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Christine MH-UK · 05-16-2006, 03:28 PM

I thought I would group them together to avoid cluttering things up. There's nothing terribly earth shattering, although it is good to know that the scientists are hard at work:

http://mct.aacrjournals.org/cgi/cont...stract/5/2/317
Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells, M.D. Anderson

"HER2 overexpression is one of the most recognizable molecular alterations in breast tumors known to be associated with a poor prognosis. In the study described here, we explored the effect of HER2 overexpression on the sensitivity of breast cancer cells to the growth-inhibitory effects of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a synthetic triterpenoid, both in vitro and in vivo in a xenograft model of breast cancer...[our] findings provide the first in vitro and in vivo evidence that CDDO effectively inhibits HER2 tyrosine kinase activity and potently suppresses the growth of HER2-overexpressing breast cancer cells and suggest that CDDO has a therapeutic potential in advanced breast cancer."

http://www.corporate-ir.net/ireye/ir...item_id=852586

From Immunogen investor relations:
"Trastuzumab-DM1 . Phase I testing in patients with HER2-positive metastatic breast cancer began in April 2006." It is a tumour activated prodrug. This one sentence is all of interest in the press release.

http://cancerres.aacrjournals.org/cg...ct/65/21/10113

HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice

"The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in

40% of human breast cancers and at higher frequencies in preinvasive ductal carcinoma in situ (DCIS). Cox-2 expression is particularly associated with overexpression of human epidermal growth factor receptor 2 (HER2/neu). To definitively interrogate the role of Cox-2 in mammary neoplasia, we have used a genetic approach, crossing Cox-2-deficient mice with a HER2/neu transgenic strain, MMTV/NDL. At 20 weeks of age, mammary glands from virgin MMTV/NDL females contained multiple focal tumors, or mammary intraepithelial neoplasias, which histologically resembled human DCIS. Mammary tumor multiplicity and prostaglandin E2 (PGE2) levels were significantly decreased in Cox-2 heterozygous and knockout animals relative to Cox-2 wild-type controls. Notably, the proportion of larger tumors was decreased in Cox-2-deficient mice. HER2/neu-induced mammary hyperplasia was also substantially reduced in Cox-2 null mice. Additionally, mammary glands from Cox-2 knockout mice exhibited a striking reduction in vascularization, and expression of proangiogenic genes was correspondingly reduced. Decreased vascularization was observed both in dysplastic and normal-appearing regions of Cox-2-null mammary glands. Our data provide the first genetic evidence that Cox-2 contributes to HER2/neu-induced mammary tumorigenesis. This finding may help to explain the reduced risk of breast cancer associated with regular use of nonsteroidal anti-inflammatory drugs."

http://www.bioportfolio.com/april_06...st_cancer.html

Trastuzumab breast cancer therapy efficacy predicted by PTEN activity

original article from British Journal of Cancer (PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer, 2006;94(2):247-252).

"We propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level."

http://www.bioportfolio.com/april_06...zes_ErbB2.html
Herceptin sensitizes ErbB2-overexpressing cells to apoptosis

herceptin sensitizes ErbB2-overexpressing cells to apoptosis by reducing antiapoptotic Mcl-1 expression..."In 29 human breast tumors immunostained for ErbB2 and Mcl-1, we found that when ErbB2 was overexpressed, there was a corresponding increase in Mcl-1 expression. Using murine fibroblasts that express human ErbB2, but no other ErbB family member (NE2), these cells showed resistance to both taxol- and etoposide-induced apoptosis compared with parental cells...In addition, NE2 cells preferentially express the antiapoptotic Bcl-2 family member Mcl-1 compared with parental cells, and treatment with herceptin reduces Mcl-1 expression."

http://www.aveopharma.com/content/me...p/q/news-id/38
Corporate Press Release Based on AACR 2006 presentation:
AV-412, a novel EGFR/HER2 kinase inhibitor, demonstrates potent anti-tumor activity against both Tarceva® and Iressa®-sensitive and resistant tumors -- AV-412 holds promise as a broader-acting EFGR/HER2 inhibitor
No mention of breast cancer per se, but it is seen as a drug that might work across EGFR/HER2 solid tumours.

05-16-2006, 03:28 PM	#1
Christine MH-UK Senior Member Join Date: Sep 2005 Posts: 414	Various leads on her2 cancer I thought I would group them together to avoid cluttering things up. There's nothing terribly earth shattering, although it is good to know that the scientists are hard at work: http://mct.aacrjournals.org/cgi/cont...stract/5/2/317 Synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces growth arrest in HER2-overexpressing breast cancer cells, M.D. Anderson "HER2 overexpression is one of the most recognizable molecular alterations in breast tumors known to be associated with a poor prognosis. In the study described here, we explored the effect of HER2 overexpression on the sensitivity of breast cancer cells to the growth-inhibitory effects of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), a synthetic triterpenoid, both in vitro and in vivo in a xenograft model of breast cancer...[our] findings provide the first in vitro and in vivo evidence that CDDO effectively inhibits HER2 tyrosine kinase activity and potently suppresses the growth of HER2-overexpressing breast cancer cells and suggest that CDDO has a therapeutic potential in advanced breast cancer." http://www.corporate-ir.net/ireye/ir...item_id=852586 From Immunogen investor relations: "Trastuzumab-DM1 . Phase I testing in patients with HER2-positive metastatic breast cancer began in April 2006." It is a tumour activated prodrug. This one sentence is all of interest in the press release. http://cancerres.aacrjournals.org/cg...ct/65/21/10113 HER2/neu-Induced Mammary Tumorigenesis and Angiogenesis Are Reduced in Cyclooxygenase-2 Knockout Mice "The inducible prostaglandin synthase cyclooxygenase-2 (Cox-2) is overexpressed in 40% of human breast cancers and at higher frequencies in preinvasive ductal carcinoma in situ (DCIS). Cox-2 expression is particularly associated with overexpression of human epidermal growth factor receptor 2 (HER2/neu). To definitively interrogate the role of Cox-2 in mammary neoplasia, we have used a genetic approach, crossing Cox-2-deficient mice with a HER2/neu transgenic strain, MMTV/NDL. At 20 weeks of age, mammary glands from virgin MMTV/NDL females contained multiple focal tumors, or mammary intraepithelial neoplasias, which histologically resembled human DCIS. Mammary tumor multiplicity and prostaglandin E2 (PGE2) levels were significantly decreased in Cox-2 heterozygous and knockout animals relative to Cox-2 wild-type controls. Notably, the proportion of larger tumors was decreased in Cox-2-deficient mice. HER2/neu-induced mammary hyperplasia was also substantially reduced in Cox-2 null mice. Additionally, mammary glands from Cox-2 knockout mice exhibited a striking reduction in vascularization, and expression of proangiogenic genes was correspondingly reduced. Decreased vascularization was observed both in dysplastic and normal-appearing regions of Cox-2-null mammary glands. Our data provide the first genetic evidence that Cox-2 contributes to HER2/neu-induced mammary tumorigenesis. This finding may help to explain the reduced risk of breast cancer associated with regular use of nonsteroidal anti-inflammatory drugs." http://www.bioportfolio.com/april_06...st_cancer.html Trastuzumab breast cancer therapy efficacy predicted by PTEN activity original article from British Journal of Cancer (PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer, 2006;94(2):247-252). "We propose PTEN as a predictive biomarker for trastuzumab efficacy. Human breast cancer SKBR3 and drug-resistant SKBR3/R cells were investigated. We also examined clinical samples from patients who had been treated with trastuzumab and analysed the relationship between trastuzumab efficacy and PTEN level." http://www.bioportfolio.com/april_06...zes_ErbB2.html Herceptin sensitizes ErbB2-overexpressing cells to apoptosis herceptin sensitizes ErbB2-overexpressing cells to apoptosis by reducing antiapoptotic Mcl-1 expression..."In 29 human breast tumors immunostained for ErbB2 and Mcl-1, we found that when ErbB2 was overexpressed, there was a corresponding increase in Mcl-1 expression. Using murine fibroblasts that express human ErbB2, but no other ErbB family member (NE2), these cells showed resistance to both taxol- and etoposide-induced apoptosis compared with parental cells...In addition, NE2 cells preferentially express the antiapoptotic Bcl-2 family member Mcl-1 compared with parental cells, and treatment with herceptin reduces Mcl-1 expression." http://www.aveopharma.com/content/me...p/q/news-id/38 Corporate Press Release Based on AACR 2006 presentation: AV-412, a novel EGFR/HER2 kinase inhibitor, demonstrates potent anti-tumor activity against both Tarceva® and Iressa®-sensitive and resistant tumors -- AV-412 holds promise as a broader-acting EFGR/HER2 inhibitor No mention of breast cancer per se, but it is seen as a drug that might work across EGFR/HER2 solid tumours.