Post on 24-Feb-2016
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Aberrations in Cancer Cells and Targeted TherapiesShermaine MitchellJuly 27 2011PhD 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 mutation2. Loss of function mutations3. Gene amplification4. 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
Nor
mal
Stag
e I
Stag
e II
Stag
e III
Stag
e IV
0.00001
0.0001
0.001
0.01
0.1
1
Rel
ativ
e FR
alp
ha T
rans
crip
ts
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
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
22
GARFT=Glycinamine Ribonucleotide formyl transferaseAICARFT= 5-Aminoimidozole 4-carboxamide ribonucleotide formyl transferaseTS= Thymidylate Synthase
Normal vs. Cancer cellsBlood Lumen
BloodLumen Normal Solid Tumors
RFC
vv
PCFT FRα23
Antifolates
Aminopterin MTX Pemetrexed…
Questions????