Aberrations in Cancer Cells and Targeted Therapies
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Aberrations in Cancer Cells and Targeted TherapiesShermaine MitchellJuly 27 2011PhD Candidate
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Targeted therapy
Standard Chemo-therapy
Patient
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Normal cells vs. Cancer cells
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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 disease1. Gain of function mutation2. Loss of function mutations3. Gene amplification4. Overexpression
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How do cells receive instruction?
Cell growth/division Cell growth arrest Cell death
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Intracellular signaling
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Targeted Therapy
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Growth factor signaling
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Overexpression of receptor
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Herceptin
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Mutations in Effector Molecules
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Lipidmodification for function
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Loss of function mutation: evading apoptosis
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Onyx -015
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Old Dog with New Tricks
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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 FRα20
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Courtesy of Christina Cherian
Ovarian Cancer
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Mechanisms of Intracellular Folate Transport
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• Predominant transporter of (anti)folates
Zhao R, Matherly LH, Goldman ID: Expert Rev. Mol. Med., 2009
PCFT=Proton-coupled folate transporterRFC=Reduced folate carrier
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Folates Essential water soluble B
vitamin Amino acid synthesis Essential for DNA
synthesisa. Thymidylate (dTMP):TSb. 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
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GARFT=Glycinamine Ribonucleotide formyl transferaseAICARFT= 5-Aminoimidozole 4-carboxamide ribonucleotide formyl transferaseTS= Thymidylate Synthase
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Normal vs. Cancer cellsBlood Lumen
BloodLumen Normal Solid Tumors
RFC
vv
PCFT FRα23
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Antifolates
Aminopterin MTX Pemetrexed…
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Questions????