<ul><li>Zuleika M. Corales </li></ul><ul><li>Undergraduate Student </li></ul><ul><li>University of Puerto Rico </li></ul><...
Outline
Introduction <ul><li>Ovarian Cancer   </li></ul><ul><ul><ul><li>Eighth most common cancer among  </li></ul></ul></ul><ul><...
Focal Adhesion Kinase <ul><li>FAK </li></ul><ul><ul><li>Non-receptor tyrosine kinase that plays an  </li></ul></ul><ul><ul...
<ul><li>FAK as a signal integrator </li></ul>Focal Adhesion Kinase
Ovarian Cancer Therapy <ul><ul><li>FAK inhibitors  </li></ul></ul><ul><ul><ul><li>Interact with FAK in the ATP-binding dom...
New FAK Inhibitors <ul><ul><li>Inhibitor 1:  JAK2-10 </li></ul></ul><ul><ul><li>Structure </li></ul></ul>JAK2-10 FAK ATP B...
Hypothesis   JAK2-10 , inhibitor of JAK, also inhibits FAK activity.
Aim  To determine whether  JAK2-10  inhibits FAK activation in SKOV3 ovarian cancer cells .
Methods <ul><li>Time- response experiment </li></ul><ul><li>Cell treatment  (5 μM of  JAK2-10,  SKOV3 ) </li></ul>NT Treat...
<ul><ul><ul><ul><li>Western Blot </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Antibodies </li></ul></ul></ul></ul>Methods ...
-  +  -  +  -  + 24-hr 48-hr 72-hr Tota l FAK β-Actin Results (-)     untreated (+)     treated   2.5X10 4 cells/mL <ul>...
Methods B  NT  5  10 μM  JAK2-10 <ul><li>Growth Inhibition Assay </li></ul>After 72-hr
Results <ul><li>J AK2-10  does not inhibits cell growth. </li></ul>Dose (μM) % Growth
Conclusions & Ongoing Work <ul><li>JAK2-10  effectively inhibited FAK activation after  </li></ul><ul><li>72-hr SKOV3 trea...
New FAK Inhibitors TAE226 ME-TAE226
Synthesis <ul><li>Steps for the synthesis of   ME-TAE226 </li></ul>
Future Directions <ul><li>To determine whether  ME-TAE226  inhibits FAK  </li></ul><ul><li>activation without affecting th...
Acknowledgements <ul><ul><li>MARC  (  Minority Accesses to Research Careers )Program </li></ul></ul><ul><ul><li>U54MDCC/PR...
References <ul><ul><li>Chatzizacharias N.K, kouraklis G.P, Theocharis S.T. Focal  </li></ul></ul><ul><ul><li>adhesion kina...
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Novel Tyrosine Kinase Inhibitors for Ovarian Cancer

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Transcript of "Novel Tyrosine Kinase Inhibitors for Ovarian Cancer"

  1. 1. <ul><li>Zuleika M. Corales </li></ul><ul><li>Undergraduate Student </li></ul><ul><li>University of Puerto Rico </li></ul><ul><li>Mayagüez Campus </li></ul><ul><li>Summer 2008 </li></ul>Novel Tyrosine Kinase Inhibitors for Ovarian Cancer Experimental Therapeutics Department Dr. Gabriel Lopez-Berestein, MD
  2. 2. Outline
  3. 3. Introduction <ul><li>Ovarian Cancer </li></ul><ul><ul><ul><li>Eighth most common cancer among </li></ul></ul></ul><ul><ul><ul><li>women. </li></ul></ul></ul><ul><li>Estimated cases from ovarian cancer in the </li></ul><ul><li>United States in 2008 : </li></ul>
  4. 4. Focal Adhesion Kinase <ul><li>FAK </li></ul><ul><ul><li>Non-receptor tyrosine kinase that plays an </li></ul></ul><ul><ul><li>important role in signal transduction pathways. </li></ul></ul><ul><li>FAK is an important regulator and mediator </li></ul><ul><li>of : </li></ul>
  5. 5. <ul><li>FAK as a signal integrator </li></ul>Focal Adhesion Kinase
  6. 6. Ovarian Cancer Therapy <ul><ul><li>FAK inhibitors </li></ul></ul><ul><ul><ul><li>Interact with FAK in the ATP-binding domain. </li></ul></ul></ul><ul><ul><ul><li>Prevent FAK autophosphorylation. </li></ul></ul></ul><ul><ul><li>What is the problem with these inhibitors? </li></ul></ul><ul><ul><ul><li>Not specific. </li></ul></ul></ul><ul><ul><ul><li>Inhibit the insulin receptor. </li></ul></ul></ul><ul><ul><li>Goal </li></ul></ul><ul><ul><ul><li>To create more specific FAK inhibitors. </li></ul></ul></ul>
  7. 7. New FAK Inhibitors <ul><ul><li>Inhibitor 1: JAK2-10 </li></ul></ul><ul><ul><li>Structure </li></ul></ul>JAK2-10 FAK ATP Binding Pocket
  8. 8. Hypothesis JAK2-10 , inhibitor of JAK, also inhibits FAK activity.
  9. 9. Aim To determine whether JAK2-10 inhibits FAK activation in SKOV3 ovarian cancer cells .
  10. 10. Methods <ul><li>Time- response experiment </li></ul><ul><li>Cell treatment (5 μM of JAK2-10, SKOV3 ) </li></ul>NT Treated 72 -hr <ul><li>Protein Extraction </li></ul>24- hr 48 -hr 24-hr 48-hr 72-hr
  11. 11. <ul><ul><ul><ul><li>Western Blot </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Antibodies </li></ul></ul></ul></ul>Methods <ul><li>pFAK & Total FAK antibodies </li></ul><ul><ul><li>1:2,000 primary antibody </li></ul></ul><ul><ul><li>1:2,000 secondary antibody </li></ul></ul><ul><li>β- Actin </li></ul><ul><ul><li>1:10,000 primary antibody </li></ul></ul><ul><ul><li>1:10,000 secondary antibody </li></ul></ul>From Molecular Cell Biology by Harvey Lodish et al. Credit: NIAID
  12. 12. - + - + - + 24-hr 48-hr 72-hr Tota l FAK β-Actin Results (-)  untreated (+)  treated 2.5X10 4 cells/mL <ul><li>JAK2-10 inhibits FAK phosphorylation. </li></ul>- + - + - + 24-hr 48-hr 72-hr pFAK β-Actin 5μM JAK2-10 5μM JAK2-10 SKOV3 Cells
  13. 13. Methods B NT 5 10 μM JAK2-10 <ul><li>Growth Inhibition Assay </li></ul>After 72-hr
  14. 14. Results <ul><li>J AK2-10 does not inhibits cell growth. </li></ul>Dose (μM) % Growth
  15. 15. Conclusions & Ongoing Work <ul><li>JAK2-10 effectively inhibited FAK activation after </li></ul><ul><li>72-hr SKOV3 treatment. </li></ul><ul><li>Since JAK2-10 did not have any effect on cell </li></ul><ul><li>proliferation, we plan to test the effect of this </li></ul><ul><li>inhibitor on cell migration and invasion. </li></ul>
  16. 16. New FAK Inhibitors TAE226 ME-TAE226
  17. 17. Synthesis <ul><li>Steps for the synthesis of ME-TAE226 </li></ul>
  18. 18. Future Directions <ul><li>To determine whether ME-TAE226 inhibits FAK </li></ul><ul><li>activation without affecting the insulin receptor. </li></ul>
  19. 19. Acknowledgements <ul><ul><li>MARC ( Minority Accesses to Research Careers )Program </li></ul></ul><ul><ul><li>U54MDCC/PRCC Partnership for Excellence in Cancer Research </li></ul></ul><ul><ul><li>Dr. Rene Nieves, Dr. Ilka Rios </li></ul></ul>
  20. 20. References <ul><ul><li>Chatzizacharias N.K, kouraklis G.P, Theocharis S.T. Focal </li></ul></ul><ul><ul><li>adhesion kinase: a promising target for anticancer therapy. </li></ul></ul><ul><ul><li>Expert Opin. Ther. Targets (2007) 11(10):1315-1328. </li></ul></ul><ul><ul><li>Gabarra-Niecko V, Schaller M.D, Dunty J.M. FAK regulates </li></ul></ul><ul><ul><li>biological processes important for the pathogenesis of cancer. </li></ul></ul><ul><ul><li>Cancer and Metastasis . 22: 359-374. </li></ul></ul><ul><ul><li>Gordon W. MacLean., et al. The role of focal- adhesion kinase in </li></ul></ul><ul><ul><li>cancer: A new therapeutic opportunity. Nature 2005;5:505-15. </li></ul></ul><ul><ul><li>Halder J, Lin Y.G., et al. Therapeutic Efficacy of a Novel Focal Adhesion </li></ul></ul><ul><ul><li>Kinase </li></ul></ul><ul><ul><li>Inhibitor TAE226 in Ovarian Carcinoma. Cancer Res 2007;67:(22). </li></ul></ul><ul><ul><li>Maroesja J. van Nimwegen, Bob van de Water. Focal adhesion </li></ul></ul><ul><ul><li>kinase: A potential target in cancer therapy. Biochemical </li></ul></ul><ul><ul><li>Pharmacology 2007; 73:597-609. </li></ul></ul>
  21. 21. Thanks!!!

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