Transcript Abberations in Cancer Cells and Targeted therapies

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?
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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
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1
0.1
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0.01
0.001
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0.0001
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Courtesy
of Christina Cherian
20
Stage IV
Stage III
Stage II
Stage I
0.00001
Normal
Relative FR alpha Transcripts
Ovarian Cancer
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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
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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
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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…
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Questions????