important new drug vs Herceptin resistance on fast track for development

[Lani]

It was developed by modifying celebrex! full article freely available

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]

[alw]

Lani - I noticed this article is from last year. Has something new come up regarding OSU-03012? or are you just posting as you came across?

It appears as though this would also cross the BBB - so it would be very good news if this were coming to clinical trials soon.

Thanks for posting this.

Amy

[Lani]

what happened is that I found a new article by Dr.Bruggemeier whom I remembered had done lots of important work in the area. So I put his name into PubMed to see if there was an article of his I had missed I found this one.

Since it said it was being put on a faster track I thought it worth mentioning.

Unlike most of my posts, this one was not "hot off the press"