Various leads on her2 cancer

[Christine MH-UK]

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.

[R.B.]

Thank you for that post.

The COX 2 finding was particularly interesting, particularly as to fats and dietary implications, low level whole body inflamation, inflamatory conditions inc IBS etc. Poor mice!

An article on BC and genetic arrays clealry demonstrated that Her is only one a a series of highly overexpressed genes in BC. I will post the link when it resurfaces.

Another interesting link suggested the possibility that some cancerous cells produce their own oestrogen?!


RB

[DeborahNC]

I have an article on PTEN-null cancer cells and the use of Quercetin that is interesting if someone can tell me how to cut & paste here.

[Christine MH-UK]

I just highlight the text I want to post, ctrl+c to copy, go to the window and type ctrl+V. This is for copying from html. If you want to copy from adobe acrobat, you need to click on the little triangle and highlight the text to copy, then click the copy text icon. However, it doesn't always work.

[DeborahNC]

Thank you so much for the help!



The antiproliferative effect of Quercetin in cancer cells is mediated via inhibition of the PI3K-Akt/PKB pathway.

Gulati N, Laudet B, Zohrabian VM, Murali R, Jhanwar-Uniyal M.

Department of Neurosurgery, New YorkMedicalCollege, Valhalla, NY10595, USA.

BACKGROUND: The tumor suppressor gene PTEN, mutated in 40-50% of patients with brain tumors, especially those with glioblastomas, maps to chromosome 10q23.3 and encodes a dual-specificity phosphatase. PTEN exerts its effects partly via inhibition of protein tyrosine kinase B (Akt/Protein Kinase B), which is involved in the phosphatidylinositol (PtdIns) 3-kinase (PI3K)-mediated cell-survival pathway. The naturally occurring bioflavonoid Quercetin (Qu) shares structural homology with the commercially available selective PI3K inhibitor, LY 294002 (LY). Here, the effects of Qu on the Akt/PKB pathway were evaluated. MATERIALS AND METHODS: The human breast carcinoma cell lines, HCC1937, with homozygous deletion of the PTEN gene, and T47D, with intact PTEN, were time-treated with Qu or LY and analyzed for activated levels of Akt by measuring phospho-Akt (p-Akt) levels using immunoblotting analysis. To detect p-Akt, the T47D cells were treated with EGF prior to treatment with or without Qu or LY Cell proliferation after 24-h treatment with Qu or LY was quantified by the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. RESULTS: Treatment with Qu (25 microM) for 0.5, 1 and 3 h completely suppressed constitutively activated Akt/PKB phosphorylation at Ser-473 in HCC1937 cells. Pre-exposing T47D cells to Qu (25 microM) or LY (10 microM) abrogated EGF-induced Akt/PKB phosphorylation at Ser-473. Both Qu (100 microM) and LY (50 microM) treatments for 24 h significantly decreased cell proliferation, as shown by the MTT assay. CONCLUSION: Pharmacologically safe doses of the naturally occurring bioflavonoid Qu inhibit the PI3K-Akt/PKB pathway, in a manner similar to that of the commercially available LY. Overall, our results indicated that Qu inhibited the constitutively activated-Akt/PKB pathway in PTEN-null cancer cells, and suggest that this compound may have therapeutic benefit against tumorigenesis and cancer progression.