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Download Abberations in Cancer Cells and Targeted therapies
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Aberrations in Cancer Cells and Targeted Therapies Shermaine Mitchell July 27 2011 PhD Candidate Targeted therapy Standard Chemotherapy Patient Normal cells vs. Cancer cells 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. 2. 3. 4. Gain of function mutation Loss of function mutations Gene amplification Overexpression How do cells receive instruction? Cell growth/division Cell growth arrest Cell death Intracellular signaling Targeted Therapy Growth factor signaling Overexpression of receptor Herceptin Mutations in Effector Molecules Lipidmodification for function Loss of function mutation: evading apoptosis Onyx -015 Old Dog with New Tricks Ovarian Cancer 1 0.1 0.01 0.001 0.0001 Courtesy of Christina Cherian 20 Stage IV Stage III Stage II Stage I 0.00001 Normal Relative FR alpha Transcripts 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 Mechanisms of Intracellular Folate Transport •Predominant transporter of (anti)folates PCFT=Proton-coupled folate transporter RFC=Reduced folate 21 carrier Zhao R, Matherly LH, Goldman ID: Expert Rev. Mol. Med., 2009 Folates 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 22 Synthase 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 Normal vs. Cancer cells Normal Lumen Solid Tumors Blood Lumen v v 23 RFC PCFT FRα Blood Antifolates Aminopterin MTX Pemetrexed… Questions????
