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Aberrations in Cancer Cells and Targeted Therapies

Aberrations in Cancer Cells and Targeted Therapies. Shermaine Mitchell July 27 2011 PhD Candidate. Targeted therapy. Standard Chemo-therapy. Patient. Normal cells vs. Cancer cells. Cancer…what is it?. Uncontrolled growth of abnormal cells in the body Benign and or pre-malignant tumors

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Aberrations in Cancer Cells and Targeted Therapies

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  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 • Gain of function mutation • Loss of function mutations • Gene amplification • Overexpression

  5. How do cells receive instruction? Cell growth/division Cell growth arrest Cell death

  6. Intracellular signaling

  7. Targeted Therapy

  8. Growth factor signaling

  9. Overexpression of receptor

  10. Herceptin

  11. Mutations in Effector Molecules

  12. Lipidmodification for function

  13. Loss of function mutation: evading apoptosis

  14. Onyx -015

  15. Old Dog with New Tricks

  16. 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 Ovarian Cancer Courtesy of Christina Cherian

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

  18. Folates 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 • Essential water soluble B vitamin • Amino acid synthesis • Essential for DNA synthesis a. Thymidylate (dTMP):TS b. Purine nucleotides : GARFT + AICARFT GARFT=Glycinamine Ribonucleotide formyl transferase AICARFT= 5-Aminoimidozole 4-carboxamide ribonucleotide formyl transferase TS= Thymidylate Synthase

  19. Normal vs. Cancer cells Solid Tumors Normal Blood Blood Lumen Lumen vv RFC PCFT FRα

  20. Antifolates • Aminopterin • MTX • Pemetrexed…

  21. Questions????

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