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Old 06-08-2015, 09:46 AM   #1
Lani
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Lightbulb another door to shut to keep the "puppy" from escaping to the yard to chase squirrels

Sci Signal. 2015 May 26;8(378):ra52. doi: 10.1126/scisignal.aaa6922.
HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive
.
Singh N1, Joshi R1, Komurov K2.

Abstract
Targeting non-oncogenic vulnerabilities may provide additional therapeutic approaches in tumors that are resistant to oncogene-targeted therapy. Using a computational pathway-based approach, we interrogated clinical breast cancer genomic data sets for candidate non-oncogenic vulnerabilities in breast cancers that have genomic amplification of ERBB2, which encodes human epidermal growth factor 2 (HER2). HER2-positive (HER2(+)) breast cancers showed increased expression of genes encoding proteins in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Genetic ablation or pharmacological inhibition of ERAD led to irrecoverable ER stress and selectively killed HER2(+) breast cancer cells. Cell death caused by ERAD inhibition partially depended on increased HER2-mTOR signaling, which imposed an increased proteotoxic burden on the ER. Cell death in response to ER stress required the IRE1α-JNK pathway, which was selectively suppressed in HER2(+) breast cancers by phosphatases that inactivate JNK. Accordingly, the cytotoxicity of inhibiting ERAD as well as JNK phosphatases was synergistic in HER2(+) but not in HER2-negative breast cancer cells. Therefore, our study suggests that reactivation of oncogene-induced stress by targeting stress-adaptive pathways may be a beneficial approach for therapy-resistant breast cancers.
Copyright 2015, American Association for the Advancement of Science.
PMID: 26012635 [PubMed - in process]
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Old 06-09-2015, 12:38 PM   #2
Mtngrl
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Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir

As I soldier on from one drug combo to the next--and stay alive--I keep waiting and hoping for a new idea, a new pathway, a new "knockout punch" for the HER2. Where there's life there's hope, and I'm glad to be alive.

Thank you, Lani, for keeping us advised of new research.
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4/19/11 Diagnosed invasive ductal carcinoma in left breast; 2.3 cm tumor, 1 axillary lymph node, weakly ER+, HER2+++
4/29/11 CT scan shows suspicious lesions on liver and lungs
5/17/11 liver biopsy
5/24/11 liver met confirmed--Stage IV at diagnosis
5/27/11 Begin weekly Taxol & Herceptin for 3 months (standard of care at the time of my DX)
7/18/11 Switch to weekly Abraxane & Herceptin due to Taxol allergy
8/29/11 CT scan shows no new lesions & old lesions shrinking
9/27/11 Finish Abraxane. Start Herceptin every 3 weeks. Begin taking Arimidex
10/17/11--Brain MRI--No Brain mets
12/5/11 PET scan--Almost NED
5/15/12 PET scan shows progression-breast/chest/spine (one vertebra)
5/22/12 Stop taking Arimidex; stay on Herceptin
6/11/12 Started Tykerb and Herceptin on clinical trial (w/no chemo)
9/24/12 CT scan--No new mets. Everything stable.
3/11/13 CT Scan--two small new possible mets and odd looking area in left lung getting larger.
4/2/13--Biopsy of suspicious area in lower left lung. Mets to lung confirmed.
4/30/13 Begin Kadcyla/TDM-1
8/16/13 PET scan "mixed," with some areas of increased uptake, but also some definite improvement, so I'll stay on TDM-1/Kadcyla.
11/11/13 Finally get hormone receptor results from lung biopsy of 4/2/13. My cancer is no longer ER positive.
11/13/13 PET scan mixed results again. We're calling it "stable." Problems breathing on exertion.
2/18/14 PET scan shows a new lesion and newly active lymph node in chest, other progression. Bye bye TDM-1.
2/28/14 Begin Herceptin/Perjeta every 3 weeks.
6/8/14 PET "mixed," with no new lesions, and everything but lower lungs improving. My breathing is better.
8/18/14 PET "mixed" again. Upper lungs & one spine met stable, lower lungs less FDG avid, original tumor more avid, one lymph node in mediastinum more avid.
9/1/14 Begin taking Xeloda one week on, one week off. Will also stay on Herceptin and Perjeta every three weeks.
12/11/14 PET Scan--no new lesions, and everything looks better than it did.
3/20/15 PET Scan--no new lesions, but lower lung lesions larger and a bit more avid.
4/13/15 Increasing Xeloda dose to 10 days on, one week off.
7/1/15 Scan "mixed" again, but suggests continuing progression. Stop Xeloda. Substitute Abraxane every 3 weeks starting 7/13.
10/28/15 PET scan shows dramatic improvement everywhere. All lesions except lower lungs have resolved; lower lungs noticeably improved.
12/18/15 Last Abraxane. Continue on Herceptin and Perjeta alone beginning 1/8/16.
1/27/16 PET scan shows cancer is stable.
5/11/16 PET scan shows uptake in some areas that were resolved on the last two scans.
6/3/16 Begin Kadcyla and Tykerb combination
6/5 - 6/23 Horrible diarrhea from K&T together. Got pneumonia.
7/15/16 Begin Kadcyla only every 3 weeks.
9/6/16 Begin radiation therapy on right lung lesion that caused the pneumonia.
10/3/16 Last of 12 radiation treatments to right lung.
11/4/16 Huffing and puffing, low O2, high heart rate, on tiniest bit of exertion. Diagnosed as radiation pneumonitis. Treated with Prednisone.
11/11/16 PET scan shows significant improvement to radiated part of right lung BUT a bunch of new lung lesions, and the bone met is getting worse.
11/22/16 Begin Eribulin and Herceptin. H every 3 weeks. E two weeks on, one week off.
3/6/17 Scan shows progression in lungs. Bone met a little better.
3/23/17 Lung biopsy. Tumor sampled is ER-, PR+ (5%), HER2+++. Getting Herceptin and Perjeta as a maintenance treatment.
5/31/17 Port placement
6/1/17 Start Navelbine & Tykerb
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Old 06-12-2015, 10:16 PM   #3
linn65
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Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir

Layman's Terms please.......what is the door we need to shut to keep the puppies from chasing those squirrels.
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IDC breast cancer
7/2012 diagnosed with multiple solid lesions
7/20/12 biopsy done. ER+ 30 PR -, HER+++,k167 80% Grade 2
9/2012 biopsy on lymph node - showed malignant

9/2012 Pre-adjunctive TCH chemo.

12/6/12 MRI after Pre-adj.
Results: Modest Decrease in size of left breast malignancy As well as the associated satellite lesions and auxiliary Adenopathy compared to prior study. Doctors hoped for better but good response it didn't grow.

12/18/2012 left masectomy with axillary nodes
Size 3.2 CM, Nottingham score 9/9
Grade 3, no evidence of in situ carcinoma
Areas of angiolymphatic are identified
Carcinoma is 0.5 cm from inked deep
Margin of excision
Attached axillary lymph nodes: metastatic
Carcinoma in 6 of 8 nodes.
Size of largest node 1.5 cm
Extracapsular
ER + 73%, PR+2%, HER2+

2/27/13 6 weeks of IMRT radiation finished

2/2013 Started on Tamoxifan 5 years.

8/2013 will take last Herceptin, 17 treatments total every 3 weeks.

BRCA1 & BRAC2 - Negative

August 28, 2013 DIEP flap on the left breast.
February 2014 Nip & Tuck
March 14, 2014 nipple reconstruction and removed port.
August 14, 2014 lump in lymph nodes under arm and above clavicle. Stage IV
August 28, 2014 herceptin And projeta starting and port put back in.

3/18/15 stopped arimidex.
3/18/15 progression....Tdm1
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Old 06-13-2015, 03:44 AM   #4
Lani
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Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir

linne, I truly thought those WERE layman's terms.

(((my "puppy" analogy posted previously:
Cancer is like a puppy dog that wants to get out of the house to chase the squirrels. Herceptin is like locking the front door. They puppy may learn it is possible to get out to play with the squirrels by going out the backdoor instead (eg, using her3, EGFR, IGFR, ER, etc paths to escape the blockade of the her2 pathway). Giving chemo is often like accelerating the aging of the puppy. It gets taller and able to jump on the dresser and jump out the window!!

For Stage IVs, it is usually just a question of what they will add next to herceptin if monotherapy is inssufficient to keep it from progressing(like which window/door to close in addition in the case of the puppy) )))

The long words in the abstract describing the ERAD PATHWAY merely describe another window
that needs to be closed to prevent the puppy from escaping to the backyard to wreak havoc chasing the squirrels ie, preventatively blockingia another possible escape route cancer tries to take.Cancer consistently tries to adapt (evolution in real-time) to escape considering previously blocked routes of escape as its goal of relentless growth and migration is not easily thwarted.

GOOD ENOUGH?
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Old 06-13-2015, 10:58 AM   #5
Mtngrl
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Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir

Lani--

I love your puppy and squirrels analogies. And, again, thanks for posting results of emergent research and wisdom.

Love,
Amy
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Old 10-03-2015, 09:24 PM   #6
norkdo
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Re: another door to shut to keep the "puppy" from escaping to the yard to chase squir

Lani! Brilliant analogy! Works for me! Thank yu so much for your tireless work. Thank you very much!
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fall 2008: mammo of rt breast worrisome so am asked to redo mammo and have ultrasound of rt breast.I delay it til january 2009 and the results are "no cancer in rt breast. phew."
found plum sized lump in right breast the day before my dad died: April 17th 2011. saw it in mirror, while i was wearing a top, examining my figure after losing 10 lbs on dr. bernstein diet.
diagnosed may 10 2011

mast/lymphectomy: june 7 2011, 5/20 cancerous nodes. stage 3a before radiation oncologist during our first mtg on july 15th says he found cancer on the lymph node of my breast bone. Now stage 3b.
her2+++, EN-, PN-. Rt brst tumors:3 at onset, 4.5 cm was the big one
chemos: 3fec's followed by 3 taxotere, total of 18 wks chemo. sept: halfway thru chemo the mastectomy scar decides to open and ooze pus. (not healed before chemo) eventually with canasten powder sent by friend in ny (illegal in canada) it heals.
radiations:although scheduled to begin 25 january 2012, I am so terrified by it (rads cause other cancers) I don't start til february, miss a bunch, reschedule them all and finally finish 35 rads mid april. reason for 7 extra atop the 28 scheduled is that when i first met my rads oncologist he said he saw a tumor on the lymph node of my breastbone. extra 7 are special kind of beam used for that lymphnode. rads onc tells me nobody ever took so long to do rads so he cannot speak for effectiveness. trials had been done only on consecutive days so......we'll see.....
10 mos of herceptin started 6 wks into chemo. canadian onc says 10 mos is just as effective as the full yr recommended by dr. slamon......so we'll see..completed july 2012.
Sept 18 2012: reconstruction and 3 drains. fails. i wear antibiotic pouch on my job for two months and have 60 consecutive days visiting a nursing centre where they apply burn victims' silver paper and clean the oozing infection daily. silicone leaks out daily. plastic surgeon in caribbean. emergency dept wont remove "his" work. He finally appears and orders me in into an emergency removal of implant. I make him promise no drains and I get my way. No infection as a result. Chest looks like a map of Brazil. Had a perfectly good left breast on Sept 17th but surgeon wanted to "save another woman an operation" ? so he had crashed two operations together on my left breast, foregoing the intermediary operation where you install an expander. the first surgeon a year earlier had flat out refused to waste five hours on his feet taking both boobs. flat out refusal. between the canadian health system saving money and both these asses, I got screwed. who knows when i can next get enough time off work (i work for myself and have no substitute when my husband is on contract) to get boobs again. arrrgh.


I have a blog where I document this trip and vent.
www.nora'scancerblog.blogspot.com . I stopped the blog before radiation. I think the steroids made me more angry and depressed and i just hated reading it anymore
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