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07-12-2009, 07:22 PM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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her2+ breast cancer is addicted to AKT signalling=?curable with AKT inhibitors
I heard Dr. Rosen talk at the May AACR annual meeting about oncogene addiction, but these are the most positive results he has presented, especially that AKT inhibitors are well tolerated.
Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling
Qing-Bai She1, Sarat Chandarlapaty1#, Qing Ye1#, Jose Lobo1, Kathleen M. Haskell2, Karen R. Leander2, Deborah DeFeo-Jones2, Hans E. Huber2, Neal Rosen1*
1 Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, 2 Department of Cancer Research, Merck Research Laboratories, West Point, Pennsylvania, United States of America
Background
Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy.
Methodology/Principal Findings
A selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the latter selected for resistance to Herceptin. Furthermore, chronic administration of the drug was well-tolerated, causing only transient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt.
Conclusions/Significance
These data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling, and that effective inhibition of Akt in tumors is feasible and effective in vivo. These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and other cancers that are addicted to the pathway including tumors with resistant to Herceptin.
Citation: She Q-B, Chandarlapaty S, Ye Q, Lobo J, Haskell KM, et al. (2008) Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling. PLoS ONE 3(8): e3065. doi:10.1371/journal.pone.0003065
AVAILABLE FOR READING FOR FREE ON PLOS ONE.
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07-12-2009, 07:47 PM
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#2
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Senior Member
Join Date: Jun 2006
Location: san luis obispo, ca
Posts: 1,150
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Thanks Lani. Which Dr. Rosen are you speaking of?
Love,
Vickie
__________________
Love and Hugs, Vickie
Life's not about waiting for the storm to pass,
It's about learning to dance in the rain.
Feb 04 IBC IIIC/IV er-/pr- her2+++
3/04 TCH X4
7/ 04 MRM 9/04 Taxol/herceptin wkly 1 yr 33X rads
11/04 skin mets 33x rads,10/05 Avast/Herc. 11 mos.
8/ 06 PET mets lymphs, neck
9/ 06 Navelbine/herceptin
11/ 06 PET NED
2/ 07 skin mets, 4/07 Xeloda, 5/07 add Tykerb
2/ 08 Tykerb failed. Doxil /Herceptin 6 months
8/08 PET skin mets, 8/08 Abraxane/Avastin
11/ 08 PET prog., skin mets
1/09 PET/CT progress, 1/09 Ixempra, 2/09 add Xeloda and low dose Naltrexone
2/09 off Ixempra/Xeloda
3/09 navelbine/herc/cytoxin 4/09 PET shows regress.7/09 start Topotecan. Failed.
8/09 extensive mets rgt brst, back and torso. starting Pazopanib clinical trial.
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07-12-2009, 10:55 PM
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#3
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Dr. Neal Rosen, the last listed of the authors
He has been involved in breast cancer research for years and gave a talk on what "oncogene addiction" really means--many articles use the term incorrectly..
Much of his research has been on Heat Shock Protein inhibitors, some of which
may come on the market in the foreseeable future and seem to work well with herceptin for her2+ breast cancer.
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07-13-2009, 04:04 AM
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#4
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Thanks Lani for another really positive article.
Is there a link that I could go to understand oncogene addiction?It is no doubt very complex!!
Is there any info about natural AKT inhibitors?
Many thanks
Ellie
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07-13-2009, 05:55 PM
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#5
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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I think this is the lecture he gave at the 2009 aacr annual meeting
it is available for purchase (not one of the free ones) however
HOME / NEAL ROSEN; FEEDBACK LOOPS IN CANCER SIGNAL TRANSDUCTION PATHWAYS
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NEAL ROSEN; Feedback Loops in Cancer Signal Transduction Pathways
Session Id: CR08-153 Type: Downloadable
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http://www.conferencemedia.net/store...-pathways.html
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07-14-2009, 03:15 AM
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#6
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Thanks Lani
I will spend my money and try to educate myself some more!
Ellie
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07-14-2009, 07:07 AM
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#7
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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before you do I want to make sure this is the lecture I think it is
I am not home to check my AACR meeting materials. If you remind me via the board around the end of the month I will try to do so.
I would hate for you to buy the wrong lecture!
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07-14-2009, 02:51 PM
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#8
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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07-15-2009, 04:47 AM
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#9
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Thanks Lani and Rich
Do we know of any natural AKT inhibitors??
Thanks Ellie
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