HER2 Support Group Forums - View Single Post - Novel Cancer Therapies Aim to Destroy the Disease at Its Root: The Cancer Stem Cell

Rich66 · 06-10-2009, 09:44 AM

U-M researchers link pathway to breast cancer stem cells

Drug that inhibits this pathway shown to reduce stem cell population

added 6/01/09 Ann Arbor - A gene well known to stop or suppress cancer plays a role in cancer stem cells, according to a new study from the University of Michigan Comprehensive Cancer Center. The researchers found that several pathways linked to the gene, called PTEN, also affected the growth of breast cancer stem cells.

Meet the Expert
Max S. Wicha, M.D.

Read the article

Download the images

Further, by using a drug that interferes with that pathway, the researchers produced an up to 90 percent decrease in the number of cancer stem cells within a tumor.
The study appears in the June issue of PLoS Biology, a journal from the Public Library of Science.
PTEN is the most frequently inactivated tumor suppressor gene in several cancers, including breast cancer, where it is inactivated in about 40 percent of patients. PTEN is linked to poor outcomes and is associated with aggressive cancers resistant to chemotherapy and current targeted therapies.
The U-M researchers deleted PTEN in tumors grown in cell cultures and in mice, and found an increase in the number of stem cells. They also looked at pathways associated with PTEN and reported that a pathway called PI3-K/Akt regulated the cancer stem cell population by activating another stem cell pathway, Wnt, which is also implicated in multiple cancer types.
"Although there has been considerable progress in identifying cancer stem cells in a variety of tumor types, the pathways that drive the transformation of these cells are not well understood," says lead study author Hasan Korkaya, D.V.M., Ph.D., research investigator in internal medicine at the U-M Medical School.
Researchers at U-M were the first to identify stem cells in breast cancer. These cells represent fewer than 5 percent of the cells in a tumor but are believed to be responsible for fueling a tumor’s growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells.
In the current study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumors in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone showed no effect on the number of cancer stem cells in the tumor. But adding perifosine reduced the cancer stem cell population by up to 90 percent.
What's more, the cells treated with perifosine – either with or without docetaxel – were less likely to grow a secondary tumor, compared to the cells treated with just docetaxel.
"This is most exciting since perifosine and other drugs that target this pathway are currently in clinical development. If cancer stem cells do contribute to tumor relapse, then adding drugs that target these cells may help to make our current therapies more effective," says study senior author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.

Breast cancer U-M Cancer AnswerLine, 800-865-1125

Similar article: http://www.sciencedaily.com/releases...0601211427.htm





1: PLoS Biol. 2009 Jun 2;7(6):e1000121. Epub 2009 Jun 2. Links: Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling.

Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, Clouthier SG, Wicha MS.
Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. hkorkaya@med.umich.edu
Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/beta-catenin pathway through the phosphorylation of GSK3-beta. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/beta-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells.
PMID: 19492080 [PubMed - in process]



1: Orv Hetil. 2009 Feb 22;150(8):373-8. Links: Akt enzyme: new therapeutic target in cancer and diabetes?

Cseh A, Szebeni B, Szalay B, Vásárhelyi B.
Semmelweis Egyetem, Altalános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest Bókay u. 54. 1083, Hungary. sceharon@gmail.com
Alteration of apoptotic processes plays a central role in the development and progression of several chronic disorders. Proteins responsible for the regulation of apoptosis are therapeutic targets; these include the Akt enzyme. Akt enzyme is expressed in most cell types. Akt activation is regulated by growth factors, insulin, and also environmental factors as altered oxygen tension and high temperature. Akt is a central regulator of cellular metabolism and survival. Akt function is reportedly altered in some disorders. An increased activity of Akt has been described in prostate, breast, colon, and pancreatic cancer, as well as in hematological malignancies. Akt is also a factor in the pathomechanism of diabetes as it determines beta-cell apoptosis of Langerhans islets and insulin sensitivity of the cells. Several studies revealed that some of the marketed drugs including statins, thiazolidinediones and ACE inhibitors modulate Akt activity. There are efforts to develop specific Akt inhibitors that may improve the efficacy of chemotherapy. Triciribine and perifosine are two Akt inhibitors in developmental phase 1 and 2 that may improve survival in breast cancer, pancreas cancer, gastrointestinal stroma tumor, sarcoma and melanoma, and in hematological malignancy.
PMID: 19218147 [PubMed - indexed for MEDLINE]

06-10-2009, 09:44 AM	#11
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	U-M researchers link pathway to breast cancer stem cells Drug that inhibits this pathway shown to reduce stem cell population added 6/01/09 Ann Arbor - A gene well known to stop or suppress cancer plays a role in cancer stem cells, according to a new study from the University of Michigan Comprehensive Cancer Center. The researchers found that several pathways linked to the gene, called PTEN, also affected the growth of breast cancer stem cells. Meet the Expert Max S. Wicha, M.D. Read the article Download the images Further, by using a drug that interferes with that pathway, the researchers produced an up to 90 percent decrease in the number of cancer stem cells within a tumor. The study appears in the June issue of PLoS Biology, a journal from the Public Library of Science. PTEN is the most frequently inactivated tumor suppressor gene in several cancers, including breast cancer, where it is inactivated in about 40 percent of patients. PTEN is linked to poor outcomes and is associated with aggressive cancers resistant to chemotherapy and current targeted therapies. The U-M researchers deleted PTEN in tumors grown in cell cultures and in mice, and found an increase in the number of stem cells. They also looked at pathways associated with PTEN and reported that a pathway called PI3-K/Akt regulated the cancer stem cell population by activating another stem cell pathway, Wnt, which is also implicated in multiple cancer types. "Although there has been considerable progress in identifying cancer stem cells in a variety of tumor types, the pathways that drive the transformation of these cells are not well understood," says lead study author Hasan Korkaya, D.V.M., Ph.D., research investigator in internal medicine at the U-M Medical School. Researchers at U-M were the first to identify stem cells in breast cancer. These cells represent fewer than 5 percent of the cells in a tumor but are believed to be responsible for fueling a tumor’s growth and spread. Researchers believe that the ultimate cure of cancer will require killing these cancer stem cells. In the current study, researchers looked at a drug called perifosine, which inhibits the Akt pathway. Tumors in mice were treated with perifosine or docetaxel, a standard chemotherapy drug. The docetaxel alone showed no effect on the number of cancer stem cells in the tumor. But adding perifosine reduced the cancer stem cell population by up to 90 percent. What's more, the cells treated with perifosine – either with or without docetaxel – were less likely to grow a secondary tumor, compared to the cells treated with just docetaxel. "This is most exciting since perifosine and other drugs that target this pathway are currently in clinical development. If cancer stem cells do contribute to tumor relapse, then adding drugs that target these cells may help to make our current therapies more effective," says study senior author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center. Breast cancer U-M Cancer AnswerLine, 800-865-1125 Similar article: http://www.sciencedaily.com/releases...0601211427.htm 1: PLoS Biol. 2009 Jun 2;7(6):e1000121. Epub 2009 Jun 2. Links Regulation of mammary stem/progenitor cells by PTEN/Akt/beta-catenin signaling. Korkaya H, Paulson A, Charafe-Jauffret E, Ginestier C, Brown M, Dutcher J, Clouthier SG, Wicha MS. Comprehensive Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA. hkorkaya@med.umich.edu Recent evidence suggests that many malignancies, including breast cancer, are driven by a cellular subcomponent that displays stem cell-like properties. The protein phosphatase and tensin homolog (PTEN) is inactivated in a wide range of human cancers, an alteration that is associated with a poor prognosis. Because PTEN has been reported to play a role in the maintenance of embryonic and tissue-specific stem cells, we investigated the role of the PTEN/Akt pathway in the regulation of normal and malignant mammary stem/progenitor cell populations. We demonstrate that activation of this pathway, via PTEN knockdown, enriches for normal and malignant human mammary stem/progenitor cells in vitro and in vivo. Knockdown of PTEN in normal human mammary epithelial cells enriches for the stem/progenitor cell compartment, generating atypical hyperplastic lesions in humanized NOD/SCID mice. Akt-driven stem/progenitor cell enrichment is mediated by activation of the Wnt/beta-catenin pathway through the phosphorylation of GSK3-beta. In contrast to chemotherapy, the Akt inhibitor perifosine is able to target the tumorigenic cell population in breast tumor xenografts. These studies demonstrate an important role for the PTEN/PI3-K/Akt/beta-catenin pathway in the regulation of normal and malignant stem/progenitor cell populations and suggest that agents that inhibit this pathway are able to effectively target tumorigenic breast cancer cells. PMID: 19492080 [PubMed - in process] 1: Orv Hetil. 2009 Feb 22;150(8):373-8. Links Akt enzyme: new therapeutic target in cancer and diabetes? Cseh A, Szebeni B, Szalay B, Vásárhelyi B. Semmelweis Egyetem, Altalános Orvostudományi Kar I. Gyermekgyógyászati Klinika Budapest Bókay u. 54. 1083, Hungary. sceharon@gmail.com Alteration of apoptotic processes plays a central role in the development and progression of several chronic disorders. Proteins responsible for the regulation of apoptosis are therapeutic targets; these include the Akt enzyme. Akt enzyme is expressed in most cell types. Akt activation is regulated by growth factors, insulin, and also environmental factors as altered oxygen tension and high temperature. Akt is a central regulator of cellular metabolism and survival. Akt function is reportedly altered in some disorders. An increased activity of Akt has been described in prostate, breast, colon, and pancreatic cancer, as well as in hematological malignancies. Akt is also a factor in the pathomechanism of diabetes as it determines beta-cell apoptosis of Langerhans islets and insulin sensitivity of the cells. Several studies revealed that some of the marketed drugs including statins, thiazolidinediones and ACE inhibitors modulate Akt activity. There are efforts to develop specific Akt inhibitors that may improve the efficacy of chemotherapy. Triciribine and perifosine are two Akt inhibitors in developmental phase 1 and 2 that may improve survival in breast cancer, pancreas cancer, gastrointestinal stroma tumor, sarcoma and melanoma, and in hematological malignancy. PMID: 19218147 [PubMed - indexed for MEDLINE]