RTKs and rational cancer therapy

1
RTKs and rational cancer therapy
Dr Andrejs Liepins/Science Photo Library
2
Are we making progress?
3
In looking at 5-year survival, we need to
remember we are are making a LOT of progress in
cancer detection for some cancers
4
And we need to remember advances in detection
when it comes to survival rates
5
How does current chemotherapy work?
6
KILL dividing cells!
7
(No Transcript)
8
Chemotherapy kills all dividing cells
Amanda Dugger 2007 ACS Hero of Hpe
9
There has to be a better way!
Amanda Dugger 2007 ACS Hero of Hpe
10
Lets go Back to the 1970s
Bishop and Varmus
11
Retroviruses can cause cancer by picking
up mutated versions of normal cellular genes
Alberts et al. Fig. 24-23
12
Many viral oncogenes are kinases, including RTKs
Alberts et al.
13
Different families of RTKs recognize a diverse
set of different ligands
Alberts et al. Fig. 15-47
14
And that was just a few of the RTK families
doi10.1016/j.cell.2010.06.011
15
The EGF receptor family
Adding complexity, in mammals many RTKs and
ligands are encoded by multi-gene families
Valberga, Anals. Oncogene 07
16
Ligand binding activates RTKs by dimerization
Lodish et al. Fig. 20-21
17
RTK signaling ultimately leads to activation of a
transcription factor
Gilbert Fig. 6.14
18
Most ligands that induce receptor
dimerization act as dimers
Alberts et al. Fig. 15-48
19
EGF and TGF-alpha induce receptor dimerization by
an unusual mechanism
Garrett et al., Ogiso et al., Cell 2002, 110
763, 775
20
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
21
While HER2 is overexpressed in some
neuroblastomas, it is not commonly mutated there
22
However, it did provide the earliest example of
a mutated RTK in a tumor
23
Her discovery allowed Cori Bargmann to make a
bold prediction
24
"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"
25
She was right!
"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"
26
Activating mutations in RTKs take several forms
but all lead to ligand-independent dimerization
and thus activation
Lodish et al. Fig. 24-16
27
Heres a cool example
A chimeric oncogenic version of the trk
RTK isolated from a human colon carcinoma
Lodish et al. Fig. 24-16
28
Tropomyosin dimerization dimerizes the
receptor even in the absence of ligand
Lodish et al. Fig. 24-16
29
However, mutational activation of RTKs in human
tumors is rare
30
So why are you telling us all this?
31
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
32
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
33
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
34
They are enzymes--what should we do?
35
An example of an inhibitor (in red and
green) designed to block the active site of the
insulin receptor tyrosine kinase (in gray)
36
Iressa, an EGFR inhibitor Illustrates the ups And
downs Of this form of therapy
aka Gefitinib
37
Iressa 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
38
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 675-81
www.iressa-us.com
39
Data suggested that Iressa benefits a small
subset of patients Including never-smokers
and Patients of Asian descent
Curr Treat Options Oncol. 2007 Feb8(1)28-37
40
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 Feb8(1)28-37
41
It only works on patients with activating
mutations in the kinase domain of the EGF receptor
42
It has been partially replaced by Erlotinib
(Tarceva), another EGFR inhibitor approved for
second line treatment of non-small cell lung
cancer
43
Erlotinib (Tarceva) works, but how well?
Median Survival 6.7 months vs. 4.7 months in
placebo control
44
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
45
BUT even when kinase inhibitors work well
initially....
46
Relapses often occur
47
Relapses often occur
How could that happen?
48
Have you heard The one about Natural selection?
49
Drug treatment selects for mutant cancer cells
with Second site mutations in kinase blocking
drug binding or other RTKs (e.g., c-Met) gene
amplified
50
Luckily drugs are not the only approach
51
Herceptin-- The corporate view
52
Genentech.com
53
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
54
The 3-dimensional structure of an antibody
Alberts et al. Fig. 23-34
55
The antibody-antigen recognition event
is exquisitely specific
Yellow and blue heavy and light chains
Greenantigen (in this case would be EGF Receptor)
Red amino acids in contact
Alberts et al. Fig. 23-35
56
Data from Phase III clinical trials of Herceptin
Genentech.com
57
Data from Phase III clinical trials of Herceptin
Genentech.com
58
Herceptin is now approved for treatment
of Metastatic breast cancer
59
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
60
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
61
By early 2009 follow-up data and additional
trials Confirm a 50 reduction in recurrance And
30 improvement in survival
Clin Breast Cancer. 2008 Dec8 Suppl 4S157-65.
62
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 Dec8 Suppl 4S157-65.
63
But like a freight train, it can run you over....
Cardiac toxicity in a few percent of
patients Costs 60,000!
64
Two anti-EGFR and one anti VEGFR antibodies are
also FDA approved
http//en.wikipedia.org/wiki/Monoclonal_antibody_t
herapy
65
And back to the pathway.
Farnesyl transferase inhibitors largely failures
Raf inhibitors
Mek inhibitors
Gilbert Fig. 6.14
66
The RTK-Ras pathway offers 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)
67

• Tumors develop resistance to raf inhibitors
• Through many routes!
• Amplification of mutant B-raf gene
• Upregulation of PDGF receptor
• Mutation of N-ras
• Mutations in B-raf
• Mutations in Mek