would  be  the  5  year  survival  rate  without  chemotherapy?  

A.  2%  B.  33%  C.  61%  

Morgan,  G.,  et  al.  Clinical  Oncology  (2004)  16:  549-­‐560  

63%  -­‐  61%  =  2%  of  survival  rate  can  be  aBributed  to  chemotherapy  

The  5  year  survival  rate  for  all  cancers  is  63%  

Each  type  of  cancer  responds  differently  to  chemotherapy  

Adapted  from  Morgan,  G.,  et  al.  Clinical  Oncology  (2004)  16:  549-­‐560  

0%  

5%  

10%  

15%  

20%  

25%  

30%  

35%  

40%  

45%  

Increase  in    5-­‐yr  survivors  a;

er  che

mo    

Radia?on  therapy  damages  DNA  

hBp://www.cancer.gov/cancertopics/factsheet/Therapy/radia?on  

Radia?on  is  targeted  to  a  specific  body  part  

Cell  death,  tumor  shrinkage  

Cancer  cells  are  bad  at  repairing  DNA  

Normal  cells  can  also  be  affected  

DNA  Damage  

Radia?on  Therapy  causes  side  effects  

hBp://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm  

Radia?on  therapy  has  a  small  therapeu?c  window  

Skin  irrita?on,  scar  ?ssue  

Fa?gue,  memory  loss  

Very  rare  secondary  tumors  

Chronic  bowel  effects  

hBp://www.gpnotebook.co.uk/simplepage.cfm?ID=2060451853  

Different  cancers  respond  very  differently  to  radia?on  therapy  

Responsive  Cancers   Resistant  Cancers  

Lymphoma   Melanoma  

Medulloblastoma   Glioma  

Neuroblastoma   Large  bowel  cancer  

Summary:  Current  Cancer  Therapies  

•  Chemotherapy  aBacks  cells  that  divide  rapidly  

•  Radia?on  therapy  damages  DNA  in  cancer  cells    

•  Both  chemotherapy  and  radia?on  therapy  have  small  therapeu?c  windows  

General  vs.  Specific  Features  of  Cancer  Cells  

Uncontrolled  cell  division  and  DNA  replica?on   Specific  DNA  muta?on  

There  are  many  diverse  types  of  cancer  

Muta?on  A  Signaling  Pathway  A  

Muta?on  B  Signaling  Pathway  B  

Muta?on  C  Signaling  Pathway  C  

Targeted  therapies  aBack  specific  mutated  proteins  

Normal  protein   Oncogenic  protein  

Targeted  Therapy  

Targeted  therapies  aBack  specific  mutated  proteins  

Normal  protein  

Targeted  Therapy  

Oncogenic  protein  blocked  

Targeted  therapies  only  work  for  pa?ents  with  the  correct  muta?on

Targeted  Therapy  A   Targeted  Therapy  B   Targeted  Therapy  C  

Targeted  Therapies  have  fewer  side  effects  

Targeted  therapies  have  a  wider  therapeu?c    window  

Joint  pain,  fa?gue,  skin  lesions  

nausea,  muscle  pain,  diarrhea  

hBp://www.nejm.org/doi/pdf/10.1056/NEJMoa1002011  hBp://www.nejm.org/doi/pdf/10.1056/NEJM200104053441401    

•  In  95%  of  CML  cases,  the  oncogene  is  BCR-­‐ABL,  which  increase  cell  division  

hBp://www.cancer.gov/cancertopics/factsheet/Therapy/targeted  

Uncontrolled  cell  division  

Chronic  myelogenous  leukemia  (CML)  is  a  cancer  of  white  blood  cells  

Oncogenic  BCR-­‐ABL  Turns  on  cell  division  proteins  in  signaling  pathway  

Gleevec/Ima?nib  blocks  the  responsible  oncogene  

Druker,  et  al.  NEJM  (2006)  355:2408-­‐2417,  hBp://www.cancer.gov/cancertopics/factsheet/Therapy/targeted  

Oncogenic  BCR-­‐ABL   Signaling  pathways  blocked  

• CML  has  89%  5-­‐year  survival  rate  compared  to  23%  in  1975  

• Gleevec  can  be  used  for  other  cancers  that  have  BCR-­‐ABL    

Uncontrolled  cell  division  is  stabilized  

Gleevec/ima?nib  

B-­‐raf  oncogene  in  melanoma  

•  Melanoma  is  resistant  to  chemotherapy  and  radia?on  

•  40-­‐60%  of  melanomas  have  a  oncogene  called  B-­‐raf  

B-­‐raf  

Abnormal  cell  

growth  and  

division  

Ras  

Growth  signal  

Mek  

Cancer  Cell  

B-­‐raf  oncogene  in  melanoma  

hBp://www.nlm.nih.gov/medlineplus/news/fullstory_109152.html,  hBp://www.nejm.org/doi/full/10.1056/NEJMoa1002011  

Over-­‐ac?vate  signaling  pathways  for  cell  division  

B-­‐raf  

Tumor  forma?on  

PLX4032  inhibits  oncogenic  B-­‐raf  

B-­‐raf  

PLX4032  

Oncogenic  B-­‐Raf  Prevent  overac?ve  cell  division  

Tumors  shrink  

PLX4032  effec?veness  during  clinical  trials  

Bollag,  et  al.  Nature  (2010)  467:  596-­‐599.    

Before   Aner  

PLX4032  clinical  trial  

•  How  effec?ve  is  PLX4032  long-­‐term?  Chapman,  et  al.  NEJM  2011  

Half  of  pa?ents  given  PLX4032  

Half  of  pa?ents  given  chemotherapy  

6  months  

63%  less  risk  of  death    

Chemotherapy  group  given  opportunity  to  try  PLX4032  

Summary:  Cancer  Therapies  

•  Chemotherapy  and  radia?on  therapy  aBack  general  features  of  cancer  cells  

•  Targeted  therapies  aBack  specific  features  (muta?ons)  of  cancer  cells  

•  Understanding  the  gene?cs  of  cancer  is  important  for  developing  therapies