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12-05-2009, 09:26 AM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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another way to improve effects of herceptin by dual(triple) targetting
Int J Cancer. 2009 Dec 3. [Epub ahead of print]
Targeting endothelin A receptor enhances anti-proliferative and anti-invasive effects of the HER2 antibody trastuzumab in HER2-overexpressing breast cancer cells.
Fischgräbe J, Götte M, Michels K, Kiesel L, Wülfing P.
Department of Obstetrics and Gynecology, University of Münster, Albert-Schweitzer-Str. 33, 48149 Münster/Germany.
Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in human breast cancers. It is known to drive tumor growth and progression and represents a prominent target in breast cancer therapy. The endothelin (ET) system, in particular ET-1 and its receptor ET(A)R, is of major relevance for breast cancer growth and invasion. Having previously demonstrated coexpression of ET(A)R and HER2 in breast tumors, this study was designed to investigate molecular interactions of HER2 (including the epidermal growth factor receptor EGFR as its major coreceptor) and ET signaling, and the potential benefit of a combined anti-HER2/ET(A)R treatment in human breast cancer cells. Dual HER2-ET(A)R targeting utilizing trastuzumab (monoclonal anti-HER2 antibody) and the ET(A)R antagonist atrasentan was superior to each agent alone in inhibiting basal and EGF-induced proliferation and invasion of HER2-overexpressing BT-474 and SK-BR-3 cells. EGF-induced invasion was partially inhibited by atrasentan alone, suggesting the involvement of ET(A)R in EGF receptor mediated invasion of breast cancer cells. Moreover, secretion of the pro-invasive ET-1 was shown to be induced by EGF via EGFR and HER2, including MAPK-dependent signaling. In turn, an ET-1/ET(A)R-dependent regulation of EGFR protein expression and phosphorylation (at Tyr845) was observed, which may contribute to the additional anti-proliferative and anti-invasive effects of atrasentan on trastuzumab treated cells; reconfirming, atrasentan failed to enhance inhibitory effects of EGFR-targeted agents. This study suggests complex interactions between HER2/EGFR and ET pathways in breast cancer and supports the hypothesis that dual HER2-ET(A)R targeting may represent a highly effective approach in breast cancer treatment. (c) 2009 UICC.
PMID: 19960438
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12-05-2009, 11:43 AM
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#2
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Member
Join Date: Feb 2009
Posts: 23
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Re: another way to improve effects of herceptin by dual(triple) targetting
Lani ~ you always post similar study findings and I want to thank you very much. I consider myself a smart woman but I just do not understand what this all means. Would you convert this to a lay person language?
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12-05-2009, 12:48 PM
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#3
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Re: another way to improve effects of herceptin by dual(triple) targetting
cancer is like a puppy dog that likes to go out into the yard and chase squirrels--if you lock the front door, it tries to go out the back, and if you block that it looks for another escape.
Blocking her2 causes those cancer cells with the possibility (those already with the genes turned on or those which can change so that the genes get turned on) to outcompete the rest and grow, escape and metastasize further.
It turns out this ETA is another pathway shared in her2+ breast cancers which her2 cancers often use to escape the blocking of her2. By blocking both simultaneously, you make it that much harder for it to escape the treatment.
Since ETA blocking seems to also keep EGF(R) from also being used as an escape route, it is triple blocking. Many cancer researchers feel triple targetted therapy will be the most successful targeted therapy of the future.
EGFR is also known as her1 and is a frequent partner in crime of her2--her2 rarely acts alone to have its effects.
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12-05-2009, 12:51 PM
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#4
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Re: another way to improve effects of herceptin by dual(triple) targetting
hint--read the last sentence first, and then try to work your way through the abstract. Look at the non-medical words and make a sentence of them. Then fill in a non-scary word such as ice cream, chocolate or cherries. It make the reading seem easier, and hopefully won't add pounds!
Chocolate is frequently overexpressed in human breast cancers. It is known to drive tumor growth and progression and represents a prominent target in breast cancer therapy. The ice cream system, in particular ET-1 and its receptor ET(A)R, is of major relevance for breast cancer growth and invasion. Having previously demonstrated coexpression of ice cream and chocolate in breast tumors, this study was designed to investigate molecular interactions of chocolate(including white chocolate as its major coreceptor) and ice cream signaling, and the potential benefit of a combined anti-chocolate/ice cream treatment in human breast cancer cells. Dual chocolat/ice cream targeting utilizing trastuzumab (monoclonal anti-HER2 antibody) and the ET(A)R antagonist atrasentan was superior to each agent alone in inhibiting basal and EGF-induced proliferation and invasion of chocolate overexpressing BT-474(her2+ER+) and SK-BR-3 (her2+ER_)cells. EGF-induced invasion was partially inhibited by atrasentan alone, suggesting the involvement of ice cream in ice cream receptor mediated invasion of breast cancer cells. Moreover, secretion of the pro-invasive ice cream was shown to be induced by white chocolate via white chocolate receptor and chocolate, including MAPK-dependent signaling. In turn, ice cream-dependent regulation of white chocolate protein expression and phosphorylation (at Tyr845) was observed, which may contribute to the additional anti-proliferative and anti-invasive effects of atrasentan on trastuzumab treated cells; reconfirming, atrasentan failed to enhance inhibitory effects of white chocolate-targeted agents. This study suggests complex interactions between chocolate/white chocolate and ice cream pathways in breast cancer and supports the hypothesis that dual chocolate-ice cream targeting may represent a highly effective approach in breast cancer treatment. (c) 2009 UICC.
Now wasn't that easier?
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12-05-2009, 02:14 PM
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#5
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Senior Member
Join Date: Nov 2005
Location: Ireland
Posts: 3,463
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Re: another way to improve effects of herceptin by dual(triple) targetting
Lol, thanks Lani and it's more fun trying to understand it this way
I also read all the info you post but at times do have problems understanding it all so thanks Diane...glad I'm not the only one!
__________________
Tricia
Dx July '05 IDC 1.9cm Triple positive 3/9 nodes positive
A/C X 4 ..Taxol/Herceptin x 12 wks then herceptin 1 yr
Rads x 36 ..oophorectomy August '06
Currently taking Arimidex..
June 2011 osteopenia/ zometa x1 yearly- stopped Zometa 2015 as Dexa show normal bone density.
Stopped Arimidex July 2014- Restarted Arimidex 2015 for a further two years on the advice of my Onc.
2014 Normal Dexa scan
2018 Mammo all clear, still NED!
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12-05-2009, 04:21 PM
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#6
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Senior Member
Join Date: Sep 2005
Location: Central Coast, CA
Posts: 3,207
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Re: another way to improve effects of herceptin by dual(triple) targetting
lani,
bravo!
very tasty...
__________________
Chris in Scotts Valley
June 2002 extensive hi grade DCIS (pre-cancer-stage 0, clean sentinal node) Mastectomy/implant - no chemo, rads. "cured?"
9/2004 Diag: Stage IV extensive liver mets (!) ER/PR- Her2+++
10/04-3/05 Weekly Taxol/Carboplatin/Herceptin , complete response!
04/05 - 4/07 Herception every 3 wks, Continue NED
04/07 - recurrence to liver - 2 spots, starting tykerb/avastin trial
06/07 8/07 10/07 Scans show stable, continue on Tykerb/Avastin
01/08 Progression in liver
02/08 Begin (TDM1) trial
08/08 NED! It's Working! Continue on TDM1
02/09 Continue NED
02/10 Continue NED. 5/10 9/10 Scans NED 10/10 Scans NED
12/10 Scans not clear....4/11 Scans suggest progression 6/11 progression confirmed in liver
07/11 - 11/11 Herceptin/Xeloda -not working:(
12/11 Begin MM302 Phase I trial - bust:(
03/12 3rd times the charm? AKT trial
5/12 Scan shows reduction! 7/12 More reduction!!!!
8/12 Whoops...progression...trying for Perjeta/Herceptin (plus some more nasty chemo!)
9/12 Start Perjeta/Herceptin, chemo on hold due to infection/wound in leg, added on cycle 2 &3
11/12 Poops! progression in liver, Stop Perjeta/Taxo/Herc
11/12 Navelbine/Herce[ptin - try for a 3 cycles, no go.
2/13 Gemzar/Carbo/Herceptin - no go.
3/13 TACE procedure
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12-05-2009, 09:03 PM
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#7
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Member
Join Date: Feb 2009
Posts: 23
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Re: another way to improve effects of herceptin by dual(triple) targetting
thanks Lani!!! Ice cream is SO much better!
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12-05-2009, 09:45 PM
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#8
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Senior Member
Join Date: Sep 2008
Location: Eugene, Oregon
Posts: 347
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Re: another way to improve effects of herceptin by dual(triple) targetting
Now your speakin our language! Good tactic.
__________________
"Dancers Against Cancer" in the Eugene, OR Komen Race for the Cure 2010
Diagnosed 8/7/08 with stage 3 invasive ductal carcinoma, micropapillary pattern, Her2 3+, ER+,PR-, grade II, positive lymph nodes.
Received 6doses of Taxotere, Carboplatin with Herceptin continuing for a year...DONE.
1/28/09 Left Modified Radical Mastectomy, Right Simple Mastectomy.
Surgery pathology: No invasive carcinoma present and 17 lymph nodes removed all negative! Only small amount of carcinoma in situ in left breast.
March/April '09, Radiation to left chest wall.
Currently involved in Neratinib clinical trial.
"Well being I won
and wisdom too,
I grew and joyed in my growth;
from a word to a word
I was led to a word
from a deed to another deed." (Odin)
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