1. Aberrations in Cancer Cells and Targeted Therapies Shermaine Mitchell July 27 2011 PhD Candidate

2. Targeted therapy Standard Chemo- therapy Patient

3. Normal cells vs. Cancer cells

4. Cancer…what is it? Uncontrolled growth of abnormal cells in the body Benign and or pre-malignant tumors ARE NOT CANCER A disease of the genome: Cancer is a genetic disease 1. Gain of function mutation 2. Loss of function mutations 3. Gene amplification 4. Overexpression

5. How do cells receive instruction? Cell growth/divisionCell growth arrestCell death

6. Intracellular signaling

8. Targeted Therapy

10. Growth factor signaling

11. Overexpression of receptor

12. Herceptin

13. Mutations in Effector Molecules

14. Lipidmodification for function

16. Loss of function mutation: evading apoptosis

18. Onyx -015

19. Old Dog with New Tricks

20. Ovarian Cancer Most lethal gynecological cancer 65% of patients are diagnosed with stage III or stage IV disease Recurring and resistant to treatment 21,880 new cases 13,850 deaths 85-90% of ovarian cancers overexpress FRα 20 Courtesy of Christina Cherian Ovarian Cancer

21. Mechanisms of Intracellular Folate Transport 21 Predominant transporter of (anti)folates Zhao R, Matherly LH, Goldman ID: Expert Rev. Mol. Med., 2009 PCFT=Proton-coupled folate transporter RFC=Reduced folate carrier

22. Folates Essential water soluble B vitamin Amino acid synthesis Essential for DNA synthesis a. Thymidylate (dTMP):TS b. Purine nucleotides : GARFT + AICARFT Antifolates Structural analogs of folic acid Disrupt DNA synthesis Recognized by cellular machinery used by folates a. receptors b. intracellular targets Inhibition of folate dependent enzymes Nucleotide depletion 22 GARFT=Glycinamine Ribonucleotide formyl transferase AICARFT= 5-Aminoimidozole 4-carboxamide ribonucleotide formyl transferase TS= Thymidylate Synthase

23. Normal vs. Cancer cells 23

24. Antifolates Aminopterin MTX Pemetrexed…

25. Questions????