[Rich66]

(synergizes with chemo, potential chemo dose reducer, w/2DG, anti-CSC, gene modifying, anti glycolysis yet more, aromatase inhib, effective acrosss tissue type differences, HexokinaseII, Cyclin D1 inhibitior, anti-inflammation/Il-8, immune enhancing, VEGF inhib, mTOR, AKT, AMPk, w/MNTX, monotherapy potential in triple neg, tripled neoadj response)


Metformin in Breast Cancer: Time for Action

http://jco.ascopubs.org/cgi/reprint/27/20/3271
3 page PDF

By inhibiting transcription of key gluconeogenesis genes in the liver and increasing glucose uptake in skeletal muscle, metformin reduces levels of circulating glucose, increases insulin sensitivity, and reduces the hyperinsulinemia associated with insulin resistance,⁵ all of which are factors associated with breast cancer prognosis.

View larger version (25K):

[in this window] [in a new window] [PowerPoint Slide for Teaching]

Fig 1. Mechanism of metformin action. IR, insulin receptor; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homolog; Akt, v-akt murine thymoma viral oncogene homolog; Erk, extracellular signal-regulated kinase; TSC2, tuberous sclerosis complex tumor suppressor gene 2; mTOR, mammalian target of rapamycin; BC, breast cancer cell.

Possible need to monitor B12 ?
http://www.diabetesselfmanagement.co...12_deficiency/





Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Breakthrough

http://www.sciencedaily.com/releases/2009/06/
090603131433.htm

ScienceDaily (June 3, 2009) — Researchers at McGill University and the University of Pennsylvania have discovered that a widely used anti-diabetic drug can boost the immune system and increase the potency of vaccines and cancer treatments. Their findings will be published June 3 in the journal Nature.
The discovery was made by Dr. Russell Jones, an assistant professor at McGill's Goodman Cancer Centre and the Department of Physiology, Faculty of Medicine, Yongwon Choi, PhD, professor of pathology and laboratory medicine, and postdoctoral fellow Erika Pearce, PhD, of the University of Pennsylvania. They discovered that the widely prescribed diabetes treatment metformin increases the efficiency of the immune system's T-cells, which in turn makes cancer and virus-fighting vaccines more effective.
The specialized white blood cells of the human immune system known as "T-cells" remember pathogens they have encountered from previous infections or vaccinations, enabling them to fight subsequent infections much faster. This "immunological memory" has been the subject of intense study for many years, but until now the underlying cellular mechanisms behind it were not well understood. Now, the researchers say, they can use diabetic therapies to manipulate T-cell response and enhance the immune system's response to infections and cancer alike.
"Many genes involved in diabetes regulation also play a role in cancer progression," Jones explained. "There is also a significant body of data suggesting that diabetics are more prone to certain cancers. However, our study is the first to suggest that by targeting the same metabolic pathways that play a role in diabetes, you can alter how well your immune system functions."
"We serendipitously discovered that the metabolizing, or burning, of fatty acids by T-cells following the peak of infection is critical to establishing immunological memory," Pearce added. "We used metformin, which is known to operate on fatty-acid metabolism, to enhance this process, and have shown experimentally in mice that metformin increases T-cell memory as well as the ensuing protective immunity of an experimental anti-cancer vaccine."
Few talk about cancer and diabetes in the same breath. However, recent advances have uncovered common links between cancer and diabetes, in particular how metabolic pathways, the basic chemical reactions that happen in our cells, are controlled in these diseases. The recent findings suggest a new link between the metabolic pathways deregulated in cancer and diabetes and their role in immune cell function. The results suggest that common diabetic therapies which alter cellular metabolism may enhance T-cell memory, providing a boost to the immune system. This could lead to novel strategies for vaccine and anti-cancer therapies.
"Our findings were unanticipated, but are potentially extremely important and could revolutionize current strategies for both therapeutic and protective vaccines," Choi said.

---

Journal reference:

• Erika L. Pearce, Matthew C. Walsh, Pedro J. Cejas, Gretchen M. Harms, Hao Shen, Li-San Wang, Russell G. Jones & Yongwon Choi. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature, 2009; DOI: 10.1038/nature08097

Adapted from materials provided by McGill University, via EurekAlert!, a service of AAAS. Retrieved June 3, 2009, from http://www.sciencedaily.com* /releases/2009/06/090603131433.htm





Metformin Selectively Targets Cancer Stem Cells, and Acts Together with Chemotherapy to Block Tumor Growth and Prolong Remission

FULL TEXT
Heather A. Hirsch¹, Dimitrios Iliopoulos¹, Philip N. Tsichlis² and Kevin Struhl^{1 1} Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and ² Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts
Requests for reprints: Kevin Struhl, Harvard University, 240 Longwood Avenue, Boston, MA 02115. Phone: 617-432-2104; Fax: 617-432-2529; E-mail: kevin@hms.harvard.edu.


The cancer stem cell hypothesis suggests that, unlike most cancer cells within a tumor, cancer stem cells resist chemotherapeutic drugs and can regenerate the various cell types in the tumor, thereby causing relapse of the disease. Thus, drugs that selectively target cancer stem cells offer great promise for cancer treatment, particularly in combination with chemotherapy. Here, we show that low doses of metformin, a standard drug for diabetes, inhibits cellular transformation and selectively kills cancer stem cells in four genetically different types of breast cancer. The combination of metformin and a well-defined chemotherapeutic agent, doxorubicin, kills both cancer stem cells and non–stem cancer cells in culture. Furthermore, this combinatorial therapy reduces tumor mass and prevents relapse much more effectively than either drug alone in a xenograft mouse model. Mice seem to remain tumor-free for at least 2 months after combinatorial therapy with metformin and doxorubicin is ended. These results provide further evidence supporting the cancer stem cell hypothesis, and they provide a rationale and experimental basis for using the combination of metformin and chemotherapeutic drugs to improve treatment of patients with breast (and possibly other) cancers. [Cancer Res 2009;69(19):7507–11]





Metformin and Pathologic Complete Responses to Neoadjuvant Chemotherapy in Diabetic Patients With Breast Cancer
FULL TEXT: http://jco.ascopubs.org/cgi/content/full/27/20/3297

Sao Jiralerspong, Shana L. Palla, Sharon H. Giordano, Funda Meric-Bernstam, Cornelia Liedtke, Chad M. Barnett, Limin Hsu, Mien-Chie Hung, Gabriel N. Hortobagyi, Ana M. Gonzalez-Angulo From the Departments of Breast Medical Oncology, Biochemistry and Molecular Biology, Quantitative Sciences, Surgical Oncology, Pharmacy, Molecular and Cellular Oncology, and Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX; and the Department of Gynecology and Obstetrics, University of Muenster, Muenster, Germany.
Corresponding author: Ana M. Gonzalez-Angulo, MD, Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: agonzalez@mdanderson.org.
Purpose Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy.
Patients and Methods We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using ² tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model.
Results The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use.
Conclusion Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.




Metformin As an Addition to Conventional Chemotherapy in Breast Cancer

TO THE EDITOR: We were most interested to read the article by Jiralerspong et al.1 This study showed that patients with breast cancer and diabetes who received metformin plus neoadjuvant therapy had a higher pathologic complete response rate than patients with diabetes who were not in receipt of metformin did. Jiralerspong et al1 and Goodwin et al,2 who wrote the accompanying editorial, suggest that the possible beneficial action of metformin in breast cancer may be related to activation of adenosine monophosphate–activated protein kinase, which may ultimately result in a rapid inhibition of cellular protein synthesis and growth of tumor cells. We suggest, however, that additional mechanisms may play a part.
It is a well-accepted fact that chronic inflammation is a major contributory factor to cancer development and progression, and elevated levels of various nonspecific markers of inflammation in the serum have been shown to be associated with poor survival in a number of different cancers. Pierce et al3 have recently assessed the relationship between circulating levels of C-reactive protein and serum amyloid A and breast cancer survival. They showed that raised levels of these inflammatory markers were associated with a significantly reduced overall survival and a trend toward a reduced diseasefree survival. Patients with type 2 diabetes mellitus tend to have higher C-reactive protein concentrations than those without it, suggesting that inflammation may contribute to the higher risk of breast cancer and worse prognosis of malignant disease in these patients.4 There is evidence to suggest that metformin has a positive impact on inflammation and endothelial dysfunction. Metformin was compared with another oral hypoglycaemic agent, repaglinide, in nonobese patients with type 2 diabetes and shown to be more effective in reducing levels of tumor necrosis factor alpha, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, vonWillebrand factor, soluble intercellular adhesion molecule-1, and soluble E-selectin.5 A further study has shown that metformin is capable of producing a significant decrease in the levels of vascular endothelial growth factor and plasminogen activator inhibitor-1.6 Because an inflammatory component is present in the microenvironment of most neoplastic tissues, this in itself is a logical target for drug intervention. It thus follows that metformin maybe of value as an adjunct to conventional chemotherapy, in a wide spectrum of malignant diseases, and not only in patients with diabetes.
Tal Grenader, Anthony Goldberg, and Linda Shavit
Department of Oncology, Department of Medicine, Sha’are Zedek Medical
Center, Jerusalem, Israel
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Jiralerspong S, Palla SL, Giordano SH, et al: Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27:3297-3302, 2009
2. Goodwin PJ, Ligibel JA, Stambolic V: Metformin in breast cancer: Time for action. J Clin Oncol 27:3271-3273, 2009
3. Pierce BL, Ballard-Barbash R, Bernstein L, et al: Elevated biomarkers of inflammation are associated with reduced survival among breast cancer patients.
J Clin Oncol 27:3437-3444, 2009
4. Dandona P: Effects of antidiabetic and antihyperlipidemic agents on C-reactive protein. Mayo Clin Proc 83:333-342, 2008
5. Lund SS, Tarnow L, Stehouwer CD, et al: Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 158:631-641, 2008
6. Ersoy C, Kiyici S, Budak F, et al: The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Diabetes Res Clin Pract 81:56-60, 2008
DOI: 10.1200/JCO.2009.25.4110; published online ahead of print at www.jco.org on November 2, 2009
■ ■ ■
JOURNAL OF CLINICAL ONCOLOGY C O R R E S P O N D E N C E
Journal of Clinical Oncology, Vol 27, 2009 © 2009 by American Society of Clinical Oncology 1
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1...O.2009.25.4110

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




The following 2 studies do not necessarily contradict previously noted synergistic (beyond glucose) efficacy against multiple BC types. Instead, it suggests it can work by itself in triple negative breast cancer due to it's heavier reliance on glucose:


Cell Cycle. 2009 Jul 1;8(13):2031-40. Epub 2009 Jul 21.
Metformin induces unique biological and molecular responses in triple negative breast cancer cells.

Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, Thor AD.
Department of Pathology, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA.
Comment in:

• Cell Cycle. 2009 Sep 1;8(17):2681.

Triple negative (TN) breast cancer is more frequent in women who are obese or have type II diabetes, as well as young women of color. These cancers do not express receptors for the steroid hormones estrogen or progesterone, or the type II receptor tyrosine kinase (RTK) Her-2 but do have upregulation of basal cytokeratins and the epidermal growth factor receptor (EGFR). These data suggest that aberrations of glucose and fatty acid metabolism, signaling through EGFR and genetic factors may promote the development of TN cancers. The anti-type II diabetes drug metformin has been associated with a decreased incidence of breast cancer, although the specific molecular subtypes that may be reduced by metformin have not been reported. Our data indicates that metformin has unique anti-TN breast cancer effects both in vitro and in vivo. It inhibits cell proliferation (with partial S phase arrest), colony formation and induces apoptosis via activation of the intrinsic and extrinsic signaling pathways only in TN breast cancer cell lines. At the molecular level, metformin increases P-AMPK, reduces P-EGFR, EGFR, P-MAPK, P-Src, cyclin D1 and cyclin E (but not cyclin A or B, p27 or p21), and induces PARP cleavage in a dose- and time-dependent manner. These data are in stark contrast to our previously published biological and molecular effects of metformin on luminal A and B, or Her-2 type breast cancer cells. Nude mice bearing tumor xenografts of the TN line MDA-MB-231, treated with metformin, show significant reductions in tumor growth (p = 0.0066) and cell proliferation (p = 0.0021) as compared to untreated controls. Metformin pre-treatment, before injection of MDA-MB-231 cells, results in a significant decrease in tumor outgrowth and incidence. Given the unique anti-cancer activity of metformin against TN disease, both in vitro and in vivo, it should be explored as a therapeutic agent against this aggressive form of breast cancer.

PMID: 19440038 [PubMed - indexed for MEDLINE]





5154] Selective Effects of Glucose, Insulin and Leptin by Molecular Breast Cancer Subtype.

Deng X-S, Liu B, Fan Z, Edgerton SM, Lind SE, Thor AD University of Colorado Denver, Aurora, CO

Background: Type II diabetes and obesity are important risk factors for post-menopausal luminal A (LA) and triple negative (TN) pre-menopausal breast cancers, particularly in African American (AA) and Hispanic women. Breast cancer patients with these chronic metabolic diseases also have a worse prognosis, independent of other factors. We have published that metformin inhibits cell growth (S phase arrest) and induces apoptosis, only in TN cell lines in vivo and in vitro. It is less active, growth inhibitory (G1 arrest) and does not induce apoptosis in other breast cancer cell subtypes (Cell Cycle, 2009).
Methods: We investigated the effects of glucose as a mitogen at physiologic (5mM), metabolic syndrome (7mM) or diabetic levels (10mM), with or without insulin (100 ng/ml) or leptin (100 ng/ml) using cell lines representing all molecular subtypes of breast cancer. Metformin was then used in combination with the above, to determine whether it would block the mitogenic or signaling effects of supraphysiological glucose, insulin or leptin.
Results: The LA (MCF-7) and 2 of 5 TN cell lines (derived from AA patients; HCC 1806 and MDA 468) showed the most cell growth in response to glucose >5mM (75% for MCF-7, 30-50% for AA TN lines). Three TN cell lines from Caucasians (MDA231, HCC1937, BT20), the HER2 (SKBR3) and luminal B (BT-474) cells showed less growth induction with glucose >5mM. In TN lines only, glucose associated mitogenesis was associated with increased EGFR, pEGFR, IGF1R, pIGF1R, AKT and pAKT and decreases in AMPK, pAMPK, p38, IRS2, and the cyclins D1, E and A in a dose dependent manner. Metformin abrogated glucose induced cell growth and the aforementioned protein expression/phosphorylation changes involving EGFR, IGF1R, and AKT, increased AMPK and pAMPK and induced a profound reduction in Cyclin D1 across all glucose concentrations in TN cell lines from AA women. It reduced but did not eliminate glucose associated mitogenesis in the TN cell lines from Caucasian patients. Metformin had a more variable effect on cell lines of other molecular subtypes grown under high glucose conditions. The 5 TN breast cancer cell lines were uniformly resistant to both leptin and insulin associated mitogenesis, across a wide range of glucose concentrations. In contrast, both leptin and insulin significantly promoted LA breast cancer cell growth. These effects were resistant to metformin treatment. Leptin and insulin had the least growth promoting effects on HER2 breast cancer cell lines, whereas they induced modest growth induction in LB cell lines.
Conclusions: All TN cell lines showed significant mitogenesis in response to glucose >5mM, whereas they were uniformly resistant to both leptin and insulin. The glucose associated mitogenesis was more pronounced in lines derived from AA patients, as were the anti-mitgenic effects of metformin. LA cells showed marked growth induction by glucose, leptin and insulin, whereas HER2 cell lines showed general resistance to all of these factors. These data suggest that metabolic and hormonal shifts with obesity and diabetes, as well as metformin response vary by the molecular subtype of breast cancer cells and ethnicity.

Saturday, December 12, 2009 5:30 PM

Poster Session 5: Tumor Biology: Metabolism and Breast Cancer (5:30 PM-7:30 PM)






Diabetes Drug Kills Cancer Stem Cells in Combination Treatment in Mice
September 14, 2009




• Metformin is more effective than chemotherapy alone
• Study supports cancer stem cells hypothesis
• Laboratory study focused on breast cancer cells
Listen to a recorded mp3 of the teleconference.
PHILADELPHIA - In a one-two punch, a familiar diabetes drug reduced tumors faster and prolonged remission in mice longer than chemotherapy alone by targeting cancer stem cells, Harvard Medical School researchers reported in the September 14 online first edition of Cancer Research, a journal of the American Association for Cancer Research.
"We have found a compound selective for cancer stem cells," said lead researcher Kevin Struhl, Ph.D., the David Wesley Gaiser professor of biological chemistry and molecular pharmacology at Harvard Medical School. "What's different is that ours is a first-line diabetes drug."
These findings add to a growing body of preliminary evidence in cells, mice and people that metformin may improve breast cancer outcomes in people. In this study, the diabetes drug seemed to work independently of its ability to improve insulin sensitivity and lower blood sugar and insulin levels, all of which are also associated with better breast cancer outcomes.
The results fit within the cancer stem cell hypothesis, an intensely studied idea that small subsets of cancer cells have a special power to initiate tumors, fuel tumor growth and promote recurrence of cancer. Cancer stem cells appear to resist conventional chemotherapies, which kill the bulk of the tumor.
"There is a big desire to find drugs specific to cancer stem cells," said Struhl. "The cancer stem cell hypothesis says you cannot cure cancer unless you also get rid of the cancer stem cells. From a purely practical point of view, this could be tested in humans. It's already [in use as] a first-line diabetes drug."
The possible usefulness of a diabetes drug against cancer lends credence to an emerging idea that, in the vast and complex alphabet soup of molecular interactions within cells, a relatively few biological pathways will turn out to be most important for many different diseases, Struhl suggested.
In experiments led by postdoctoral fellows Heather Hirsch, Ph.D., and Dimitrios Iliopoulos, Ph.D., the combination of metformin and the cancer drug doxorubicin killed human cancer stem cells and non-stem cancer cells in culture. The researchers used four genetically distinct breast cancer cell lines.
In mice, pretreatment with metformin prevented the otherwise dramatic ability of human breast cancer stem cells to form tumors. In other mice where tumors took hold for 10 days, the combination therapy also reduced tumor mass more quickly and prevented relapse for longer than doxorubicin alone. In the two months between the end of treatment and the end of the experiment, tumors regrew in the mice treated with chemotherapy alone, but not in those who received both drugs. Metformin was ineffective in treating tumors when used alone.
"This is an exciting study," said Jennifer Ligibel, M.D., a medical oncologist at the Dana-Farber Cancer Institute and a Harvard Medical School instructor in medicine. Ligibel and colleagues at the National Cancer Institute of Canada Clinical Trials Group are developing a large-scale phase II trial and will study its metformin's impact on recurrence in women treated for early stage breast cancer.
"There is a lot of interest in studying metformin in breast cancer, but so far we do not have direct evidence that metformin will improve outcomes in patients," said Ligibel, who was not involved in the current study "That's what this trial is for."
So far, observational studies have suggested a lower risk of cancers, including breast cancer, and better response to chemotherapy in patients with diabetes who are treated with metformin, she said. Results of basic science studies have also suggested plausible biological mechanisms. The study from the Struhl lab suggests a potential new pathway through which metformin could have an effect on breast cancer cells, according to Ligibel.
In their search for compounds that selectively destroy cancer stem cells, researchers hope to improve cancer outcomes. But the story is never as simple in human cancers, according to Kornelia Polyak, M.D., Ph.D., a breast cancer researcher at the Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School.
Cancer stem cells are a shifty target, said Polyak, who was not involved in the current study. For example, any cancer cell can acquire the properties of a cancer stem cell, and cancer stem cells can change into non-stem cancer cells, which can be just as deadly. Clinical trials in people are needed to test these ideas, according to Polyak.
The study by Struhl and colleagues is an offshoot of a larger project in his lab to systematically track how gene activity changes when cells transform into cancer. These changes were remarkably similar to gene dynamics in diabetes and other inflammatory conditions.
The researchers reasoned that if a common genetic pathway underlies different diseases, drugs that work against one disease might work against another. In a screen, the most effective drug inhibiting the transformation of cells into cancer was metformin, which led to the experiments in this study. They were further encouraged by the low dose of metformin needed for the effect in the laboratory, compared to the amount needed for analogous molecular experiments in basic diabetes research. The relative dosage for treating or preventing cancer is unknown and untested in people.
Struhl and Harvard Medical School have applied for a patent for a combined therapy of metformin and a lower dose of chemotherapy, which is being tested in animals. The National Institutes of Health and the American Cancer Society funded this research.


News Briefing: The American Association for Cancer Research hosted a news briefing about the results of this study Monday, Sept. 14, 2009.
Download* the mp3 of the press briefing (8.74 MB, 38 minutes and 11 seconds)

*On a PC, right mouse click on the "Download" link and select "Save link as..." in Firefox or "Save Target as..." in Internet Explorer.

Panelists:
Moderator - Frank Rauscher, III, Ph.D.
Editor in Chief, Cancer Research
Professor, Gene Expression and Regulation Program
The Wistar Institute
Kevin Struhl, Ph.D.
David Wesley Gaiser Professor of Biological Chemistry and Molecular Pharmacology
Harvard Medical School
George Prendergast, Ph.D.
President, CEO and Professor
Lankenau Institute for Medical Research
Jennifer Ligibel, M.D.
Medical Oncologist
Dana-Farber Cancer Institute
Download panelist photos through the following links

Frank Rauscher, III, Ph.D.
Kevin Struhl, Ph.D.
George Prendergast, Ph.D.
Jennifer Ligibel, M.D.
Read the full Cancer Research study here.

Subscribe to the AACR News Feed
Subscribe to the Cancer Research RSS Feed
Media Contacts:
Jeremy Moore
(267) 646-0557
jeremy.moore@aacr.org
Harvard Medical School
Carol Cruzan Morton
(617) 432-0442
communications@hms.harvard.edu
# # #



Cancer Stem Cell Teleconference (August 14, 2009)

Sponsored by Cancer Research
A variety of researchers involved in the discussion but..

Foreword and comments by:
Frank Rauscher III, editor of Cancer Research

Interesting article/profile on Rauscher: LINK
Frank J. Rauscher III, Ph.D.
Professor
Gene Expression and Regulation Program
215-898-0995, Office
215-898-3929, Fax


A familiar diabetes drug reduced tumors faster and prolonged remission in mice longer than chemotherapy alone by targeting cancer stem cells, Harvard Medical School researchers reported in Cancer Research. The American Association for Cancer Research hosted a news briefing about the results of this study on Monday, Sept. 14, 2009. Read the press release and listen to the teleconference below for more information on the study and panelists.

Download* the mp3 of the press briefing (8.74 MB, 38 minutes and 11 seconds)

NOTES:

CSC hypothesis
Metformin: well known and safe, kills CSCs at low concentrations (lower than diabetes dose). Works on all breast cancer phenotypes, not connected to diabetes.
Synergizes with chemo (Doxo). Combination: regression quicker, no relapse for 3 months (as of teleconference). Could mean chemo could be lower dose. Safety profile means trials could start immediately.
Should be considered for cancer prevention.

Cancer cells are gluttons for glucose.

Metformin may produce immune memory to stave off cancer.

Inflammatory/immune response involved are important.

Metformin may be useful as low toxicity way to deplete dormant cancer cells i.e. CSCs.

Patients with higher insulin have increased breast cancer and mortality.
Diabetics on Metformin less on both accounts and better response rate to chemo.

Metformin may also have direct impact outside insulin (AMPK, MTOR)

NCI Canada MA32, post adjuvant Metformin monotherapy trial, available through cooperative groups in US (eg Dana Farber), enrollment in 2010?

Neoadjuvant Metformin trial in works.

Q&A

5-10% cancer stem cells. CSC far more tumor forming when injected.
Concentrations in experiments much lower than what diabetics use.
Less glucose response but more immune response, possibly inflammatory response.

Q: Why doesn't metformin monotherapy not show effect?
A: tried on fully formed tumor. At concentrations used, little effect on formed tumors. Other non cancer stem cells continue growing.

Italian study looking at Metformin in metastatic setting.

Principles involved not specific to breast cancer.

------------------------------------------------------------------------------




Breast Cancer Res Treat. 2010 Feb 5. [Epub ahead of print]
Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells.

Zakikhani M, Blouin MJ, Piura E, Pollak MN.
Department of Oncology, McGill University, Montreal, QC, Canada.
Rapamycin and its analogues inhibit mTOR, which leads to decreased protein synthesis and decreased cancer cell proliferation in many experimental systems. Adenosine 5'- monophosphate-activated protein kinase (AMPK) activators such as metformin have similar actions, in keeping with the TSC2/1 pathway linking activation of AMPK to inhibition of mTOR. As mTOR inhibition by rapamycin is associated with attenuation of negative feedback to IRS-1, rapamycin is known to increase activation of AKT, which may reduce its anti-neoplastic activity. We observed that metformin exposure decreases AKT activation, an action opposite to that of rapamycin. We show that metformin (but not rapamycin) exposure leads to increased phosphorylation of IRS-1 at Ser(789), a site previously reported to inhibit downstream signaling and to be an AMPK substrate phosphorylated under conditions of cellular energy depletion. siRNA methods confirmed that reduction of AMPK levels attenuates both the IRS-1 Ser(789) phosphorylation and the inhibition of AKT activation associated with metformin exposure. Although both rapamycin and metformin inhibit mTOR (the former directly and the latter through AMPK signaling), our results demonstrate previously unrecognized differences between these agents. The data are consistent with the observation that maximal induction of apoptosis and inhibition of proliferation are greater for metformin than rapamycin.

PMID: 20135346


Article LINK

Contact: Dama Kimmon
dama.kimmon@uc.edu
513-558-4519
University of Cincinnati Academic Health Center
Popular diabetes drug works differently than thought

CINCINNATI—The popular diabetes medication metformin works in different fashion than the current widely accepted view. This new finding could lead to wider use of the drug—particularly in people with cancer and diseases linked to TSC deficiency like tuberous sclerosis and lymphangioleiomyomatosis (LAM).
The results of this study, led by George Thomas, PhD, scientific director of UC's Metabolic Diseases Institute, are published in the May 5 edition of Cell Metabolism.
Metformin, marketed first by Bristol-Myers Squibb as Glucophage and now available in generic form and a number of combinations, is widely prescribed to people with type 2 diabetes and may be extended to the treatment of certain cancers. The drug blocks the production of glucose (sugar) and increases sensitivity to insulin—a hormone that converts sugar and other foods into energy within the body.
Researchers have thought that metformin, an energy-deprivation agent, disables the mTOR (mammalian target of rapamycin) complex by first activating the tuberous sclerosis complex (TSC) proteins through the enzyme AMPK.
Thomas' team determined that mTOR could actually be disabled without AMPK, and even without TSC. The team was able to determine that metformin works to knock out mTOR through another enzyme, RAG GTPase.
"We've poked a hole in dogma," says Thomas, a professor in the cancer and cell biology department. "Scientists can and should go back and ask about things they had crossed off their list."
The importance of this finding, says Thomas, is the possibility it holds for broader use of metformin.
"Metformin is already prescribed to 100 million people worldwide, and our study raises the question, 'Could this drug be used even more widely?'"
A drug like metformin, which improves insulin sensitivity, could be seen as a possible viable alternative to drugs that target mTOR, but that may have long-term deleterious effects on insulin production. Type 2 diabetes results from the body's inability to properly use insulin. If left unmanaged, diabetes can lead to vision loss, kidney failure, heart attack, stroke and nerve or blood vessel damage.



J Angiogenes Res. 2010 Feb 19;2(1):5.
Methylnaltrexone potentiates the anti-angiogenic effects of mTOR inhibitors.

(available as user injectable Relistor)

Singleton PA, Mambetsariev N, Lennon FE, Mathew B, Siegler JH, Moreno-Vinasco L, Salgia R, Moss J, Garcia JG.
Department of Medicine, University of Chicago, 5841 S Maryland Avenue, W604, Chicago, IL 60637, USA. psinglet@medicine.bsd.uchicago.edu

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Abstract

BACKGROUND: Recent cancer therapies include drugs that target both tumor growth and angiogenesis including mammalian target of rapamycin (mTOR) inhibitors. Since mTOR inhibitor therapy is associated with significant side effects, we examined potential agents that can reduce the therapeutic dose. METHODS: Methylnaltrexone (MNTX), a peripheral mu opioid receptor (MOR) antagonist, in combination with the mTOR inhibitors temsirolimus and/or rapamycin, was evaluated for inhibition of VEGF-induced human pulmonary microvascular endothelial cell (EC) proliferation and migration as well as in vivo angiogenesis (mouse Matrigel plug assay). RESULTS: MNTX inhibited VEGF-induced EC proliferation and migration with an IC50 of approximately 100 nM. Adding 10 nM MNTX to EC shifted the IC50 of temsirolimus inhibition of VEGF-induced proliferation and migration from approximately 10 nM to approximately 1 nM and from approximately 50 to approximately 10 nM respectively. We observed similar effects with rapamycin. On a mechanistic level, we observed that MNTX increased EC plasma membrane-associated tyrosine phosphate activity. Inhibition of tyrosine phosphatase activity (3,4-dephostatin) blocked the synergy between MNTX and temsirolimus and increased VEGF-induced tyrosine phosphorylation of Src with enhanced PI3 kinase and mTOR Complex 2-dependent phosphorylation of Akt and subsequent activation of mTOR Complex 1 (rapamycin and temsirolimus target), while silencing Src, Akt or mTOR complex 2 components blocked VEGF-induced angiogenic events. CONCLUSIONS: Our data indicate that MNTX exerts a synergistic effect with rapamycin and temsirolimus on inhibition of VEGF-induced human EC proliferation and migration and in vivo angiogenesis. Therefore, addition of MNTX could potentially lower the dose of mTOR inhibitors which could improve therapeutic index.

PMID: 20298531 [PubMed]PMCID: PMC2831839Free PMC Article




Regarding track record of using Metformin in non-diabetics:

Role of Metformin for Weight Management in Patients Without Type 2 Diabetes 2008
http://www.theannals.com/cgi/reprint/42/6/817



Oncogene. 2010 Feb 15. [Epub ahead of print]
Inhibition of cancer cell proliferation and metastasis by insulin receptor downregulation.

Zhang H, Fagan DH, Zeng X, Freeman KT, Sachdev D, Yee D.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Insulin receptor (IR) and the type I IGF receptor (IGF1R) are structurally and functionally related. The function of IGF1R in cancer has been well documented and anti-IGF1R strategies to treat cancer have shown initial positive results. However, the role of IR in tumor biology, independent of IGF1R, is less clear. To address this issue, short hairpin RNA (shRNA) was used to specifically downregulate IR in two cancer cell lines, LCC6 and T47D. Cells with reduced IR showed reduced insulin-stimulated Akt activation, without affecting IGF1R activation. Cells with reduced IR formed fewer colonies in anchorage-independent conditions. LCC6 IR shRNA xenograft tumors in mice had reduced growth, angiogenesis and lymphangiogensis when compared with LCC6 wild-type cells. Accordingly, LCC6 IR shRNA clones produced less hypoxia-inducible factor-1alpha, vascular endothelial growth factor (VEGF)-A and VEGF-D. Furthermore, LCC6 IR shRNA cells formed fewer pulmonary metastases when compared with LCC6 wild-type cells. Using in vivo luciferase imaging, we have shown that LCC6 IR shRNA cells have less seeding and colonization potential in the lung and liver of mice than LCC6 cells. In conclusion, downregulation of IR inhibited cancer cell proliferation, angiogenesis, lymphangiogenesis and metastasis. Our data argue that IR should also be targeted in cancer therapy.

Oncogene advance online publication, 15 February 2010; doi:10.1038/onc.2010.17.




Cancer Res. 2009 Aug 15;69(16):6539-45.
Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth.

Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E.
Departments of Medicine, CURE, Digestive Diseases Research Center, Molecular Biology Institute, University of California at Los Angeles, 90095-1786, USA.
Recently, we identified a novel crosstalk between insulin and G protein-coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. Metformin, the most widely used drug in the treatment of type 2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTOR. Here, we determined whether metformin disrupts the crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, and BxPC-3) with insulin (10 ng/mL) for 5 minutes markedly enhanced the increase in intracellular [Ca(2+)] induced by GPCR agonists (e.g., neurotensin, bradykinin, and angiotensin II). Metformin pretreatment completely abrogated insulin-induced potentiation of Ca(2+) signaling but did not interfere with the effect of GPCR agonists alone. Insulin also enhanced GPCR agonist-induced growth, measured by DNA synthesis, and the number of cells cultured in adherent or nonadherent conditions. Low doses of metformin (0.1-0.5 mmol/L) blocked the stimulation of DNA synthesis, and the anchorage-dependent and anchorage-independent growth induced by insulin and GPCR agonists. Treatment with metformin induced striking and sustained increase in the phosphorylation of AMPK at Thr(172) and a selective AMPK inhibitor (compound C, at 5 micromol/L) reversed the effects of metformin on [Ca(2+)](i) and DNA synthesis, indicating that metformin acts through AMPK activation. In view of these results, we tested whether metformin inhibits pancreatic cancer growth. Administration of metformin significantly decreased the growth of MIAPaCa-2 and PANC-1 cells xenografted on the flank of nude mice. These results raise the possibility that metformin could be a potential candidate in novel treatment strategies for human pancreatic cancer.

PMID: 19679549 [PubMed - indexed for MEDLINE]

PMID: 20154728 [PubMed - as supplied by publisher]v



Cancer Res. 2010 Mar 9. [Epub ahead of print]
Targeting Cancer Cell Metabolism: The Combination of Metformin and 2-Deoxyglucose Induces p53-Dependent Apoptosis in Prostate Cancer Cells.

Ben Sahra I, Laurent K, Giuliano S, Larbret F, Ponzio G, Gounon P, Le Marchand-Brustel Y, Giorgetti-Peraldi S, Cormont M, Bertolotto C, Deckert M, Auberger P, Tanti JF, Bost F.
Authors' Affiliations: Institut National de la Sante et de la Recherche Medicale (INSERM), U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 7, Cellular and Molecular Physiopathology of Obesity and Diabetes; Université de Nice Sophia-Antipolis, Faculté de Médecine, Institut Signalisation et Pathologies; INSERM, U895, C3M, Team 1; INSERM, U576; INSERM, U634; Université de Nice Sophia-Antipolis, Centre Commun de Microscopie Appliquée; and INSERM, U895, C3M, Team 2, Nice, France.
Targeting cancer cell metabolism is a new promising strategy to fight cancer. Metformin, a widely used antidiabetic agent, exerts antitumoral and antiproliferative action. In this study, the addition of metformin to 2-deoxyglucose (2DG) inhibited mitochondrial respiration and glycolysis in prostate cancer cells leading to a severe depletion in ATP. The combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone, leading to 96% inhibition of cell viability in LNCaP prostate cancer cells. In contrast, a moderate effect on cell viability was observed in normal prostate epithelial cells. At the cellular level, the combination of metformin and 2DG induced p53-dependent apoptosis via the energy sensor pathway AMP kinase, and the reexpression of a functional p53 in p53-deficient prostate cancer cells restored caspase-3 activity. In addition to apoptosis, the combination of metformin and 2DG arrested prostate cancer cells in G(2)-M. This G(2)-M arrest was independent of p53 and correlated with a stronger decrease in cell viability than obtained with either drug. Finally, metformin inhibited 2DG-induced autophagy, decreased beclin 1 expression, and triggered a switch from a survival process to cell death. Our study reinforces the growing interest of metabolic perturbators in cancer therapy and highlights the potential use of the combination of metformin and 2DG as an anticancerous treatment. Cancer Res; 70(6); 2465-75.

PMID: 20215500 [PubMed - as supplied by publisher]


Autophagy. 2010 Jul 21;6(5). [Epub ahead of print]
The combination of metformin and 2-deoxyglucose inhibits autophagy and induces AMPK dependent apoptosis in prostate cancer cells.

Sahra IB, Tanti JF, Bost F.
INSERM, U895, Centre Méditerranéen de Médecine Moléculaire (C3M), Team 7, Cellular and Molecular Physiopathology of Obesity and Diabetes, Nice, France; Université de Nice Sophia-Antipolis, Faculté de Médecine, Institut Signalisation et pathologies, Nice, France.
Abstract

Targeting cancer cell metabolism is a promising new strategy to fight cancer. Metformin, a widely used antidiabetic agent, and 2-deoxyglucose (2DG) drastically affect cancer cell metabolism. Recently, we showed that the combination of the two drugs was much more harmful for cancer cells than the treatment with metformin or 2DG alone. At the cellular level, this combination leads to p53- and AMPK-dependent apoptosis. Furthermore, we showed that metformin inhibits 2DG-induced autophagy, decreases beclin 1 expression and triggers a switch from a survival process to cell death.

PMID: 20559023 [PubMed - as supplied by publisher]






Breast Cancer Res Treat. 2010 Mar 19. [Epub ahead of print]
Metformin inhibits aromatase expression in human breast adipose stromal cells via stimulation of AMP-activated protein kinase.

Brown KA, Hunger NI, Docanto M, Simpson ER.
Prince Henry's Institute of Medical Research, P.O. Box 5152, Clayton, VIC, 3168, Australia, Kristy.Brown@princehenrys.org.
AMP-activated protein kinase (AMPK) is recognized as a master regulator of energy homeostasis. In concert with the AMPK-kinase LKB1, it has been shown to provide a molecular link between obesity and postmenopausal breast cancer via its actions to inhibit aromatase expression, hence estrogen production, within the breast. The anti-diabetic drug metformin is known to increase the activity of AMPK and was therefore hypothesized to inhibit aromatase expression in primary human breast adipose stromal cells. Results demonstrate that metformin significantly decreases the forskolin/phorbol ester (FSK/PMA)-induced expression of aromatase at concentrations of 10 and 50 muM. Consistent with the hypothesized actions of metformin to increase AMPK activity, treatment with 50 muM metformin results in a significant increase in phosphorylation of AMPK at Thr172. Interestingly, metformin also causes a significant increase in LKB1 protein expression and promoter activity, thereby providing for the first time an additional mechanism by which metformin activates AMPK. Furthermore, metformin inhibits the nuclear translocation of CRTC2, a CREB-coactivator known to increase aromatase expression which is also a direct downstream target of AMPK. Overall, these results suggest that metformin would reduce the local production of estrogens within the breast thereby providing a new key therapeutic tool that could be used in the neoadjuvant and adjuvant settings and conceivably also as a preventative measure in obese women.

PMID: 20300828 [PubMed - as supplied by publisher]






Cell Cycle. 2010 Mar 21;9(6). [Epub ahead of print]
Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena.

Martin-Castillo B, Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA.
Catalan Institute of Oncology (ICO) and Girona Biomedical Research Institute (IdIBGi), Girona, Catalonia, Spain.
In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs ("metabolic rehabilitation"). In the early 2000s, Anisimov's experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors. Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients' survival in type 2 diabetics. At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may constitute a novel "hybrid anti-cancer pill" physically combining both the long-lasting effects of antibodies-by persistently lowering levels of blood insulin and glucose-and the immediate potency of a cancer cell-targeting molecular agent-by suppressing the pivotal AMPK/mTOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER1 and HER2-. In this scenario, we discuss the relevance of metformin doses in pre-clinical models regarding metformin's mechanisms of action in clinical settings. We examine recent landmark studies demonstrating metformin's ability to specifically target the cancer-initiating stem cells from which tumor cells develop, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion hypothesis). We present the notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self-maintenance and repair (hormesis) might trigger counterintuitive detrimental effects. Ongoing chemopreventive, neoadjuvant and adjuvant trials should definitely establish whether metformin's ability to kill the "dandelion root" beneath the "cancer soil" likely exceeds metformin-related dangers of hormesis.

PMID: 20305377 [PubMed - as supplied by publisher]


Curr Mol Med. 2010 Aug 16. [Epub ahead of print]
Metformin and Energy Metabolism in Breast Cancer: From Insulin Physiology to Tumour-initiating Stem Cells.

Vazquez-Martin A, Oliveras-Ferraros C, CufÃ* S, Martin-Castillo B, Menendez JA.
Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain. jmenendez@iconcologia.net.
Abstract

A whole new area of investigation has emerged recently with regards to the anti-diabetic drug metformin and breast cancer. Metformin's anti-breast cancer actions, observed in population studies, in rodents and in cultured tumour cells, are especially encouraging because they attack not only the most common bulk of the tumour cells but also the more rare tumour-initiating stem cells. Here, we illustrate the multifaceted and redundant mechanisms through which metformin-reprogrammed energy metabolism at both the organismal and cellular levels constitutes a novel and valuable strategy to prevent and treat breast cancer disease.

PMID: 20712585 [PubMed - as supplied by publisher]