RTKs and rational cancer therapy

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RTKs and rational cancer therapy
Dr Andrejs Liepins/Science Photo Library
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Are we making progress?
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In looking at 5-year survival, we need to
remember we are are making a LOT of progress in
cancer detection for some cancers
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And we need to remember detection when it comes
to survival rates
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How does current chemotherapy work?
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KILL dividing cells!
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(No Transcript)
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Chemotherapy Kills all dividing cells
Amanda Dugger 2007 ACS Hero of Hpe
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There has to be a better way!
Amanda Dugger 2007 ACS Hero of Hpe
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Lets go Back to the 1970s
Bishop and Varmus
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Retroviruses can cause cancer by picking
up mutated versions of normal cellular genes
Alberts et al. Fig. 24-23
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Many viral oncogenes are kinases, including RTKs
Alberts et al.
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Different families of RTKs recognize a diverse
set of different ligands
Alberts et al. Fig. 15-47
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And that was just a few of the RTK families
doi10.1016/j.cell.2010.06.011
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The EGF receptor family
Adding complexity, In mammals many RTKs and
ligands Are encoded by Multi-gene families
Valberga, Anals. Oncogene 07
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Ligand binding activates RTKs by dimerization
Lodish et al. Fig. 20-21
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RTK signaling ultimately leads to activation of a
transcription factor
Gilbert Fig. 6.14
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Most ligands that induce receptor
dimerization act as dimers
Alberts et al. Fig. 15-48
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EGF and TGF-alpha induce receptor dimerization by
an unusual mechanism
Garrett et al., Ogiso et al., Cell 2002, 110
763, 775
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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
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While HER2 is overexpressed in some
neuroblastomas, it is not commonly mutated there
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
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However, it did provide the earliest example of
a mutated RTK in a tumor
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It also allowed Cori Bargmann to make a bold
prediction
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"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"
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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"
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Activating mutations in RTKs take several forms
but all lead to ligand-independent dimerization
and thus activation
Lodish et al. Fig. 24-16
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Heres a cool example
A chimeric oncogenic version of the trk RTK was
isolated from a human colon carcinoma
Lodish et al. Fig. 24-16
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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
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However, mutational activation of RTKs in human
tumors is rare
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So why are you telling us all this?
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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
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HER2 is Amplified in 30 of Breast Cancer Cases
HER2 normal
HER2 amplified
Kim et al, JKMS 08
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This and other RTKs are 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
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They are enzymes--what should we do?
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An example of an inhibitor (in red and
green) designed to block the active site of the
insulin receptor tyrosine kinase (in gray)
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Iressa, an EGFR inhibitor Illustrates the ups And
downs Of this form of therapy
aka Gefitinib
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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
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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
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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
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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
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It only works on patients with activating
mutations in the kinase domain of the EGF receptor
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It has been partially replaced by Erlotinib
(Tarceva), another EGFR inhibitor approved for
second line treatment of non-small cell lung
cancer
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Erlotinib (Tarceva) works, but how well?
Median Survival 6.7 months vs. 4.7 months in
placebo control
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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
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Even when kinase inhibitors work well
initially....
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Relapses often occur
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Relapses often occur
How could that happen?
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Have you heard The one about Natural selection?
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Second site mutations in kinase block drug
binding Or other RTKs (e.g., c-Met) are gene
amplified
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Luckily drugs are not the only approach
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Herceptin-- The corporate view
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Genentech.com
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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
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The 3-dimensional structure of an antibody
Alberts et al. Fig. 23-34
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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
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Data from Phase III clinical trials of Herceptin
Genentech.com
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Data from Phase III clinical trials of Herceptin
Genentech.com
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Herceptin is now approved for treatment
of Metastatic breast cancer
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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
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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
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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.
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But like a freight train, it can run you over....
Cardiac toxicity in a few percent of
patients Costs 60,000
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Two anti-EGFR and one anti VEGFR antibodies are
also FDA approved
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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