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03-08-2011, 12:14 PM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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need to attack her family receptors on multiple fronts for best efficacy
Hit multiple targets for maximum benefit in HER2-positive breast cancer, studies suggest
[Eureka News Service]
Combining targeted therapies might be required for maximum anti-tumor activity when treating HER2-positive breast cancers, according to two new studies by Vanderbilt-Ingram Cancer Center (VICC) investigators.
The findings, reported in two papers in the Proceedings of the National Academy of Sciences (PNAS), suggest that upregulation of the HER3 receptor limits the effectiveness of two classes of targeted therapies (HER2- and PI3 kinase-targeted therapies). Therefore targeting HER3 together with these agents should improve their clinical utility.
Around 25 percent of breast cancers have increased expression of the HER2 receptor, which is associated with more aggressive tumors and a poorer prognosis. HER2-targeted therapies like trastuzumab (Herceptin) and lapatinib (Tykerb) are effective in many women with HER2-positive breast tumors.
"But even in patients who respond to HER2-targeted therapies, the clinical response tends to be short-lived and tumors become resistant," said Carlos Arteaga, M.D., professor of Medicine and Cancer Biology, and director of the VICC Breast Cancer Research Program.
HER2 is a member of the EGF receptor family involved in signaling pathways that promote cell growth. HER2 must interact and form complexes with other members of the EGF receptor family, and its main partner in activating pathways that promote tumor growth is HER3. This complex of HER2/HER3 is a potent activator of the PI3K/Akt pathway, the key survival pathway in HER2-positive cancers.
"Based on this evidence, we hypothesized that, for these therapies to have maximum effect, HER3 and its output to the PI3K/Akt pathway must be completely shut down," Arteaga said.
A postdoctoral fellow in Arteaga's laboratory, Joan Garrett, Ph.D., led experiments to examine the effect of the HER2 tyrosine kinase inhibitor, lapatinib, on HER3 expression and activity.
She found that inhibiting HER2 with lapatinib led to an increase in HER3 expression and activation in both HER2-positive human breast tumors and cell lines. Inhibiting HER3 in HER2-positive breast cancers growing in mice made tumor cells markedly more sensitive to lapatinib. Additionally, blocking both HER2 and HER3 was more effective at inhibiting the activity of PI3K/Akt pathway than either inhibitor alone.
Those results, published March 7 in PNAS, show that upregulation of HER3 limits the effectiveness of HER2-targeted therapies and that a combination of drugs that target both HER2 and HER3 should be considered for optimal clinical benefit.
Since PI3K/Akt is the key pro-survival signaling pathway downstream of HER2, the investigators also examined the utility of inhibitors of PI3K in HER2-positive breast cancer cells.
Those experiments, led by postdoctoral fellow Anindita Chakrabarty, Ph.D., and published Feb. 28 also in PNAS, showed a similar upregulation of HER3 in response to treatment with a PI3K inhibitor currently in clinical development. In turn, this compensatory upregulation of HER3 partially reactivated the PI3K/Akt pathway and limited the action of the PI3K inhibitor.
"This shows that therapeutic use of PI3K inhibitors would be limited if used as single agents in HER2-positive cancers. These results have implications for other cancers treated with this class of drugs," Arteaga said. However, he notes PI3K inhibitors might have clinical merit when used in combination with HER2-HER3 antagonists.
Since both HER3 inhibitors and PI3K inhibitors are now in clinical development, "these studies provide a scientific rationale for how a combination of the new drugs with HER2-targeted therapies might be used to provide better results for many patients with breast cancer," Arteaga said.
Arteaga is also the Donna S. Hall Chair in Breast Cancer Research and interim director of the Division of Hematology/Oncology at Vanderbilt University. The research was supported by grants from the National Institutes of Health, the American Cancer Society, the Lee Jeans Translational Breast Cancer Research Program, and a Stand Up to Cancer (SU2C)/AACR Dream Team Translational Research Grant.
ABSTRACT: Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase
[Proceedings of the National Academy of Sciences]
Sustained and complete inhibition of HER3 and its output to PI3K/Akt are required for the optimal antitumor effect of therapeutic inhibitors of the HER2 oncogene. Here, we show that, after inhibition of the HER2 tyrosine kinase with lapatinib, there is PI3K/Akt and FoxO3a-dependent up-regulation of HER3 mRNA and protein. Up-regulated HER3 was then phosphorylated by residual HER2 activity, thus partially maintaining P-Akt and limiting the antitumor action of lapatinib. Inhibition of HER3 with siRNA or a neutralizing HER3 antibody sensitized HER2+ breast cancer cells and xenografts to lapatinib both in vitro and in vivo. Combined blockade of HER2 and HER3 inhibited pharmacodynamic biomarkers of PI3K/Akt activity more effectively than each inhibitor alone. These results suggest that because of HER3-mediated compensation, current clinical inhibitors of HER2 and PI3K/Akt will not block the PI3K pathway completely. They also suggest that therapeutic inhibitors of HER3 should be used in combination with HER2 inhibitors and PI3K pathway inhibitors in patients with HER2- and PI3K-dependent cancers.
ABSTRACT: Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors
[Proceedings of the National Academy of Sciences]
We examined the effects of an inhibitor of PI3K, XL147, against human breast cancer cell lines with constitutive PI3K activation. Treatment with XL147 resulted in dose-dependent inhibition of cell growth and levels of pAKT and pS6, signal transducers in the PI3K/AKT/TOR pathway. In HER2-overexpressing cells, inhibition of PI3K was followed by up-regulation of expression and phosphorylation of multiple receptor tyrosine kinases, including HER3. Knockdown of FoxO1 and FoxO3a transcription factors suppressed the induction of HER3, InsR, IGF1R, and FGFR2 mRNAs upon inhibition of PI3K. In HER2+ cells, knockdown of HER3 with siRNA or cotreatment with the HER2 inhibitors trastuzumab or lapatinib enhanced XL147-induced cell death and inhibition of pAKT and pS6. Trastuzumab and lapatinib each synergized with XL147 for inhibition of pAKT and growth of established BT474 xenografts. These data suggest that PI3K antagonists will inhibit AKT and relieve suppression of receptor tyrosine kinase expression and their activity. Relief of this feedback limits the sustained inhibition of the PI3K/AKT pathway and attenuates the response to these agents. As a result, PI3K pathway inhibitors may have limited clinical activity overall if used as single agents. In patients with HER2-overexpressing breast cancer, PI3K inhibitors should be used in combination with HER2/HER3 antagonists.
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03-09-2011, 01:33 AM
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#2
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Senior Member
Join Date: May 2010
Location: Melbourne, Australia
Posts: 434
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Re: need to attack her family receptors on multiple fronts for best efficacy
Thanks Lani.
Trish
__________________
5/2004 (R) 30mm bre gr3 infiltrating ductal ca 16/18nodes er (2+) pr (3+) HER2 (3+)
6/2004 6 cycles(FEC), Oct 40 rads, Tamoxifen
5/2006 oopherectomy, Arimedex
12/2006 liver mets largest 9cm
1/2007 Herceptin,
3/2007 Taxol + Herc
1/2008 Herc alone
4/2008 Multiple bone mets,Zometa
7/2008 Herc + Gemcitabine
8/2008 Herc+Navelbine/vinoralbine
10/2008 Herc+Carboplatin+Taxol
12/2008 Tykerb+Xeloda
2/2010 Herceptin + trial drug
5/2010 Herceptin+Tykerb
8/2010 Tykerb+Abraxane
9/2010 Abraxane
12/2010 Abraxane+Tyk+Herc
4/2011 Tyk+Herc+Femara
6/2011 Liver and bone mets prog.Abraxane continue Herceptin,Tykerb,Femara and Zometa
8/2011 Probable liver progression and increased neuropathy. Xeloda with Tyk+Herc. Zometa 6 weekly.
9/2011 Liver progression,TM +++. Cyclophosphamide and Methotrexate metro Herc Zometa
10/2011 liver mets prog.Herc, 3 Tykerb +2mg decodron daily,Zometa
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03-09-2011, 04:46 AM
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#3
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Re: need to attack her family receptors on multiple fronts for best efficacy
Lani
Are there any her 3 targeted drugs available for bc at present??
Many thanks once again for posting.
Ellie
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03-10-2011, 12:14 AM
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#4
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Re: need to attack her family receptors on multiple fronts for best efficacy
Not sure I understand your question
Do you mean are there 3 targeted drugs for bc or do you mean are there any her3 targetted drugs?
Approved targeted drugs against bc are tamoxifen, AIs both targeted vs ER, herceptin vs her2, avastin vs VEGFR...there are also EGFR targeted monoclonal antibody drugs but they are approved for head and neck cancer.
Then there are the tyrosine kinase inhibitors which are more promiscous (yes, that is the word they use) as most target more than one receptor eg lapatinib targets egfr and her2
There is a monoclonal antibody not yet approved that prevents her2 and her3 from dimerizing It is called pertuzumab and Genentech has it in trials.
Hope this answered your question
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03-10-2011, 12:29 AM
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#5
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Senior Member
Join Date: May 2010
Location: Melbourne, Australia
Posts: 434
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Re: need to attack her family receptors on multiple fronts for best efficacy
Do M Tor inhibitors fit in here? I thought I read a post that Sorafenib (a drug for kidney cancer as I understand it) was an M Tor inhibitor.
Trish
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03-10-2011, 02:54 AM
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#6
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Senior Member
Join Date: Feb 2009
Posts: 1,526
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Re: need to attack her family receptors on multiple fronts for best efficacy
Thanks Lani
I did mean targeted therapy that attacks the her 3 receptor. By chance I saw my own onc yesterday. He was talking about pertuzumab and though still in trials felt this would be another good drug to add to improve outcomes.
Ellie
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03-10-2011, 09:12 AM
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#7
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Senior Member
Join Date: Sep 2005
Location: South Dakota.
Posts: 621
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Re: need to attack her family receptors on multiple fronts for best efficacy
Lani, I appreciated the drug names and what they target. Good summary, thanks.
__________________
Blessings and Peace,
Barbara
DX Oct 02 @ age 52 Stage 2B Grade 3 Mastectomy
"at least" 4.5 cm IDC 1+node ER+61% /PR-
Assiciated Intraductual component with Comedo Necrosis
Her2+ FISH8.6 IHC 2+
5 1/2 CEF Arimidex
Celebrex 400mg daily for 13 months
Prophylactic mastectomy
Estradiol #: 13
PTEN positive, "late" Herceptin (26 months after chemo)
Oct 05: Actonel for osteopenia from Arimidex.
May 08: Replaced Actonel with Zometa . Taking every 6
months.
Accepting the gift of life, I give thanks for it and live it in fullness.
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03-10-2011, 01:29 PM
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#8
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Senior Member
Join Date: Feb 2008
Location: Georgia
Posts: 1,486
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Re: need to attack her family receptors on multiple fronts for best efficacy
Lani,
Thanks for keeping us updated.
Amelia
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03-10-2011, 07:25 PM
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#9
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Member
Join Date: Oct 2010
Location: Florida
Posts: 17
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Re: need to attack her family receptors on multiple fronts for best efficacy
The Her2 vaccine I got at Penn Medicine could be loaded up with the Her3 protein too. I am going to ask Dr. Czerniecki. He told me he thought that triple negative breast cancer was really another type of her protein.
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03-11-2011, 12:18 AM
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#10
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Re: need to attack her family receptors on multiple fronts for best efficacy
shelley I think he means that quite a few triple negative bcs have elevated EGFR which is the same thing as her1
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03-11-2011, 12:31 AM
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#11
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Senior Member
Join Date: Feb 2007
Location: Paris, France
Posts: 858
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Re: need to attack her family receptors on multiple fronts for best efficacy
"She found that inhibiting HER2 with lapatinib led to an increase in HER3 expression"
Lani does this mean lapatinib could make things worse until we have a way to block HER3 at the same time?
Michka
__________________
08.2006 3 cm IDC Stage 2-3, HER2 3+ ER+90% PR 20%
FEC, Taxol+ Herceptin, Mastectomy, Radiation, Herceptin 1 year followed by Tykerb 1 year,Aromasin /Faslodex
12.2010 Mets to liver,Herceptin+Tykerb
03.2011 Liver resection ER+70% PR-
04.2011 Herceptin+Navelbine+750mg Tykerb
06.2011 Liver ned, Met to sternum. Added Zometa 09.2011 Cyberknife for sternum
11.2011 Pet clear. Stop Navelbine, continuing on Hercpetin+Tykerb+Aromasin
02.2012 Mets to lungs, nodes, liver
04.2012 TDM1, Ned in 07.2012
04.2015 Stop TDM1/Kadcyla, still Ned, liver problems
04.2016 Liver mets. Back on Kadcyla
08.2016 Kadcyla stopped working. mets to liver lungs bones
09.2016 Biopsy to liver. no more HER2, still ER+
09.2016 CMF Afinitor/Aromasin/ Xgeva.Met to eye muscle Cyberknife
01.2017 Gemzar/Carboplatin/ Ibrance/Faslodex then Taxotere
02.2017 30 micro mets to brain breathing getting worse and worse
04.2017 Liquid biopsy/CTC indicates HER2 again. Start Herceptin with Halaven
06.2017 all tumors shrunk 60% . more micro mets to brain (1mm mets) no symptoms
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03-11-2011, 09:42 PM
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#12
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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Re: need to attack her family receptors on multiple fronts for best efficacy
Quote:
Since PI3K/Akt is the key pro-survival signaling pathway downstream of HER2, the investigators also examined the utility of inhibitors of PI3K
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The pan Her approach has been floated for a while now. Makes me wonder if there is something "upstream" or underlying both her2 and her3 to inhibit.
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03-11-2011, 11:25 PM
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#13
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Re: need to attack her family receptors on multiple fronts for best efficacy
Trish--sorafinib is one of those tyrosine kinase inhibitors which are taken as pills. It is active against several angiogenic factors like VEGF (many TKIs are "promiscuous" ie, act on several targets rather than one specific target exclusively
mTor inhibitors work further down the pathway, examples are everolimus among others (two are I believe FDA approved for treating kidney cancer and for lining stents to keep blood vessels open)
Sorafinib is not an mTOr inhibitor, but rather a TKI which works against VEGFR and PDGFR and Raf kinase
Michka--yes, that means increasing her3 is one means by which a her2+ bc can evade tykerb (but not the only one). As usual cancer is a tricky thing, so it is best to block several of its means of escape
Hope this helped!
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03-11-2011, 11:29 PM
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#14
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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Re: need to attack her family receptors on multiple fronts for best efficacy
Treat the myriad downstream permutations..or block the upstream source?
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03-11-2011, 11:30 PM
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#15
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Senior Member
Join Date: May 2010
Location: Melbourne, Australia
Posts: 434
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Re: need to attack her family receptors on multiple fronts for best efficacy
As ever it has helped a lot. Thanks Lani.
Trish
__________________
5/2004 (R) 30mm bre gr3 infiltrating ductal ca 16/18nodes er (2+) pr (3+) HER2 (3+)
6/2004 6 cycles(FEC), Oct 40 rads, Tamoxifen
5/2006 oopherectomy, Arimedex
12/2006 liver mets largest 9cm
1/2007 Herceptin,
3/2007 Taxol + Herc
1/2008 Herc alone
4/2008 Multiple bone mets,Zometa
7/2008 Herc + Gemcitabine
8/2008 Herc+Navelbine/vinoralbine
10/2008 Herc+Carboplatin+Taxol
12/2008 Tykerb+Xeloda
2/2010 Herceptin + trial drug
5/2010 Herceptin+Tykerb
8/2010 Tykerb+Abraxane
9/2010 Abraxane
12/2010 Abraxane+Tyk+Herc
4/2011 Tyk+Herc+Femara
6/2011 Liver and bone mets prog.Abraxane continue Herceptin,Tykerb,Femara and Zometa
8/2011 Probable liver progression and increased neuropathy. Xeloda with Tyk+Herc. Zometa 6 weekly.
9/2011 Liver progression,TM +++. Cyclophosphamide and Methotrexate metro Herc Zometa
10/2011 liver mets prog.Herc, 3 Tykerb +2mg decodron daily,Zometa
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