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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 Shermaine Mitchell July 27 2011 PhD Candidate
Targeted therapy Standard Chemo-therapy Patient
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
How do cells receive instruction? Cell growth/division Cell growth arrest Cell death
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
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
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
Normal vs. Cancer cells Solid Tumors Normal Blood Blood Lumen Lumen vv RFC PCFT FRα
Antifolates • Aminopterin • MTX • Pemetrexed…