For Lani....

[Jean]

Do we know for certain what role PTEN alteration plays in her2 tumors?
We know there is a connection however I thought it is
still tangential. I thought that PTEN was under research at MD Anderson.
Is there any good drug to target the PI-3 Kinase/PTEN pathway
for those that test negative for PTEN? I don't believe there is any :(

Thanks Lani,
Jean

[Lani]

you've got me on a bad day...I am travelling with limited internet access. Will try to answer this weekend.

Lani

[Jean]

Safe return....

Regards,
Jean

[Jean]

Just moving this up.....Lani know how busy you are and welcome back from
your business trips - always good to get home...after one of those.

If you have or can find anything on this I would apprecite. I have
looked around but did not find anything.

Kind Regards,
Jean

[heblaj01]

Jean,
Lani is likely to provide a thorough answer to your question when able to respond.
In the meantime here are two bits of info from previous posts:


http://www.sciencedaily.com/releases/2007/01/070111121906.htm
Novel Regulation Of The Common Tumor Suppressor PTEN

http://www.her2support.org/vbulletin/showthread.php?t=24955
I3C upregulates PTEN--could broccoli make herceptin work better?

Also posts #11 & 12 in this thread:
http://www.her2support.org/vbulletin/showthread.php?p=77534

[Lani]

hit by stomach flu upon my return.

A few brief thoughts...I posted already how Tykerb's efficacy doesn't depend on the presence of PTEN and therefore should work on those with her2+ tumors who are not PTEN positive.

Will try to add more later...

[Jean]

Hoping you feel better fast....yes, I am already in contact!
You can now add mind reader to propeller head....

Sending healing energy.
Jean

[Jean]

Many thanks,
I was anxious to know if any new class of drugs have been noted (besides
the natural food track) to increase the level of PTEN....or if any drugs being
tested have shown some hope?

Good links and enjoyed reading....
Regards,
jean

[Lani]

1: Mol Pharmacol. 2006 Nov;70(5):1534-41. Epub 2006 Aug 3. Links
Overcoming trastuzumab resistance in HER2-overexpressing breast cancer cells by using a novel celecoxib-derived phosphoinositide-dependent kinase-1 inhibitor.

Tseng PH,
Wang YC,
Weng SC,
Weng JR,
Chen CS,
Brueggemeier RW,
Shapiro CL,
Chen CY,
Dunn SE,
Pollak M,
Chen CS.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, 336 Parks Hall, The Ohio State University, 500 West 12th Avenue, Columbus, 43210-1291, USA.
Although trastuzumab has been successfully used in patients with HER2-overexpressing metastatic breast cancer, resistance is a common problem that ultimately culminates in treatment failure. In light of the importance of Akt signaling in trastuzumab's antitumor action, we hypothesized that concurrent inhibition of Akt could enhance trastuzumab sensitivity and moreover reverse the resistant phenotype in HER2-positive breast cancer cells. Based on our finding that celecoxib mediates antitumor effects through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling independently of cyclooxygenase-2 (COX-2), we used celecoxib as a scaffold to develop a COX-2-inactive PDK-1 inhibitor, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012). Here, we investigated the effect of OSU-03012 on trastuzumab-mediated apoptosis in four breast cancer cell lines with different HER2 expression and trastuzumab-resistance status, including MDA-MB-231, BT474, SKBR3, and insulin-like growth factor-I receptor-overexpressing SKBR3 (SKBR3/IGF-IR). Effects of trastuzumab and OSU-03012, individually or in combination, on cell viability and changes in pertinent biomarkers including HER2 expression, phosphorylation of Akt, p27(kip1), and the PDK-1 substrate p70(S6K) were assessed. OSU-03012 alone was able to trigger apoptosis in all cell lines with equal potency (IC(50) = 3-4 microM), suggesting no cross-resistance with trastuzumab. Medium dose-effect analysis indicates that OSU-03012 potentiated trastuzumab's antiproliferative effect in HER2-positive cells, especially in SKBR3/IGF-IR cells, through the down-regulation of PDK-1/Akt signaling. This synergy, however, was not observed in HER2-negative MDA-MB-231 cells. This combination treatment represents a novel strategy to increase the efficacy of trastuzumab and to overcome trastuzumab resistance in the treatment of HER2-positive breast cancer.
PMID: 16887935 [PubMed - indexed for MEDLINE]

[Lani]

utilizing a drug already approved for myeloma

Mol Cancer Ther. 2006 Dec;5(12):3042-51. Epub 2006 Dec 5. Links
Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner.

Cardoso F,
Durbecq V,
Laes JF,
Badran B,
Lagneaux L,
Bex F,
Desmedt C,
Willard-Gallo K,
Ross JS,
Burny A,
Piccart M,
Sotiriou C.
Translational Research Unit, Center for Education and Research in Food and Chemical Industry, Universite libre de Bruxelles, Belgium. fatima.cardoso@bordet.be
BACKGROUND: Preclinical and clinical studies have shown that the proteasome inhibitor bortezomib (PS341, Velcade) is highly effective when combined with chemotherapeutic agents. The value of trastuzumab (Herceptin) in HER-2-positive (3+ score by immunohistochemistry or fluorescence in situ hybridization positive) breast cancer is also known; however, the response rate is <40% for metastatic breast cancer. These two pharmacologic agents prevent nuclear factor-kappaB (NF-kappaB) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27(kip1), suggesting that combining bortezomib with trastuzumab could increase trastuzumab efficacy. METHODS: Drug cytotoxicity, both individually and together, and drug effects on p27 localization and NF-kappaB activation were investigated on four breast cancer cell lines: SKBR-3 (HER-2+++), MDA-MB-453 (HER-2++), HER-2-transfected MCF-7 (HER-2+++), and MCF-7 (HER-2-). RESULTS: Bortezomib induced apoptosis in HER-2-positive and HER-2-negative breast cancer cells in a dose- and time-dependent manner. Together, these drugs induced apoptosis of HER-2++/+++ cells at low concentrations, which had no effect when used alone, indicating there was a synergistic effect. Sequential treatment (trastuzumab then bortezomib) induced either necrosis or apoptosis, depending on the trastuzumab preincubation time. Susceptibility to bortezomib alone and the drug combination correlated with NF-kappaB activity and p27 localization. CONCLUSIONS: The addition of bortezomib to trastuzumab increases the effect of trastuzumab in HER-2+++/++ cell lines in a synergistic way. This effect likely results from the ability of these two drugs to target the NF-kappaB and p27 pathways. The potential clinical application of this drug combination is under current evaluation by our group in a phase 1 clinical trial.
PMID: 17148762 [PubMed - in process]

[Lani]

6: Fujita T, Doihara H, Washio K, Kawasaki K, Takabatake D, Takahashi H, Tsukuda K, Ogasawara Y, Shimizu N. Related Articles, Links
Proteasome inhibitor bortezomib increases PTEN expression and enhances trastuzumab-induced growth inhibition in trastuzumab-resistant cells.
Anticancer Drugs. 2006 Apr;17(4):455-62.
PMID: 16550004 [PubMed - indexed for MEDLINE]
7: Fujita T, Doihara H, Kawasaki K, Takabatake D, Takahashi H, Washio K, Tsukuda K, Ogasawara Y, Shimizu N. Related Articles, Links
PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer.
Br J Cancer. 2006 Jan 30;94(2):247-52.
PMID: 16404430 [PubMed - indexed for MEDLINE]
8: Lan KH, Lu CH, Yu D. Related Articles, Links
Mechanisms of trastuzumab resistance and their clinical implications.
Ann N Y Acad Sci. 2005 Nov;1059:70-5. Review.
PMID: 16382045 [PubMed - indexed for MEDLINE]
9: Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH. Related Articles, Links
Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2.
Int J Cancer. 2005 Sep 1;116(3):359-67.
PMID: 15800944 [PubMed - indexed for MEDLINE]
10: Meric-Bernstam F, Mills GB. Related Articles, Links
Mammalian target of rapamycin.
Semin Oncol. 2004 Dec;31(6 Suppl 16):10-7; discussion 33. Review.
PMID: 15799239 [PubMed - indexed for MEDLINE]
11: Altundag K, Altundag O, Morandi P, Gunduz M. Related Articles, Links
PTEN activation may contribute to exquisite antitumor response to trastuzumab.
Breast. 2005 Apr;14(2):175; author reply 176. No abstract available.
PMID: 15767191 [PubMed - indexed for MEDLINE]
12: Pandolfi PP. Related Articles, Links
Breast cancer--loss of PTEN predicts resistance to treatment.
N Engl J Med. 2004 Nov 25;351(22):2337-8. No abstract available.
PMID: 15564551 [PubMed - indexed for MEDLINE]
13: Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. Related Articles, Links
PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.
Cancer Cell. 2004 Aug;6(2):117-27.
PMID: 15324695 [PubMed - indexed for MEDLINE]
14: Crowder RJ, Lombardi DP, Ellis MJ. Related Articles, Links
Successful targeting of ErbB2 receptors-is PTEN the key?
Cancer Cell. 2004 Aug;6(2):103-4.
PMID: 15324690 [PubMed - indexed for MEDLINE]

Easiest way to start is to google Entrez PubMED and put the PMID numbers into the search bar. That will get you abstracts for most, full articles for those that have free access

Hope this helps

[Lani]

Genes Chromosomes Cancer. 2007 Apr;46(4):397-405. Links
Effects of ERBB2 amplicon size and genomic alterations of chromosomes 1, 3, and 10 on patient response to trastuzumab in metastatic breast cancer.

Morrison LE,
Jewell SS,
Usha L,
Blondin BA,
Rao RD,
Tabesh B,
Kemper M,
Batus M,
Coon JS.
Research and Development, Abbott Molecular Inc., Des Plaines, IL.
Trastuzumab is widely used for advanced breast cancer patients with ERBB2-amplified tumors. Nevertheless, over half of these patients do not have an objective response. One reason may be altered expression of genes that might compensate for ERBB2 inhibition. We previously mapped the gene-rich region of chromosome 17 telomeric to ERBB2, and reported considerable variability in the telomeric extent of the ERBB2 amplicon. Here we examined whether the variable amplicon size may be associated with patient response to trastuzumab. In addition, we looked at associations between response and several signaling pathway-related genes unrelated to the ERBB2 amplicon, including AKT3, PTEN, PIK3CA, and PTGS2. In 35 patients with ERBB2-amplified metastatic breast cancer, with 40% overall response to trastuzumab, fluorescence in situ hybridization identified the telomeric extent of the ERBB2 amplicon and the status of the several pathway-related genes. Objective response strongly correlated with the telomeric amplicon size, with 62% of patients with shorter amplicons responding, compared with only 7% of patients with longer amplicons (P = 0.0015). Abnormal copy number of PTGS2 was marginally associated with objective response (P = 0.066), while abnormal copy numbers of two reference loci, 1q25 and the chromosome 10 centromere, were significantly associated with response. Pairwise combinations of copy number status of these loci and ERBB2 amplicon size provided stronger associations and identified a group of patients without responders. These results suggest that patient selection for trastuzumab may be improved by considering ERBB2 amplicon size and genomic status of the 1q25, PTGS2, and centromere 10 loci. (c) 2007 Wiley-Liss, Inc.
PMID: 17243161 [PubMed - in process]

[Jean]

You done GOOD!

Great help,
Many thanks,
Jean