exciting preclinical finding re metformin (diabetes drug) killing cancer stem cell

[Lani]

population even within herceptin resistant cell lines.

Points to adding metformin to herceptin (perhaps even prophylactically to prevent resistance)!??

Breast Cancer Res Treat. 2010 May 11. [Epub ahead of print]
The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells.
Vazquez-Martin A, Oliveras-Ferraros C, Barco SD, Martin-Castillo B, Menendez JA.

Catalan Institute of Oncology, Girona (ICO-Girona), Dr. Josep Trueta University Hospital, Ctra. França s/n, 17007, Girona, Catalonia, Spain.
Abstract
We here demonstrate that the anti-diabetic drug metformin interacts synergistically with the anti-HER2 monoclonal antibody trastuzumab (Tzb; Herceptin) to eliminate stem/progenitor cell populations in HER2-gene-amplified breast carcinoma cells. When using the mammosphere culture technique, graded concentrations of single-agent metformin (range 50-1,000 mumol/l) were found to dose-dependently reduce the number of mammospheres formed by SKBR3 (a Tzb-naïve model), SKBR3 TzbR (a model of acquired auto-resistance to Tzb) and JIMT-1 (a model of refractoriness to Tzb and other HER2-targeted therapies ab initio) HER2-overexpressing breast cancer cells. Single-agent Tzb likewise reduced mammosphere-forming efficiency (MSFE) in Tzb-naïve SKBR3 cells, but it failed to significantly decrease MSFE in Tzb-resistant SKBR3 TzbR and JIMT-1 cells. Of note, CD44-overexpressing Tzb-refractory SKBR3 TzbR and JIMT-1 cells retained an exquisite sensitivity to single-agent metformin. Concurrent combination of metformin with Tzb synergistically reduced MSFE as well as the size of mammospheres in Tzb-refractory SKBR3 TzbR and JIMT-1 cells. Flow cytometry analyses confirmed that metformin and Tzb functioned synergistically to down-regulate the percentage of Tzb-refractory JIMT-1 cells displaying the CD44(pos)/CD24(neg/low) stem/progenitor immunophenotype. Given that MSFE and mammosphere size are indicators of stem self-renewal and progenitor cell proliferation, respectively, our current findings reveal for the first time that: (a) Tzb refractoriness in HER2 overexpressors can be explained in terms of Tzb-resistant/CD44-overexpressing/tumor-initiating stem cells; (b) metformin synergistically interacts with Tzb to suppress self-renewal and proliferation of cancer stem/progenitor cells in HER2-positive carcinomas.

PMID: 20458531

Would have been nice if they tested BT474 cell line also as SkBr3 is ER-(Bt474 is ER+)

[Ellie F]

Lani
Which cell lines are her2 positive but er and pr negative? It would relly help if I could make sense of which cell lines were tested.
Many thanks
Ellie

[Rich66]

The good news keeps coming in for Metformin!

More HERE.

[Ellie F]

So why no clinical trials yet? Don't want to sound cynical but is it because as an existing drug there is no profit to be made.
Ellie

[Lani]

the money will probably need to come from Susan Komen or some other source not trying to sell a drug (metformin has been on the market for years so it must by now be off patent and available as a generic) and it usually costs quite a bit of money to pay for the time of the doctors, nurses, statisticians, etc

The same problem comes up with trials of accelerated breast irradiation and other new treatments for which no device or drug company will come up with the money.

[Lani]

I went back to November 2005 (and Joe, I couldn't find this with the search function only by googling--remember my suspicion that we lost some of my posts at some point when we had site problems...) and found this post of mine:

Thread Tools Search this Thread Rating: Display Modes
11-19-2005, 11:43 PM #1
Lani
Guest

Posts: n/a
List Of Breast Cancer Cell Lines
Previous comments have been made on the need to be discriminating when reading articles on breast cancer studies performed in vitro(in petri dishes or test tubes) or in vivo (in rats or mice usually) utilizing breast cancer cell lines. One thread recently posted on this site had to do with whether flaxseed was good or bad for her2+ breast cancer and listed a study performed by someone in Nutritional science on a breast cancer cell line implanted in mice that turned out to be both estrogen negative AND her2 negative!


I found a nice list of breast cancer cell lines which specify whether or not they are her2+. It still does not tell which are ER+, but it will help one spot right away whether the study was done on her2+ or her2- breast cancer cells and thus help those of you with her2 positive breast cancer have an idea whether the study has any likelihood of providing information useful to your cases:

The naturally HER-2/neu-overexpressing cell lines: BT-474, SK-BR3, MDA-MB-361, and MDA-MB-453
the HER-2/neu-non-overexpressing cell lines: BT-20, MDA-MB-435, MCF-7, MDA-MB-231, ZR-75–1, and T-47D
Cell lines MCF-7/HER-2, MDA-MB-231/HER-2, ZR-75–1/HER-2 and T-47D/HER-2 were previously created by transfection with a retroviral expression vector containing a full-length human HER-2/neu complementary DNA (cDNA), resulting in stable HER-2/neu overexpression

The last group of cell lists which are listed have "her2" appended to their names-- meaning they were naturally her2negative, but they did a little genetic engineering and transfected them with her2.
It is absolutely unclear whether such transformed cell lines really have much to do with tumors that developed naturally and demonstrate her2neu amplification.

So when looking to see if some drug or vitamin or supplement has an effect on YOUR TYPE OF BREAST CANCER be sure the cell lines listed are
BT-474, SK-BR3, MDA-MB-361, or MDA-MB-453 (or MCF-7/HER-2, MDA-MB-231/HER-2, ZR-75–1/HER-2 and T-47D/HER-2 --but retain your skepticism if these latter cell lines were used)

NEEDLESS to say, what happens in the test tube, petri dish or in a rat fatpad injected with cells from another species may not have much to do with what happens in real life in humans

But hopefully this will help in interpreting which of these studies MIGHT
have something to offer and which have been performed in a set of cells so different than yours that the results are unlikely to be applicable to you


Hope this helps!
Lani


In the meantime they have discovered some herceptin-resistant cell lines as well like the JIMT-2 cells and the ones described in my post about the metformin above

[Rich66]

The good news is that since it is a widely used prescription drug that a doctor has authority to prescribe off label, more docs will be willing to consider this..as opposed to supplements that they may feel are nonsense.

Regarding what it works on, the most interesting aspect of this (to me) is that it seems to work at a level more fundamental than the overlying subtypes:

Cancer abolishes the tissue-type specific differences in the phenotype of energetic metabolism
Acebo Paloma, Daniel Giner, Piedad Calvo, Blanco-Rivero Amaya, Alvaro D Ortega, Pedro L Fernández, Giovanna Roncador, Fernández-Malavé Edgar, Margarita Chamorro and José M Cuezva
Abstract Full Article
"Unexpectedly, we find that tumors from different tissues and/or histological subtypes have the same cellular content of these markers and, therefore, the same bioenergetic signature. It seems that cancer alters the expression of the markers of energetic metabolism of the cell in a tissue-specific manner (Table 1), consistent with the variable cellular response that oncogenes [3,24,25] and tumor suppressors [2,5,26] have on the phenotype of energetic metabolism. However, it is noteworthy that the bioenergetic signature is basically the same regardless of the tissue of origin and the histological type of the tumor (see β-F1/GAPDH ratio in Table 1 and Figure 2F). These findings could support that a common origin for tumors arises from an undifferentiated progenitor cell and that cancer cells undergo a process of dedifferentiation to acquire the traits of embryonic stem cells[27]. In this regard, we suggest that the bioenergetic signature of the tumors and, hence, the expression of markers of energetic metabolism partially respond to the installment of the reductive metabolic program (mainly glycolytic) that sustains cellular proliferation [15,28]. Conversely, the suppression of the tissue-specific differences in the bioenergetic signature of the tumors and its drastic reduction in certain tissues (Table 1) strongly support that containment of the mitochondrial bioenergetic activity in the cancer cell is an event required for tumor progression. Indeed, tumors with a low bioenergetic signature have a worse prognosis [6–8,10] and the activity of mitochondria has been shown to act as a tumor suppressor [12,14,29].
Owing to the convergence of breast, lung, and esophageal tumors on the same bioenergetic signature, it seems that energetic metabolism affords a common target for cancer therapy. In this regard, several groups and biotech companies are currently targeting the proteins of energetic metabolism as a promising approach to eradicate different types of tumors especially in combined therapy [30–33]. Overall, and because the bioenergetic signature provides a predictive marker of the response of tumors to chemotherapy [9], in agreement with the role of mitochondrial oxidative phosphorylation in the execution of cell death [11,13,14], we suggest that its translation to the clinics will benefit cancer patients."
....
the results support that energetic metabolism represents an additional hallmark of the phenotype of the cancer cell and a promising target for the treatment of diverse neoplasias

[Lani]

Additionally:
The 6 ER+ breast cancer cell lines used were ZR-75-1
(6), MCF-7 (33), MDA-MB-134 (5), T-47D (14), BT-474 (15), and MDA- MB-361 (4). The ER- lines consisted of breast cancer lines, BT-20 (16), Hs0578T (10), MDA-MB-330 (4), and MDA-MB-231 , SkBr3

of those I believe only MDA-MB-361 and BT-474 are ER+ and SkBr3 and MDA-MB-453 are ER-(MB-453 has a lot of androgen receptors, however). I don't know about the JIMT-2 ie, whether they were ER+ or ER- before they grew them in such a way as to become herceptin resistant.

Hope this helps!

[Ellie F]

Lani
Thanks very much for the information. It will be much easier now to interpret when reading research.

Rich
Hope someone presses ahead with research to try to treat the 'underlying' problem regardless of receptor status.

Ellie

[weety]

Gee, kind of makes me tempted to raid my husband's diabetes med stash. . .LOL!

[jml]

Hi All~
Just wanted to share that I've heard from a Research Coordinator @Simon Cancer Center at IUPUI that there ARE studies with Metformin & MBC coming down the pipeline...
Ironically, I was disqualified from their TDM1 trial because I have been on Metformin for a 7 years (for insulin resistance due to pre-med steroids, not for diabetes).
Even though the docs all agree with the preliminary research that supports Metformin, the unknown combo when combined with the study drug was deemed too uncertain & potentially toxic.
Still feeling very conflicted about all of this...

[1rarebird]

Apparently, there is at least one trial coming soon. (See http://www.cancer.gov/clinicaltrials/CAN-NCIC-MA.32 ) It is designed for early stage breast cancer and is a large US/Canadian phase III trial that has been approved but is not active as of 5/27/07. One media account predicts recruiting as early as July this year. ( http://www.scrippsnews.com/content/c...ancer-patients ) Although for early stage, perhaps it will quickly lead to findings that will encourage more trials or clinical use for later stages. Even without those trials, doctors may be more likely to use Metformin in later stage settings given its low cost and extensive safety history.

bird

[weety]

Thanks for the info! I will be watching this trial to see when it opens and what the final criteria is. Does anyone know since it is in phase III where we can find info about the phase I or II results?

[Nancy L]

Lani

Any stats on how many diabetics on metformin are diagnosed with BC each year and how does this occurence rate compare with non diabetics If cancer stem cells are feed by sugar, the metformin finding would make sense.

I am going to be asking Dr. Slamon if I should try this. I did become Herceptin resistant but he believes the Herceptin/Tykerb combo has synergy for my situation. And it is working right now. Can't ask for more than that.

Thanks

[1rarebird]

Lani will probably have more current data, but here is a link to an article published in July 2009, Journal of Clinical Oncology, which lists the numbers of breast cancer patients withand without diabetes in a cohort of 2,592 cases. http://jco.ascopubs.org/cgi/reprint/27/20/3271 (You may have to download the pdf file.) Its main author, Dr. Pamela Goodwin, is the principle investigator in the pending phase 3 Metformin Clinical Trial for early breast cancer.

bird

[Lani]

those kind of figures are hard to come by--would probably be easier to find out in Scandinavia, where there is government-run healthcare and people don't tend to move around a lot

In what way did you become herceptin-resistant--did you recur while on extended herceptin? Did the recurrence have the same characteristics as the primary ie, ER,PR,her2 status?

[Ellie F]

nancy
this is a similar question to Lani's.I seem to remember that you did recur to your neck whilst taking long term herceptin following original stage 3c bc.Dr S had said that he didn't think you would get much protection from herceptin beyond 2 years?

My question is does he believe that adding tykerb to herceptin in some ways overcomes this resistence and makes herceptin effective again?
Ellie