Download Data from Phase III clinical trials of Herceptin

Retroviruses can cause cancer by picking up
mutated versions of normal cellular genes
Alberts et al. Fig. 24-23
Many viral oncogenes are kinases, including RTKs
Alberts et al.
Different families of RTKs recognize
a diverse set of different ligands
Alberts et al. Fig. 15-47
Ligand binding activates RTKs
by dimerization
Lodish et al. Fig. 20-21
RTK signaling ultimately leads to
activation of a transcription factor
Gilbert Fig. 6.14
Most ligands that
induce receptor dimerization
act as dimers
Alberts et al. Fig. 15-48
EGF and TGF-alpha induce receptor dimerization
by an unusual mechanism
Garrett et al., Ogiso et al., Cell 2002, 110: 763, 775
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
Cori Bargmann today
"I prefer the clustering modela 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"
Activating mutations
in RTKs take
several forms but
all lead to
ligand-independent
dimerization and
thus activation
Lodish et al. Fig. 24-16
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
Gene amplification is also a common mechanism
of inappropriate gene activation in human tumors
Double minute chromosomes
Alberts et al. Fig. 24-20
Tandem duplications
An example of an inhibitor
(in red and green)
designed to block
the active site of
the insulin receptor
tyrosine kinase (in gray)
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
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 6:75-81
www.iressa-us.com
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 6:75-81
www.iressa-us.com
Data suggest that Gefitinib (Iressa)
may benefit a subset of patients
Including “never-smokers” and
Patients of Asian descent
Curr Treat Options Oncol. 2007 Feb;8(1):28-37
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
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
Genentech.com
Herceptin-- The corporate view
Genentech.com
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
The 3-dimensional structure of an antibody
Alberts et al. Fig. 23-34
The antibody-antigen
recognition event is
exquisitely specific
Yellow and blue=
heavy and light chains
Green=antigen
Red= amino acids in contact
Alberts et al. Fig. 23-35
Data from Phase III clinical trials of Herceptin
Genentech.com
Data from Phase III clinical trials of Herceptin
Genentech.com
Herceptin is now approved for treatment of
Metastatic breast cancer
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
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
And back to the pathway….
Farnesyl transferase
inhibitors Phase II
successes and failures
BAY 43-9006 (Phase II)
C-1040 Phase II failure
Gilbert Fig. 6.14
Others in Phase I