RTKs and rational cancer therapy Dr Andrejs LiepinsScience
- Slides: 73
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 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 1970 s 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 = HER 2 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 HER 2 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
HER 2 is Amplified in 30% of Breast Cancers & patients with HER 2 amplification have a worse prognosis HER 2 normal HER 2 amplified Kim et al, JKMS 08
HER 2 and other RTKs are also amplified in other cancers EGFR amplified in some glioblastomas and lung cancers Met amplified in drug resistance lung cancers HER 2 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 ZD 6474 • Covalently bind EGFR • Target multiple kinases including HER 2 and VEGFR The Oncologist, Vol. 12, No. 3, 325 -330, March 2007
. . . and many other kinases and many associated cancers are being targeted in the clinic
243 kinase inhibitors have made it into clinical trials!! Klaeger et al. , Science 358, eaan 4368 (2017)
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
Perhaps we can do better by combining inhibitors to combat acquired resistance A recent trial in non-small cell lung cancer combined erlotinib With and antibody inhibitor of the VEGF receptor Median progression-free survival (PFS) was 16. 9 months versus 13. 3 months among patients treated with erlotinib alone 1. Furuya N, Fukuhara T, Saito H, et al. Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ 026. Oral presentation at: 2018 ASCO Annual Meeting; June 1 -5, 2018; Chicago, IL.
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: S 157 -65.
By early 2009 follow-up data and additional trials Confirm a 50% reduction in recurrance And 30% improvement in survival There also Ongoing trials in HER 2 positive Gastric, uterine And endometrial cancers Clin Breast Cancer. 2008 Dec; 8 Suppl 4: S 157 -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 mentioned 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….
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
The combination of MEK and BRAF inhibitors is significantly more effective Higher response rate in advanced BRAF-mutant melanoma – 69% vs. 53% (p = 0. 0014). Median progression free survival 11. 0 vs. 8. 8 months Median overall survival 25. 1 compared to 18. 7 months 3 -year survival in patients treated with the combination was observed in 44% of patients. https: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 5885075/
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