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06-17-2010, 07:39 PM
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#1
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Senior Member
Join Date: Mar 2006
Posts: 4,778
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Dr. Slamon et al have done it again--found a new target in her2+ br cancers (against
which antibodies can be directed to treat those resistant to herceptin, or better still to treat with initially, combined with herceptin, to PREVENT herceptin resistance
Cancer Res. 2010 Jun 15. [Epub ahead of print]
FOXO1A Is a Target for HER2-Overexpressing Breast Tumors.
Wu Y, Shang X, Sarkissyan M, Slamon D, Vadgama JV.
Authors' Affiliations: Divisions of Cancer Research and Training and Hematology/Oncology, Department of Medicine, Charles R. Drew University of Medicine and Science; University of California at Los Angeles David Geffen School of Medicine, Los Angeles, California.
Abstract
Trastuzumab treatment has improved the overall survival of HER2-overexpressing breast cancer patients. However, many of these patients will eventually become resistant to treatment. The mechanisms that contribute to resistance to trastuzumab are unknown. In this study, we tested the hypothesis that targeting of the FKHR transcription factor FOXO1A in HER2-overexpressing breast tumor cells can overcome the trastuzumab resistance in vitro. We have shown that overexpression of HER2 leads to activation of phosphatidylinositol 3-kinase (PI3K)/Akt pathway and subsequent inactivation of FOXO1A in HER2-overexpressing breast cancer cells SKBR3, BT474, and MCF7-HER2. In wild-type SKBR3 and BT474 cells, trastuzumab downregulates active Akt and increases FOXO1A expression that leads to increase in p27(kip1) and decrease in cyclin D1 and finally inhibits cell proliferation. In contrast, the effect of trastuzumab was eliminated by the reduction of FOXO1A in HER2-overexpressing cells with constitutively active Akt1 (SKBR3/AA28 and BT474/AA9). The downregulation of FOXO1A resulted in nuclear export of p27(kip1). Blocking the constitutively active Akt by a specific Akt/protein kinase B signaling inhibitor-2 (API-2) significantly increased FOXO1A expression and rendered the cells more responsive to trastuzumab-induced growth inhibition. Reactivation of FOXO1A by stable or transient transfection also restored the growth-inhibitory effects of trastuzumab in SKBR3/AA28, BT474/AA9, and MCF7-HER2 cells. Knocking down FOXO1A by small interfering RNA resulted in reducing trastuzumab-induced growth inhibition. In summary, trastuzumab can inhibit proliferation of HER2-overexpressing breast cancer cells by reactivating FOXO1A through inhibition of the PI3K/Akt pathway. FOXO1A may therefore serve as a target for HER2-overexpressing breast tumors. Cancer Res; 70(13); OF1-11. (c)2010 AACR.
PMID: 20551062
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06-17-2010, 09:42 PM
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#2
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Senior Member
Join Date: Feb 2006
Location: Southern, CA
Posts: 2,511
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Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
Exciting news...thanks for posting this Lani.
Chelee
__________________
DX: 12-20-05 - Stage IIIA, Her2/Neu, 3+++,Er & Pr weakly positive, 5 of 16 pos nodes.
Rt. MRM on 1-3-06 -- No Rads due to compromised lungs.
Chemo started 2-7-06 -- TCH - - Finished 6-12-06
Finished yr of wkly herceptin 3-19-07
3-15-07 Lt side prophylactic simple mastectomy. -- Ooph 4-05-07
9-21-09 PET/CT "Recurrence" to Rt. axllia, Rt. femur, ilium. Possible Sacrum & liver? Now stage IV.
9-28-09 Loading dose of Herceptin & started Zometa
9-29-09 Power Port Placement
10-24-09 Mass 6.4 x 4.7 cm on Rt. femur head.
11-19-09 RT. Femur surgery - Rod placed
12-7-09 Navelbine added to Herceptin/Zometa.
3-23-10 Ten days of rads to RT femur. Completed.
4-05-10 Quit Navelbine--Herceptin/Zometa alone.
5-4-10 Appt. with Dr. Slamon to see what is next? Waiting on FISH results from femur biopsy.
Results to FISH was unsuccessful--this happens less then 2% of the time.
7-7-10 Recurrence to RT axilla again. Back to UCLA for options.
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06-18-2010, 08:33 AM
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#3
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Senior Member
Join Date: Oct 2005
Location: New Jersey
Posts: 3,154
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Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
God has blessed us with researchers like Dr. Slamon who is always searching for the answers.
This is very promising..
each day we get a little bit closer.
Jean
__________________
Stage 1, Grade 1, 3/30/05
Lumpectomy 4/15/05 - 6MM IDC
Node Neg. (Sentinel node)
ER+ 90% / PR-, Her2+++ by FISH
Ki-67 40%
Arimidex 5/05
Radiation 32 trt, 5/30/05
Oncotype DX test 4/17/06, 31% high risk
TOPO 11 neg. 4/06
Stopped Arimidex 5/06
TCH 5/06, 6 treatments
Herceptin 5/06 - for 1 yr.
9/06 Completed chemo
Started Femara Sept. 2006
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06-18-2010, 09:35 AM
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#4
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Senior Member
Join Date: Aug 2008
Location: San Francisco
Posts: 260
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Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
Not that I could understand much of the report, but I'm thinking this is very good news. Thanks for posting Lani and keep at it Slamon and Co. And hurry please!
__________________
4/17/08: Dx Stage IV at age 30 - extensive mets to liver, lungs, and bones. Er/Pr-, Her2+++
April 08-Aug 08:Taxotere, Cytoxan, Herceptin, Zometa - complete response!
Sept 08-Dec 08: Herceptin +Zometa for maintenance.
Jan 09-April 09: Brain mets. Add Tykerb. Watch and wait.
April 09: Gamma Knife 10 brain mets, add Xeloda.
Sept 09: Gamma Knife to 1 brain met.
Nov 09- April 10: Lung progression, add Gemzar to Herceptin, Zometa.
May 10- Sept 10: HER2 Vaccine Trial
Sept 10: Add Tykerb for more brain mets.
Oct 10: Gamma Knife to 7 brain mets.
Dec 10: Switch from Zometa to Denosumab.
Jan 11: Gamma Knife to 3 brain mets.
March 11: Gemzar/Herceptin for lung/bone progression.
April 11: More brain mets - Intrathecal Herceptin
June 11: Ixempra/Herceptin for lung, soft tissue progression.
Aug 11: Gamma Knife
Sep 11: Abraxane/Herceptin
Future: NED
Send me a PM if you'd like to follow my journey on Caringbridge.
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06-18-2010, 12:24 PM
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#5
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Senior Member
Join Date: Feb 2008
Location: South East Wisconsin
Posts: 3,431
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Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
"trastuzumab can inhibit proliferation of HER2-overexpressing breast cancer cells by reactivating FOXO1A through inhibition of the PI3K/Akt pathway."
Good thing there are currently available ways to inhibit PI3k/Akt:
Zoledronate Acid (Zometa)
Tamoxifen
Green Tea
IP6
Honokiol
Apigenin
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06-18-2010, 11:09 PM
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#6
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Senior Member
Join Date: Apr 2007
Location: LA LA Land
Posts: 1,607
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Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
"In this study, we tested the hypothesis that targeting of the FKHR transcription factor..."
Well if I've said once I've said a thousand times, we should kill those little FKHRs.
LANI - Great post, and Rich, thanks for the list of PI3k etc inhibitors.
Flori
__________________
1996 cancer WTF?! 1.3 cm lumpectomy Er/Pr neg. Her2+ (20nodes NEGATIVE) did CMF + rads. NED.
2002 recurrence. Bilateral mastectomy w/TFL autologous recon. Then ACx2. Skin lymphatic rash. Taxotere w/Herceptin x4. Herceptin/Xeloda. Finally stops spreading.
2003 - Back to surgery, remove skin mets, and will have surgery one week later when pathology can confirm margins.
‘03 latisimus dorsi flap to remove skin mets. CLEAN MARGINS. Continue single agent Herceptin thru 4/04. NED.
‘04 '05 & 06 tiny recurrences - scar line. surgery to cut out. NED each time.
1/2006 Rads again, to scar line. NED.
3/07 Heartbreaking news - mets! lungs.sternum. Try Tykerb/Xeloda. Tykerb/Carbo/Gemzar. Switch Oncs.
12/07 Herceptin.Tykerb. Markers go stable.
2/8/08 gamma knife 13mm stupid brain met.
3/08 Herceptin/tykerb/avastin/zometa.
3/09 brain NED. Lungs STABLE.
4/09 attack sternum (10 daysPHOTONS.5 days ELECTRONS)
9/09 MARKERS normal!
3/10 PET/CT=manubrium intensely metabolically active but stable. NEDhead.
Wash out 5/10 for tdm1 but 6/10 CT STABLE, PET improving. Markers normal. Brain NED. Resume just Herceptin plus ZOMETA
Dec 2010 Brain NED, lungs/sternum stable. markers normal.
MAR 2011 stop Herceptin/allergy! Go back on Tykerb and switch to Xgeva.
May-Aug 2011 Tykerb Herceptin Xgeva.
Sept 2011 Tykerb, Herceptin, Zometa, Avastin.
April 2012 sketchy drug trial in NYC. 6 weeks later I’m NED!
OCT 2012 PET/CT shows a bunch of freakin’ progression. Back to LA and Herceptin.avastin.zometa.
12/20/12 add in PERJETA!
March 2013 – 5 YEARS POST continue HAPZ
APRIL 2013 - 6 yrs stage 4. "FAILED" PETscan on 4/2/13
May 2013: rePetted - improvement in lungs, left adrenal stable, right 6th rib inactive, (must be PERJETA avastin) sternum and L1 fruckin'worsen. Drop zometa. ADD Xgeva. Doc says get rads consultant for L1 and possible biopsy of L1. I say, no thanks, doc. Lets see what xgeva brings to the table first. It's summer.
June-August 2013HAPX Herceptin Avastin Perjeta xgeva.
Sept - now - on chemo hold for calming tummy we hope. Markers stable for 2 months.
Nov 2013 - Herceptin-Perjeta-Avastin-Xgeva (collageneous colitis, which explains tummy probs, added Entocort)
December '13 BRAIN MRI ned in da head.
Jan 2014: CONTINUING on HAPX…
FEB 2014 PetCT clinical “impression”: 1. newbie nodule - SUV 1.5 right apical nodule, mildly hypermetabolic “suggestive” of worsening neoplastic lesion. 2. moderate worsening of the sternum – SUV 5.6 from 3.8
3. increasing sclerosis & decreasing activity of L1 met “suggests” mild healing. (SUV 9.4 v 12.1 in May ‘13)
4. scattered lung nodules, up to 5mm in size = stable, no increased activity
5. other small scattered sclerotic lesions, one in right iliac and one in thoracic vertebral body similar in appearance to L1 without PET activity and not clearly pathologic
APRIL 2014 - 6 YRS POST GAMMA ZAP, 7 YRS MBC & 18 YEARS FROM ORIGINAL DX!
October 2014: hold avastin, continue HPX
Feb 2015 Cancer you lost. NEDHEAD 7 years post gamma zap miracle, 8 years ST4, +19 yrs original diagnosis.
Continue HPX. Adding back Avastin
Nov 2015 pet/ct is mixed result. L1 SUV is worse. Continue Herceptin/avastin/xgeva. Might revisit Perjeta for L1. Meantime going for rads consult for L1
December 2015 - brain stable. Continue Herceptin, Perjeta, Avastin and xgeva.
Jan 2016: 5 days, 20 grays, Rads to L1 and continue on HAPX. I’m trying to "save" TDM1 for next line. Hope the rads work to quiet L1. Sciatic pain extraordinaire :((
Markers drop post rads.
2/24/16 HAP plus X - markers are down
SCIATIC PAIN DEAL BREAKER.
3/23/16 Laminectomy w/coflex implant L4/5. NO MORE SCIATIC PAIN!!! Healing.
APRIL 2016 - 9 YRS MBC
July 2016 - continue HAP plus Xgeva.
DEC 2016 - PETCT: mets to sternum, lungs, L1 still about the same in size and PET activity. Markers not bad. Not making changes if I don't need to. Herceptin/Perjeta/Avastin/Xgeva
APRIL 2017 10 YEARS MBC
December 2017 - Progression - gonna switch it up
FEB 2018 - Kadcyla 3 cycles ---->progression :(
MAY30th - bronchoscopy, w/foundation1 - her2 enriched
Aug 27, 2018 - start clinical trial ZW25
JAN 2019 - ZW25 seems to be keeping me stable
APRIL 2019 - ONE DOZEN YEARS LIVING METASTATIC
MAY 2019 - progression back on herceptin add xeloda
JUNE 2019 - "6 mos average survival" LMD & CNS new single brain met - one zap during 5 days true beam SBRT to cord met
10/30/19 - stable brain and cord. progression lungs and bones. washing out. applying for ds8201a w nivolumab. hope they take me.
12/27/19 - begin ds8401a w nivolumab. after 2nd cycle nodes melt away. after 3rd cycle chest scan shows Improvement, brain MRI shows improvement, resolved areas & nothing new. switch to plain ENHERTU. after 4th cycle, PETscan shows mostly resolved or improved results. Markers near normal. I'm stunned but grateful.
10/26/20 - June 2021 Tucatinib/xeloda/herceptin - stable ish.
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06-19-2010, 08:57 PM
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#7
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Senior Member
Join Date: Apr 2008
Posts: 1,477
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Re: Dr. Slamon et al have done it again--found a new target in her2+ br cancers (agai
Lani,
Thanks for posting!
karen
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