aberrations in cancer cells and targeted therapies shermaine mitchell july 27 2011 phd candidate
TRANSCRIPT
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
ARE NOT CANCER A disease of the genome: Cancer is a
genetic disease1. Gain of function mutation
2. Loss of function mutations
3. Gene amplification
4. 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
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
No
rmal
Sta
ge
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Sta
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II
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Sta
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0.00001
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pts
Courtesy of Christina Cherian
Ovarian Cancer
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 transporterRFC=Reduced folate carrier
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
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GARFT=Glycinamine Ribonucleotide formyl transferaseAICARFT= 5-Aminoimidozole 4-carboxamide ribonucleotide formyl transferaseTS= Thymidylate Synthase
Normal vs. Cancer cells
Blood LumenBloodLumen
Normal Solid Tumors
RFC
vv
PCFT FRα23
Antifolates
Aminopterin MTX Pemetrexed…
Questions????