Download RTKs-Herceptin

RTKs and rational cancer therapy
Dr Andrejs Liepins/Science Photo Library
Are we making progress?
In looking at “5-year” survival, we need to
remember we are are making a LOT of progress in
cancer detection for some cancers
And we need to remember advances in detection
when it comes to “survival rates”
How does
current chemotherapy work?
KILL dividing cells!
Chemotherapy
kills all
dividing cells
Amanda Dugger
2007 ACS Hero of Hpe
There has to
be a better way!
Amanda Dugger
2007 ACS Hero of Hpe
Let’s go
Back to
the
1970s
Bishop and Varmus
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
And that was
just a few
of the
RTK families
doi:10.1016/j.cell.2010.06.011
The EGF
Ligand family
The EGF
receptor family
Adding complexity,
in mammals many
RTKs and ligands
are encoded by
multi-gene families
Valberga, Anals. Oncogene 07
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
While HER2 is overexpressed in
some neuroblastomas,
it is not commonly mutated there
However, it did provide
the earliest example of a mutated RTK in a tumor
Her discovery allowed
Cori Bargmann to make a bold prediction
"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"
She was right!
"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
Here’s a cool example
A chimeric oncogenic version of the trk RTK
isolated from a human colon carcinoma
Lodish et al. Fig. 24-16
Tropomyosin dimerization dimerizes the receptor
even in the absence of ligand
Lodish et al. Fig. 24-16
However, mutational activation of RTKs in
human tumors is rare
So why are you telling us all this?
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
HER2 is Amplified in 30% of Breast Cancers & patients
with HER2 amplification have a worse prognosis
HER2 normal
HER2 amplified
Kim et al, JKMS 08
HER2 and other RTKs are also
amplified in other cancers
EGFR amplified in some glioblastomas and lung cancers
Met amplified in drug resistance lung cancers
HER2 amplified in some bladder cancers
Kit amplified in some gastrointestinal stromal tumors
They are enzymes-what should we do?
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
Illustrates the ups
And downs
Of this form
of therapy
aka Gefitinib
Iressa
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
Iressa
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
raised serious questions about
whether it prolongs life.
Curr Treat Options Oncol. 2005 6:75-81
www.iressa-us.com
Data suggested that Iressa
benefits a small subset of patients
Including “never-smokers” and
Patients of Asian descent
Curr Treat Options Oncol. 2007 Feb;8(1):28-37
Data suggested that Iressa
benefits a small subset of patients
Including “never-smokers” and
Patients of Asian descent
Why those patients?
Curr Treat Options Oncol. 2007 Feb;8(1):28-37
It only works on patients with
activating mutations in
the kinase domain of the EGF receptor
It has been partially replaced by
Erlotinib (Tarceva), another EGFR inhibitor
approved for “second line” treatment
of non-small cell lung
and pancreatic cancers
Erlotinib (Tarceva) works,
but how well?
Median Survival: 6.7 months vs.
4.7 months in placebo control
Other second generation EGFR inhibitors
are now in 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
BUT even when kinase inhibitors work well initially....
Relapses often occur
Relapses often occur
How could
that happen?
Have you heard
The one about
Natural selection?
Drug treatment selects for mutant cancer cells with
Second site mutations in the kinase domain,
blocking drug binding,
or with other RTKs (e.g., c-Met) gene amplified
Luckily drugs are not the only approach
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
(in this case would be EGF Receptor)
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 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 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
By early 2009 follow-up data and additional trials
Confirm a 50% reduction in recurrance
And 30% improvement in survival
Clin Breast Cancer. 2008 Dec;8 Suppl 4:S157-65.
By early 2009 follow-up data and additional trials
Confirm a 50% reduction in recurrance
And 30% improvement in survival
There are also
Ongoing trials in HER2 positive
Gastric, uterine
And endometrial cancers
Clin Breast Cancer. 2008 Dec;8 Suppl 4:S157-65.
But like a freight train, it can run you over....
Cardiac toxicity in a few percent of patients
Costs $60,000!
Two anti-EGFR and
one anti VEGFR antibodies
are also FDA approved
http://en.wikipedia.org/wiki/Monoclonal_antibody_therapy
And back to the pathway….
Farnesyl transferase
inhibitors largely failures
Raf inhibitors
Gilbert Fig. 6.14
Mek inhibitors
As metnioned earlier, the RTK-Ras pathway
Offers several drug targets for cancer treatment
e.g., or the Raf kinase inhibitor Vemurafenib
Approved for treatment of
Late stage melanoma August 2011)
and approved for inoperable hepatocellular carcinoma (Nov. 2007)
BUT…….
Tumors develop resistance to raf inhibitors
Through many routes!
1)Amplification of mutant B-raf gene
2)Upregulation of PDGF receptor
3)Mutation of N-ras
4)Mutations in B-raf
5)Mutations in Mek
BUT…….
Tumors develop resistance to raf inhibitors
Through many routes!
1)Amplification of mutant B-raf gene
2)Upregulation of PDGF receptor
3)Mutation of N-ras
4)Mutations in B-raf
5)Mutations in Mek
So now we add MEK inhibitors to treat this!
Trametinib FDA approved January 2014