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Rich66 · 11-14-2009, 10:33 PM

Ann Oncol. 2009 Nov 2. [Epub ahead of print]
Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemotherapy and trastuzumab: an ongoing clinical-translational research experience at the Catalan Institute of Oncology.

Martin-Castillo B, Dorca J, Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E, Garcia M, Del Barco S, Menendez JA.
Translational Research Unit, Catalan Institute of Oncology.
PMID: 19884247 [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.

Eur J Cancer. 2010 Jul 23. [Epub ahead of print]
Metformin: Taking away the candy for cancer?

Jalving M, Gietema JA, Lefrandt JD, Jong SD, Reyners AK, Gans RO, Vries EG.
Department of Medical Oncology, University Medical Centre Groningen, The Netherlands; Department of Internal Medicine, University Medical Centre Groningen, The Netherlands.
Abstract

TEXT

Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformin's anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug.

PMID: 20656475 [PubMed - as supplied by publisher]

LKB1 is a master kinase in cancer
Posted: 01 Sep 2010 11:27 AM PDT
"LKB1 is a master kinase"
What a great subheader in a paper last year by Reuben Shaw (journal link below).
Liver kinase B1 (LKB1) first got my attention at the AACR lung cancer meeting in San Diego earlier this year, when a couple of translational researchers mentioned it during informal discussions about how it might play a critical but subtle role in lung cancer and potentially other cancers.
Looking at the literature, LKB1 was first identified as a tumor suppressor gene on human chromosome 19p13, responsible for the inherited cancer disorder Peutz-Jeghers Syndrome (PJS). However, the interest at the AACR meeting centred around it being one of the most commonly mutated genes in sporadic human lung cancer, including some subtypes of non-small cell lung carcinoma (NSCLC).
Of course, being very interested in potential druggable targets, I was trying to get my head around this particular kinase. Several scientists and researchers explained to me patiently that LKB1 is involved in energy levels and metabolism, rather than cell signalling per se, so it kind of went by the wayside as other interesting targets came up lately, associated with small molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies.
Still, the fact that LKB1 and AMPK control cell growth in response to environmental nutrient changes stuck in the back of my mind while I quietly wondered whether it would eventually have it's day.
Fast forward to an AACR press conference this morning about the role of metformin, a biguanide therapy for managing hyperglycemia and diabetes, in the role of chemoprevention. I'm going to write more about that meaty topic in another more detailed post tomorrow, but what fasinated me was the mention by Dr Michael Pollak about metformin altering cell energy levels, ie a control system that senses cell energy supplies and low reserves.
It was also mentioned that the activation of the LKB1-AMPK pathway downregulates gluconeogenesis. This process represents the export of energy from hepatocytes to the organism in the form of glucose. In turn, this reduces blood glucose concentration, which results in a secondary decrease in insulin level.
Essentially, the inhibition of hepatic gluconeogenesis is now felt to be a key process underlying the utility of biguanides in the therapy of type II diabetes.
What is interesting on several levels is:

Studies showing raised levels of free or circulating IGF1 may be associated with an increased risk of developing cancer
Epidemiology studies amongst people with diabetes taking metformin who may have a lower risk of developing cancer

Of course, when we look at the broader picture, we can see the interactions across several pathways, which makes the whole situation highly complex:

Source: University of Dundee
Clearly, there is now enough evidence to warrant researching the effects of metformin in cancer prevention, especially given that it is orally available, has had no long term safety issues and is now generically available. These factors, coupled with a greater understanding of the biology of the involved pathways may make a productive new area of cancer research.
Tomorrow, I will cover the latest research involving metformin for chemoprevention in colorectal and lung cancers in more detail.

Shaw RJ (2009). LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta physiologica (Oxford, England), 196 (1), 65-80 PMID: 19245654
Shackelford DB, & Shaw RJ (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature reviews. Cancer, 9 (8), 563-75 PMID: 19629071

11-14-2009, 10:33 PM	#20
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Common Diabetes Drug May 'Revolutionize' Cancer Therapies: Unexpected T-cell Brea Ann Oncol. 2009 Nov 2. [Epub ahead of print] Incorporating the antidiabetic drug metformin in HER2-positive breast cancer treated with neo-adjuvant chemotherapy and trastuzumab: an ongoing clinical-translational research experience at the Catalan Institute of Oncology. Martin-Castillo B, Dorca J, Vazquez-Martin A, Oliveras-Ferraros C, Lopez-Bonet E, Garcia M, Del Barco S, Menendez JA. Translational Research Unit, Catalan Institute of Oncology. PMID: 19884247 [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. Eur J Cancer. 2010 Jul 23. [Epub ahead of print] Metformin: Taking away the candy for cancer? Jalving M, Gietema JA, Lefrandt JD, Jong SD, Reyners AK, Gans RO, Vries EG. Department of Medical Oncology, University Medical Centre Groningen, The Netherlands; Department of Internal Medicine, University Medical Centre Groningen, The Netherlands. Abstract TEXT Metformin is widely used in the treatment of diabetes mellitus type 2 where it reduces insulin resistance and diabetes-related morbidity and mortality. Population-based studies show that metformin treatment is associated with a dose-dependent reduction in cancer risk. The metformin treatment also increases complete pathological tumour response rates following neoadjuvant chemotherapy for breast cancer, suggesting a potential role as an anti-cancer drug. Diabetes mellitus type 2 is associated with insulin resistance, elevated insulin levels and an increased risk of cancer and cancer-related mortality. This increased risk may be explained by activation of the insulin- and insulin-like growth factor (IGF) signalling pathways and increased signalling through the oestrogen receptor. Reversal of these processes through reduction of insulin resistance by the oral anti-diabetic drug metformin is an attractive anti-cancer strategy. Metformin is an activator of AMP-activated protein kinase (AMPK) which inhibits protein synthesis and gluconeogenesis during cellular stress. The main downstream effect of AMPK activation is the inhibition of mammalian target of rapamycin (mTOR), a downstream effector of growth factor signalling. mTOR is frequently activated in malignant cells and is associated with resistance to anticancer drugs. Furthermore, metformin can induce cell cycle arrest and apoptosis and can reduce growth factor signalling. This review discusses the role of diabetes mellitus type 2 and insulin resistance in carcinogenesis, the preclinical rationale and potential mechanisms of metformin's anti-cancer effect and the current and future clinical developments of metformin as a novel anti-cancer drug. PMID: 20656475 [PubMed - as supplied by publisher] LKB1 is a master kinase in cancer Posted: 01 Sep 2010 11:27 AM PDT "LKB1 is a master kinase" What a great subheader in a paper last year by Reuben Shaw (journal link below). Liver kinase B1 (LKB1) first got my attention at the AACR lung cancer meeting in San Diego earlier this year, when a couple of translational researchers mentioned it during informal discussions about how it might play a critical but subtle role in lung cancer and potentially other cancers. Looking at the literature, LKB1 was first identified as a tumor suppressor gene on human chromosome 19p13, responsible for the inherited cancer disorder Peutz-Jeghers Syndrome (PJS). However, the interest at the AACR meeting centred around it being one of the most commonly mutated genes in sporadic human lung cancer, including some subtypes of non-small cell lung carcinoma (NSCLC). Of course, being very interested in potential druggable targets, I was trying to get my head around this particular kinase. Several scientists and researchers explained to me patiently that LKB1 is involved in energy levels and metabolism, rather than cell signalling per se, so it kind of went by the wayside as other interesting targets came up lately, associated with small molecule tyrosine kinase inhibitors (TKIs) or monoclonal antibodies. Still, the fact that LKB1 and AMPK control cell growth in response to environmental nutrient changes stuck in the back of my mind while I quietly wondered whether it would eventually have it's day. Fast forward to an AACR press conference this morning about the role of metformin, a biguanide therapy for managing hyperglycemia and diabetes, in the role of chemoprevention. I'm going to write more about that meaty topic in another more detailed post tomorrow, but what fasinated me was the mention by Dr Michael Pollak about metformin altering cell energy levels, ie a control system that senses cell energy supplies and low reserves. It was also mentioned that the activation of the LKB1-AMPK pathway downregulates gluconeogenesis. This process represents the export of energy from hepatocytes to the organism in the form of glucose. In turn, this reduces blood glucose concentration, which results in a secondary decrease in insulin level. Essentially, the inhibition of hepatic gluconeogenesis is now felt to be a key process underlying the utility of biguanides in the therapy of type II diabetes. What is interesting on several levels is: Studies showing raised levels of free or circulating IGF1 may be associated with an increased risk of developing cancer Epidemiology studies amongst people with diabetes taking metformin who may have a lower risk of developing cancer Of course, when we look at the broader picture, we can see the interactions across several pathways, which makes the whole situation highly complex: Source: University of Dundee Clearly, there is now enough evidence to warrant researching the effects of metformin in cancer prevention, especially given that it is orally available, has had no long term safety issues and is now generically available. These factors, coupled with a greater understanding of the biology of the involved pathways may make a productive new area of cancer research. Tomorrow, I will cover the latest research involving metformin for chemoprevention in colorectal and lung cancers in more detail. Shaw RJ (2009). LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta physiologica (Oxford, England), 196 (1), 65-80 PMID: 19245654 Shackelford DB, & Shaw RJ (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nature reviews. Cancer, 9 (8), 563-75 PMID: 19629071 __________________ Mom's treatment history (link)