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 doescurrent chemotherapy work?

KILL dividing cells!

Chemotherapykills all dividing cells

Amanda Dugger2007 ACS Hero of Hpe

There has to be a better way!

Amanda Dugger2007 ACS Hero of Hpe

Bishop and Varmus

Let’s goBack to the1970s

Retroviruses can cause cancer by picking upmutated 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 theRTK families

doi:10.1016/j.cell.2010.06.011

Valberga, Anals. Oncogene 07

Adding complexity,in mammals manyRTKs and ligands are encoded by multi-gene families

The EGF receptor family

The EGF Ligand family

Ligand binding activates RTKs by dimerization

Lodish et al. Fig. 20-21

RTK signaling ultimately leads toactivation 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 dimerizationby an unusual mechanism

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

“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

Neu = HER2 was first found in a Neuroblastoma cell line

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 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"

"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"

She was right!

Activating mutations in RTKs take several forms butall lead to ligand-independentdimerization and thus activation

Lodish et al. Fig. 24-16

A chimeric oncogenic version of the trk RTKisolated from a human colon carcinoma

Here’s a cool example

Lodish et al. Fig. 24-16

Tropomyosin dimerization dimerizes the receptoreven in the absence of ligand

Lodish et al. Fig. 24-16

However, mutational activation of RTKs inhuman tumors is rare

So why are you telling us all this?

Gene amplification is also a common mechanismof inappropriate gene activation in human tumors

Double minute chromosomes Tandem duplications

Alberts et al. Fig. 24-20

Kim et al, JKMS 08

HER2 amplified

HER2 normal

HER2 is Amplified in 30% of Breast Cancers & patients with HER2 amplification have a worse prognosis

HER2 and other RTKs are alsoamplified in other cancers

Met amplified in drug resistance lung cancers

EGFR amplified in some glioblastomas and 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 blockthe active site ofthe insulin receptortyrosine kinase (in gray)

Iressa, anEGFR inhibitorIllustrates the upsAnd downsOf this form of therapy

aka Gefitinib

Iressawas approved after Phase II trialsfor “third line” treatmentof non-small cell lung cancer

Curr Treat Options Oncol. 2005 6:75-81www.iressa-us.com

Iressawas approved after Phase II trialsfor “third line” treatmentof non-small cell lung cancer

Curr Treat Options Oncol. 2005 6:75-81

But Phase III clinical trial dataFrom December 2004raised serious questions aboutwhether it prolongs life.

www.iressa-us.com

Data suggested that Iressabenefits a small subset of patientsIncluding “never-smokers” andPatients of Asian descent

Curr Treat Options Oncol. 2007 Feb;8(1):28-37

Data suggested that Iressabenefits a small subset of patientsIncluding “never-smokers” andPatients of Asian descent

Curr Treat Options Oncol. 2007 Feb;8(1):28-37

Why those patients?

It only works on patients withactivating mutations inthe kinase domain of the EGF receptor

It has been partially replaced byErlotinib (Tarceva), another EGFR inhibitorapproved for “second line” treatmentof 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

The Oncologist, Vol. 12, No. 3, 325-330, March 2007

• Covalently bind EGFR

• Target multiple kinases including HER2 and VEGFR

BUT even when kinase inhibitors work well initially....

Relapses often occur

Relapses often occur

How could that happen?

Have you heardThe one aboutNatural selection?

Drug treatment selects for mutant cancer cells withSecond 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 selectionto 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-antigenrecognition event isexquisitely 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

Genentech.com

Data from Phase III clinical trials of Herceptin

Genentech.com

Data from Phase III clinical trials of Herceptin

Herceptin is now approved for treatment ofMetastatic breast cancer

However, even more exciting is data on usingHerceptin 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 usingHerceptin plus chemotherapy

for treatment of early breast cancer

FDA News Nov. 16, 2006

The FDA rapidly approved

expansion of recommended use

By early 2009 follow-up data and additional trialsConfirm 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 trialsConfirm a 50% reduction in recurrance

And 30% improvement in survival

There are alsoOngoing trials in HER2 positive

Gastric, uterineAnd 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….

Gilbert Fig. 6.14

Raf inhibitorsMek inhibitors

Farnesyl transferase inhibitors largely failures

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 gene2)Upregulation of PDGF receptor3)Mutation of N-ras4)Mutations in B-raf5)Mutations in Mek

BUT…….Tumors develop resistance to raf inhibitors Through many routes!

1)Amplification of mutant B-raf gene2)Upregulation of PDGF receptor3)Mutation of N-ras4)Mutations in B-raf5)Mutations in Mek

So now we add MEK inhibitors to treat this!

Trametinib FDA approved January 2014