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

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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

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Courtesy of Christina Cherian

Ovarian Cancer

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

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

Normal vs. Cancer cellsBlood Lumen

BloodLumen Normal Solid Tumors

RFC

vv

PCFT FRα23

Antifolates

Aminopterin MTX Pemetrexed…

Questions????