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Old 03-14-2017, 09:01 AM   #1
Cathya
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Location: Ontario, Canada
Posts: 752
Diabetes medication could be effective therapy for aggressive type of breast cancer

Diabetes medication could be effective therapy for aggressive type of breast cancer

March 7, 2017 at 11:43 AM
Researchers in China have discovered that a metabolic enzyme called AKR1B1 drives an aggressive type of breast cancer. The study, "AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program," which has been published in The Journal of Experimental Medicine, suggests that an inhibitor of this enzyme currently used to treat diabetes patients could be an effective therapy for this frequently deadly form of cancer.

Around 15-20% of breast cancers are classified as "basal-like." This form of the disease, which generally falls into the triple-negative breast cancer subtype, is particularly aggressive, with early recurrence after treatment and a tendency to quickly spread, or metastasize, to the brain and lungs. There are currently no effective targeted therapies to this form of breast cancer, which is therefore often fatal.

Crucial to basal-like breast cancer's aggressiveness is a process called epithelial-mesenchymal transition (EMT), in which the cancer cells become more motile and acquire stem cell-like properties that allow them to resist treatment and initiate tumor growth in other tissues.

Chenfang Dong and colleagues at the Zhejiang University School of Medicine in Hangzhou, China, found that the levels of a metabolic enzyme called AKR1B1 were significantly elevated in basal-like and triple-negative breast cancers and that this was associated with increased rates of metastasis and shorter survival times.

The researchers discovered that AKR1B1 expression was induced by Twist2, a cellular transcription factor known to play a central role in EMT. AKR1B1, in turn, elevated Twist2 levels by producing a lipid called prostaglandin F2 that activates the NF-B signaling pathway. This "feedback loop" was crucial for basal-like cancer cells to undergo EMT; reducing AKR1B1 levels impaired the cells' ability to migrate and give rise to cancer stem cells.

Knocking down AKR1B1 also inhibited the growth and metastasis of tumors formed by human basal-like breast cancer cells injected into mice. "Our data clearly suggests that AKR1B1 overexpression represents an oncogenic event that is responsible for the aggressive behaviors of basal-like breast cancer cells," Dong explains.

Moreover, epalrestat, a drug that inhibits AKR1B1 and is approved in Japan to treat peripheral neuropathies associated with diabetes, was similarly able to block the growth and metastasis of human basal-like breast cancer cells. "Since epalrestat is already on the market and has no major adverse side effects, our study provides a proof of principle that it could become a valuable targeted drug for the clinical treatment of basal-like breast cancer," Dong says.

Source:
Rockefeller University Press
__________________
Cathy

Diagnosed Oct. 2004 3 cm ductal, lumpectomy Nov. 2004
Diagnosed Jan. 2005 tumor in supraclavicular node
Stage 3c, Grade 3, ER/PR+, Her2++
4 AC, 4 Taxol, Radiation, Arimidex, Actonel
Herceptin for 9 months until Muga dropped and heart enlarged
Restarting herceptin weekly after 4 months off
Stopped herceptin after four weekly treatments....score dropped to 41
Finished 6 years Arimidex
May 2015 diagnosed with ovarian cancer
Stage 1C
started 6 treatments of carboplatin/taxol
Genetic testing show BRCA1 VUS
Nice! My hair came back really curly. Hope it lasts lol. Well it didn't but I liked it so I'm now a perm lady
29 March 2018 Lung biopsy following chest CT showing tumours in pleura of left lung, waiting for results to the question bc or ovarian
April 20, 2018 BC mets confirmed, ER/PR+ now Her2-
Questions about the possibility of ovarian spread and mets to bones so will be tested and monitored for these.
To begin new drug Palbociclib (Ibrance) along with Letrozole May, 2018.
Genetic testing of ovarian tumour and this new lung met will take months.
To see geneticist to be retested for BRCA this week....still BRCA VUS
CA125 has declined from 359 to 12 as of Aug.23/18


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Old 03-14-2017, 01:06 PM   #2
donocco
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Join Date: Oct 2013
Posts: 474
Re: Diabetes medication could be effective therapy for aggressive type of breast canc

I looked up the drug and got a bit of info. Epalrestat as far as diabetes goes is not a blood
sugar lowering drug. It is an Aldose reductase inhibitor and this class of drugs inhibits the production of Sorbitol a type of sugar. Sorbitol is important in the development of the Diabetic nerve complications. I think the dose is 150mg daily.I dont know if other anti-sorbitol drugs have an anti-breast cancer effect. Im not sure any anti-sorbitol drugs are FDA approved. Lipoic Acid has been used in europe to treat diabetic retinopathy. Ill check to see if Lipoic Acid has any action against AKR1b1.

Paul
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Old 03-15-2017, 05:30 AM   #3
TiffanyS
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Join Date: Sep 2016
Posts: 459
Re: Diabetes medication could be effective therapy for aggressive type of breast canc

Interesting read Cathy. Thanks for posting.

¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬ ¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬
12/15 – First mammogram
01/16 – Second mammogram and ultrasound.
01/16 – Meet surgeon and go for third mammogram, second ultrasound and biopsy. Surgeon confirms cancer in left breast and lymph nodes and sets surgery date.
01/16 – Chest scan and bone scan done– all looks good.
02/16 – Surgery - left breast mastectomy and 16 lymph nodes removed (8 had cancer).
02/16 – CT scan done – small nodules on lung but Doctor advises it’s post surgical. They will continue to monitor just in case.
03/16 – Meet radiation oncologist and find out results of Pathology Report. I’m told that I have locally advanced breast cancer, based on the size of my tumour (7 cm!) and the fact that they found cancer cells in eight lymph nodes. I’m also told that I’m HER 2 positive, with high levels of estrogen and progesterone and that my cancer is stage 3, grade 2.
03/16 – Meet oncologist and am told that my cancer is actually grade 3, and that I should have done chemo before surgery. Too late now!
03/16 – Start first of six doses of chemo (Carboplatin and Docetaxal) and Herceptin (for 18 months).
04/16 – Have port put in.
04/16 – Get second dose of chemo, but Docetaxal is left out due to liver enzymes being high. I was unable to get a full dose of Docetaxal after my first treatment.
06/16 – Finished chemo! One month off and then I start radiation.
06/16 – Start Tamoxifen.
07/16 – First radiation treatment – 24 more to go!
08/16 – Went for Genetic Testing to see if I have the BRCA gene. Tested negative for BRCA I and II
08/16 – Radiation oncologist biopsies “scar tissue” on my chest wall. I am told that I have a local recurrence and need to have rush surgery.
09/16 – Meet surgeon who advises that I need to meet with a plastic surgeon, as they will need to do a skin graft to close me up after surgery. Meet plastic surgeon and all looks good. A surgery date is set for October 4.
09/16 – Go for rush ultrasound, bone scan, breast MRI and CT scan.
09/16 – Meet oncologist who advises that the ultrasound and bone scan results look good, and that MRI shows three small masses at surgery site, but lymph nodes are clear. Still awaiting the results of the CT scan, but we are positive it will look good.
09/16 – Get a call from my oncologist, who advises that CT scan shows small spots on my lungs, and a large lymph node in the middle of my chest. This means the cancer has spread! She looks into getting me funded for TDM-1 and cancels my surgery.
10/16 – Meet oncologist, who advises that I have to take Perjeta before I can take TDM1. I start Perjeta/Herceptin every three weeks for an indefinite amount of time, and Taxol, which I will take two weeks in a row with one week off and then two weeks in a row for 8-16 treatments. Stop Tamoxifen.
10/16 – Meet surgeon, who reviews my CT scan and advises that the spots on my lungs may not be cancer, and that he doesn’t see a lymph node in my chest. He thinks it’s a spot on my lung. I’m feeling very confused! He advises that my oncologist doesn’t want me to have surgery to remove the three small masses on my scar line, as she wants to use them as a way to determine if the treatment is working. He advises that if they have not shrunk in 6 months, he will revisit surgery.
10/16 – CEA blood test to determine Tumour markers. Results were normal (2.7). My doctor advises that this could mean two things: (1) that the treatment is working, and the tumours are shrinking, or (2), that I'm one of those people who never get elevated CEA levels. Given that some people never get an elevated CEA level, this test doesn’t seem very accurate to me! Asked for PET scan, but am told I don’t qualify.
10/16 – Brain MRI – NED!
11/16 - CA-15-30 blood test – Tumour markers are normal at 19.
11/16 – Second CEA blood test – Tumours markers are still normal at 1.6 Second CA-15-30 blood test – Tumour markers are still normal at 19
11/16 – Develop lymphedema and have to wear a sleeve
12/16 – CT Scan shows that the tumors on my lungs and the lymph node in the middle of my chest are shrinking, and that some have resolved. Also, the small masses along my scar line are no longer visible. This means the medication is working!
12/16 – Small “pimple” shows up where old tumour on chest wall was located. Doctor is going to monitor it for now.
01/17 – A second “pimple” shows up on chest wall, as well as a small lump under the skin. My doctor thinks it’s scar tissue and will monitor it for now.
0/17 – Started to develop severe back pain – worried the cancer has spread to my spine.
03/17 – Third CEA blood test and CA-15-30 blood test – Both normal at 2.5 and 25
03/17 – CT Chest scan to see if there’s improvement to chest and lungs – awaiting results. If results are good, I get to stop taking Taxol!
03/17 – Second brain MRI scheduled for end of month.
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Old 03-15-2017, 11:19 AM   #4
Cathya
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Join Date: Sep 2005
Location: Ontario, Canada
Posts: 752
Re: Diabetes medication could be effective therapy for aggressive type of breast canc

I think this could be what they're talking about.

Zuri Scrivens was 33 when she was diagnosed with breast cancer.

Now 35, she’s part of a study investigating the possible benefits of metformin, a drug normally used to treat diabetes. She is also on letrozole, a drug that is used for the treatment of estrogen-positive breast cancer.

“I feel as if my initial treatment in 2011 was not specific enough for me, because some cells stuck around,” Scrivens said. “Perhaps if I’d been able to be part of these studies earlier on, I might have been put on the appropriate chemotherapy, I might have gone on the letrozole earlier, and stopped any sort of spread.”

Specificity is a crucial element in the treatment of breast cancer. Dr. Stephen Chia believes that this is where we will see the most benefits when it comes to treating breast cancer in the coming years.

A medical oncologist and chair of the Provincial Breast Tumour Group, Chia has been with the BC Cancer Agency for 11 years. He says that the drugs that will likely prove to have the most effect on cancer treatment in the next year are T-DM1 and pertuzumab. Both are antibodies that target HER2-positive cancer, generally considered a more aggressive cancer than estrogen-positive cancer.

“Studies have shown giving both antibodies with chemo is better than giving either antibody alone with chemotherapy,” he said.

“It’s not just chemotherapy that is effective, it’s also blocking the pathway receptor. We don’t truly understand everything that happens when you give a patient the antibody in terms of how it works, but it works in a significant proportion of patients.”

T-DM1 combines an antibody called trastuzumab with a cancer-killing agent, DM1. Both trastuzumab and pertuzumab block the HER2 pathways by blocking the receptors on the cancer cells.

“We’re trying to become more sophisticated with biological agents that target the receptors, or pathways,” Chia said.

Targeting the receptor allows more selective delivery of chemotherapy to the cancer cells.

“When we give chemotherapy intravenously, it circulates through the body and gets taken up across cells, both normal and abnormal,” Chia said. “Typically, the cancer has more blood vessels and HER-2 receptors, so you would expect more drug distribution there. The antibody conjugate principle is that the antibody brings the drug specific to the cells, in this case the HER-2 cells. So you bring a lot more chemo drugs specifically to cancer cells.”

Another drug he believes will have an effect on cancer treatment is called everolimus.

In combination with a hormonal drug, everolimus doubles the benefit of the hormonal drug. “It blocks a specific pathway that is activated in probably half of estrogen-positive breast cancers,” he said. The pathway is called the PI3K-mTOR pathway.

Metformin, which Scrivens is being treated with, is also being investigated for its possible benefits in treating estrogen-positive breast cancer.

“There’s a lot of interest in the insulin pathway having effects on cancer cells,” said Chia. “If shown to be effective, it could be widely applicable and not expensive.”

Scrivens had numerous treatments following her 2011 diagnosis.

The Langley resident had a right-side mastectomy following three months of chemo and five weeks of radiation therapy.

She then went tamoxifen, a hormone drug for pre-menopausal women with estrogen-positive breast cancer. She also had her left breast removed “for easy of worry, to avoid anxiety,” she said.

Yet the cancer persisted. In December of last year she discovered a pea-sized lump below her clavicle. A biopsy revealed it to be cancerous.

Her doctor, oncologist Karen Gelmon, took her off the drugs she’d been on and put her on faslodex, which stops the ovaries from functioning. Scrivens was also put in a couple of studies, including a PET-CT study. The study applies an estrogen tracer in the body to find “hot areas” that respond to estrogen.

She was also put on a genetic sequencing study that compared her new and old tumours.

“I do feel that it has been able to give us a really good look at what kind of cancer I have,” she said. “There’s a huge variety of types. So to say that this or that drug or this or that treatment will work for all women or all people that get breast cancer is false. The more you can find out, the better. That’s why these tests are so great.”

Based on those findings, Scrivens was put on letrozole, a common treatment for estrogen-positive breast cancer, following chemotherapy, and metformin.

She believes these treatments have helped.

“I feel fantastic,” she said. “Though the tough thing about cancer sometimes is that you can feel quite well. But my side-effects have been kept to a minimum, and I’ve been doing a lot of additional therapies. I do acupuncture, meditation, yoga, I’ve changed my diet a bit. All the things you need to do to stay healthy.”

Besides drug treatments, advances in radiation therapy are also helping breast cancer patients, Dr. Chia said.

Called radio surgery, it’s used on women with an advanced stage of the disease, and usually targeted to a limited number of lesions.

“They’re considering giving fairly high-dose radiation to the area to obliterate those lesions much more so than ever before,” Chia said.

“The concept is the dose you’re giving is possibly going to kill off the cells. You’re not actually doing surgery but you’re giving higher-dose radiation.”

The BC Cancer Agency is also part of a trial which is investigating whether more chemotherapy delivered before surgery rather than after might be beneficial.

“I’d like to see a day where standard chemotherapy might be a thing of the past or minimally given,” Chia said. “I don’t think we’ll get away from hormonal therapy because, in the big picture, it’s not as toxic as other therapies, and has been clearly shown to have a lot of impact on these cancers.”

He notes that women with Stage 4, or advance breast cancer, are living longer now than they have in the past.

“We believe part of that is because of newer drugs,” he said.
__________________
Cathy

Diagnosed Oct. 2004 3 cm ductal, lumpectomy Nov. 2004
Diagnosed Jan. 2005 tumor in supraclavicular node
Stage 3c, Grade 3, ER/PR+, Her2++
4 AC, 4 Taxol, Radiation, Arimidex, Actonel
Herceptin for 9 months until Muga dropped and heart enlarged
Restarting herceptin weekly after 4 months off
Stopped herceptin after four weekly treatments....score dropped to 41
Finished 6 years Arimidex
May 2015 diagnosed with ovarian cancer
Stage 1C
started 6 treatments of carboplatin/taxol
Genetic testing show BRCA1 VUS
Nice! My hair came back really curly. Hope it lasts lol. Well it didn't but I liked it so I'm now a perm lady
29 March 2018 Lung biopsy following chest CT showing tumours in pleura of left lung, waiting for results to the question bc or ovarian
April 20, 2018 BC mets confirmed, ER/PR+ now Her2-
Questions about the possibility of ovarian spread and mets to bones so will be tested and monitored for these.
To begin new drug Palbociclib (Ibrance) along with Letrozole May, 2018.
Genetic testing of ovarian tumour and this new lung met will take months.
To see geneticist to be retested for BRCA this week....still BRCA VUS
CA125 has declined from 359 to 12 as of Aug.23/18


Cathya is offline   Reply With Quote
Old 03-15-2017, 12:39 PM   #5
TiffanyS
Senior Member
 
Join Date: Sep 2016
Posts: 459
Re: Diabetes medication could be effective therapy for aggressive type of breast canc

I asked my oncologist about Metformin in the past, and she advised that our hospital took part in that study, and that it only worked on people who were HER II negative. She said there was no advantage to taking it if you were HER II positive. This article seems to state otherwise. Personally, I think TDM-1 is the drug that I need to be taking, however, OHIP won’t pay for it unless I take Perjeta first. The Perjeta seems to be working in regards to my lung mets and in regard to the lymph nodes in my chest, however, I’m fairly positive that I’ve had a second recurrence along my chest wall. I have two little pimples close to where two of my old masses used to be, as well as a pea sized lump under the skin where a third mass was. My doctor thinks it’s scar tissue, however, that’s what they said the last time, and it was cancer. The two little pimples have not grown since they showed up, but I’m convinced the pea sized lump under my skin is growing. They don’t want to biopsy the area though, because they say it could “seed” the area if it is cancer. I now have an ultrasound booked for next week, so that they can determine the size of the lump, and they are going to send me for another one in three months to see if it’s growing. If it is, we’ll know it’s cancer. Given how my cancer seems to be resistant to drugs (I had my first recurrence while on chemo), I think that I would benefit from a more specific treatment plan, customized to my personal needs based on my type of cancer. These genetic tests must be expensive though, as my doctor told me that she’s only allowed to refer a certain amount of patients per year due to budgetary issues. It’s too bad, because I think most people would benefit from these tests.

¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬ ¬¬¬¬¬¬¬¬¬¬¬¬¬¬¬
12/15 – First mammogram
01/16 – Second mammogram and ultrasound.
01/16 – Meet surgeon and go for third mammogram, second ultrasound and biopsy. Surgeon confirms cancer in left breast and lymph nodes and sets surgery date.
01/16 – Chest scan and bone scan done– all looks good.
02/16 – Surgery - left breast mastectomy and 16 lymph nodes removed (8 had cancer).
02/16 – CT scan done – small nodules on lung but Doctor advises it’s post surgical. They will continue to monitor just in case.
03/16 – Meet radiation oncologist and find out results of Pathology Report. I’m told that I have locally advanced breast cancer, based on the size of my tumour (7 cm!) and the fact that they found cancer cells in eight lymph nodes. I’m also told that I’m HER 2 positive, with high levels of estrogen and progesterone and that my cancer is stage 3, grade 2.
03/16 – Meet oncologist and am told that my cancer is actually grade 3, and that I should have done chemo before surgery. Too late now!
03/16 – Start first of six doses of chemo (Carboplatin and Docetaxal) and Herceptin (for 18 months).
04/16 – Have port put in.
04/16 – Get second dose of chemo, but Docetaxal is left out due to liver enzymes being high. I was unable to get a full dose of Docetaxal after my first treatment.
06/16 – Finished chemo! One month off and then I start radiation.
06/16 – Start Tamoxifen.
07/16 – First radiation treatment – 24 more to go!
08/16 – Went for Genetic Testing to see if I have the BRCA gene. Tested negative for BRCA I and II
08/16 – Radiation oncologist biopsies “scar tissue” on my chest wall. I am told that I have a local recurrence and need to have rush surgery.
09/16 – Meet surgeon who advises that I need to meet with a plastic surgeon, as they will need to do a skin graft to close me up after surgery. Meet plastic surgeon and all looks good. A surgery date is set for October 4.
09/16 – Go for rush ultrasound, bone scan, breast MRI and CT scan.
09/16 – Meet oncologist who advises that the ultrasound and bone scan results look good, and that MRI shows three small masses at surgery site, but lymph nodes are clear. Still awaiting the results of the CT scan, but we are positive it will look good.
09/16 – Get a call from my oncologist, who advises that CT scan shows small spots on my lungs, and a large lymph node in the middle of my chest. This means the cancer has spread! She looks into getting me funded for TDM-1 and cancels my surgery.
10/16 – Meet oncologist, who advises that I have to take Perjeta before I can take TDM1. I start Perjeta/Herceptin every three weeks for an indefinite amount of time, and Taxol, which I will take two weeks in a row with one week off and then two weeks in a row for 8-16 treatments. Stop Tamoxifen.
10/16 – Meet surgeon, who reviews my CT scan and advises that the spots on my lungs may not be cancer, and that he doesn’t see a lymph node in my chest. He thinks it’s a spot on my lung. I’m feeling very confused! He advises that my oncologist doesn’t want me to have surgery to remove the three small masses on my scar line, as she wants to use them as a way to determine if the treatment is working. He advises that if they have not shrunk in 6 months, he will revisit surgery.
10/16 – CEA blood test to determine Tumour markers. Results were normal (2.7). My doctor advises that this could mean two things: (1) that the treatment is working, and the tumours are shrinking, or (2), that I'm one of those people who never get elevated CEA levels. Given that some people never get an elevated CEA level, this test doesn’t seem very accurate to me! Asked for PET scan, but am told I don’t qualify.
10/16 – Brain MRI – NED!
11/16 - CA-15-30 blood test – Tumour markers are normal at 19.
11/16 – Second CEA blood test – Tumours markers are still normal at 1.6 Second CA-15-30 blood test – Tumour markers are still normal at 19
11/16 – Develop lymphedema and have to wear a sleeve
12/16 – CT Scan shows that the tumors on my lungs and the lymph node in the middle of my chest are shrinking, and that some have resolved. Also, the small masses along my scar line are no longer visible. This means the medication is working!
12/16 – Small “pimple” shows up where old tumour on chest wall was located. Doctor is going to monitor it for now.
01/17 – A second “pimple” shows up on chest wall, as well as a small lump under the skin. My doctor thinks it’s scar tissue and will monitor it for now.
0/17 – Started to develop severe back pain – worried the cancer has spread to my spine.
03/17 – Third CEA blood test and CA-15-30 blood test – Both normal at 2.5 and 25
03/17 – CT Chest scan to see if there’s improvement to chest and lungs – awaiting results. If results are good, I get to stop taking Taxol!
03/17 – Second brain MRI scheduled for end of month.
03/17 – Ultrasound scheduled to determine size if “pimples” on my chest wall. They will follow up with a second Ultrasound in three months, to see if they are growing
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