Retroviruses can cause cancer by picking up

1
Retroviruses can cause cancer by picking
up mutated versions of normal cellular genes
Alberts et al. Fig. 24-23
2
Many viral oncogenes are kinases, including RTKs
Alberts et al.
3
Different families of RTKs recognize a diverse
set of different ligands
Alberts et al. Fig. 15-47
4
Ligand binding activates RTKs by dimerization
Lodish et al. Fig. 20-21
5
RTK signaling ultimately leads to activation of a
transcription factor
Gilbert Fig. 6.14
6
Most ligands that induce receptor
dimerization act as dimers
Alberts et al. Fig. 15-48
7
EGF and TGF-alpha induce receptor dimerization by
an unusual mechanism
Garrett et al., Ogiso et al., Cell 2002, 110
763, 775
8
Neu HER2 was first found in a Neuroblastoma
cell line
Neuroblastoma is one of the most common solid
tumours of early childhood usually found in
babies or young children. The disease originates
in the adrenal medulla or other sites of
sympathetic nervous tissue. The most common site
is the abdomen (near the adrenal gland) . Most
patients have widespread disease at diagnosis.
http//www.cancerindex.org
9
"I prefer the clustering model- a series of
receptors on the membrane .... all have to bind
with growth factor more or less
simultaneously.... Only after they are clustered
are they able to send along the signal... The
insertion of a glutamic acid into the
transmembrane domain could trick the neu protein
into believing it was surrounded by other neu
receptors even when it stood alone"
Cori Bargmann today
10
Activating mutations in RTKs take several forms
but all lead to ligand-independent dimerization
and thus activation
Lodish et al. Fig. 24-16
11
A chimeric oncogenic version of the trk RTK was
isolated from a human colon carcinoma
Tropomyosin dimerization dimerizes the
receptor even in the absence of ligand
Lodish et al. Fig. 24-16
12
Gene amplification is also a common mechanism of
inappropriate gene activation in human tumors
Double minute chromosomes
Tandem duplications
Alberts et al. Fig. 24-20
13
An example of an inhibitor (in red and
green) designed to block the active site of the
insulin receptor tyrosine kinase (in gray)
14
An example of an inhibitor (in red and
green) designed to block the active site of the
insulin receptor tyrosine kinase (in gray)
Iressa, an EGFR inhibitor
15
Gefitinib (Iressa), an EGFR inhibitor was
approved after Phase II trials for third line
treatment of non-small cell lung cancer
Curr Treat Options Oncol. 2005 675-81
www.iressa-us.com
16
Gefitinib (Iressa), an EGFR inhibitor was
approved after Phase II trials for third line
treatment of non-small cell lung cancer
But Phase III clinical trial data From December
2004 raise serious questions about whether it
prolongs life. It may work in just fraction of
cases
Curr Treat Options Oncol. 2005 675-81
www.iressa-us.com
17
Data suggest that Gefitinib (Iressa) may benefit
a subset of patients Including never-smokers
and Patients of Asian descent
Curr Treat Options Oncol. 2007 Feb8(1)28-37
18
It has been partially replaced by Erlotinib
(Tarceva), another EGFR inhibitor approved for
second line treatment of non-small cell lung
cancer
Median Survival 6.7 months vs. 4.7 months in
placebo control
www.tarceva.com
19
Four second generation EGFR inhibitors are now
entering clinical trials
EKB-569, HKI-272, CI-1033, and ZD6474

• Covalently bind EGFR
• Target multiple kinases including HER2 and VEGFR

The Oncologist, Vol. 12, No. 3, 325-330, March
2007
20
Genentech.com
21
Herceptin-- The corporate view
22
Genentech.com
23
Antibodies have been crafted by natural
selection to allow recognition of diverse
antigens from bacterial, viral, and parasitic
invaders
Alberts et al. Fig. 23-31
24
The 3-dimensional structure of an antibody
Alberts et al. Fig. 23-34
25
The antibody-antigen recognition event
is exquisitely specific
Yellow and blue heavy and light chains
Greenantigen
Red amino acids in contact
Alberts et al. Fig. 23-35
26
Data from Phase III clinical trials of Herceptin
Genentech.com
27
Data from Phase III clinical trials of Herceptin
Genentech.com
28
Herceptin is now approved for treatment
of Metastatic breast cancer
29
However, even more exciting is recent data on
using Herceptin plus chemotherapy for treatment
of early breast cancer
Breast cancer was half as likely to come back
in patients who received Herceptin for a year
after completing chemotherapy than in patients
who received chemotherapy alone!
New England Journal of Medicine, October 20, 2005
30
However, even more exciting is recent data on
using Herceptin plus chemotherapy for treatment
of early breast cancer
The FDA rapidly approved expansion of
recommended use
FDA News Nov. 16, 2006
31
And back to the pathway.
Farnesyl transferase inhibitors Phase II
successes and failures
C-1040 Phase II failure Others in Phase I
BAY 43-9006 (Phase II)
Gilbert Fig. 6.14