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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.

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slide1

RTKs and rational cancer therapy

Dr Andrejs Liepins/Science Photo Library

slide3

In looking at “5-year” survival, we need to remember we are are making a LOT of progress in cancer detection for some cancers

slide5

How does

current chemotherapy work?

slide8

Chemotherapy

Kills all dividing cells

Amanda Dugger

2007 ACS Hero of Hpe

slide9

There has to be a better way!

Amanda Dugger

2007 ACS Hero of Hpe

slide10

Let’s go

Back to

the

1970s

Bishop and Varmus

slide11

Retroviruses can cause cancer by picking up

mutated versions of normal cellular genes

Alberts et al. Fig. 24-23

slide13

Different families of RTKs recognize

a diverse set of different ligands

Alberts et al. Fig. 15-47

slide14

And that was

just a few

of the

RTK families

doi:10.1016/j.cell.2010.06.011

slide15

The EGF receptor family

Adding complexity,

In mammals many

RTKs and ligands

Are encoded by

Multi-gene families

Valberga, Anals. Oncogene 07

slide16

Ligand binding activates RTKs

by dimerization

Lodish et al. Fig. 20-21

slide17

RTK signaling ultimately leads to

activation of a transcription factor

Gilbert Fig. 6.14

slide18

Most ligands that

induce receptor dimerization

act as dimers

Alberts et al. Fig. 15-48

slide19

EGF and TGF-alpha induce receptor dimerization

by an unusual mechanism

Garrett et al., Ogiso et al., Cell 2002, 110: 763, 775

slide20

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

slide21

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

slide22

However, it did provide

the earliest example of a mutated RTK in a tumor

slide24

"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"

slide25

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"

slide26

Activating mutations

in RTKs take

several forms but

all lead to

ligand-independent

dimerization and

thus activation

Lodish et al. Fig. 24-16

slide27

Here’s a cool example

A chimeric oncogenic version of the trk RTK

was isolated from a human colon carcinoma

Lodish et al. Fig. 24-16

slide28

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

slide31

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

slide32

HER2 is Amplified in 30% of Breast Cancer Cases

HER2 normal

HER2 amplified

Kim et al, JKMS 08

slide33

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

slide35

An example of an inhibitor

(in red and green)

designed to block

the active site of

the insulin receptor

tyrosine kinase (in gray)

slide36

Iressa, an

EGFR inhibitor

Illustrates the ups

And downs

Of this form

of therapy

aka Gefitinib

slide37

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

slide38

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

slide39

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

slide40

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

slide41

It only works on patients with

activating mutations in

the kinase domain of the EGF receptor

slide42

It has been partially replaced by

Erlotinib (Tarceva),

another EGFR inhibitor

approved for “second line” treatment

of non-small cell lung cancer

slide43

Erlotinib (Tarceva) works,

but how well?

Median Survival: 6.7 months vs.

4.7 months in placebo control

slide44

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

slide47

Relapses often occur

How could

that happen?

slide48

Have you heard

The one about

Natural selection?

slide49

Second site mutations in kinase block drug binding

Or other RTKs (e.g., c-Met) are gene amplified

slide53

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

slide55

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

slide59

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

slide60

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

slide61

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.

slide62

But like a freight train, it can run you over....

Cardiac toxicity in a few percent of patients

Costs $60,000

slide64

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