aberrations in cancer cells and targeted therapies shermaine mitchell july 27 2011 phd candidate

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

I

Sta

ge

II

Sta

ge

III

Sta

ge

IV

0.00001

0.0001

0.001

0.01

0.1

1

Rel

ativ

e F

R a

lph

a T

ran

scri

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

22

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????