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Biotech / Medical : Biotech Short Candidates -- Ignore unavailable to you. Want to Upgrade?

To: tuck who wrote (617)	12/2/2003 12:33:31 PM
From: tuck	Respond to of 897

The full text of this article might say exactly what % of RCCs overexpress MAP kinase (likely upregulated by raf kinase): >>Oncogene. 1999 Jan 21;18(3):813-22. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M. Laboratory of Cell Regulation, School of Pharmaceutical Sciences, Nagasaki University, Japan. The 41-kDa and 43-kDa mitogen-activated protein (MAP) kinases play a pivotal role in the mitogenic signal transduction pathway and are essential components of the MAP kinase cascade, which includes MAP kinase kinase (MEK) and Raf-1. As aberrant activation of signal transducing molecules such as Ras and Raf-1 has been linked with cancer, we examined whether constitutive activation of the 41-/43-kDa MAP kinases is associated with the neoplastic phenotype of 138 tumor cell lines and 102 primary tumors derived from various human organs. Constitutive activation of the MAP kinases was observed in 50 tumor cell lines (36.2%) in a rather tissue-specific manner: cell lines derived from pancreas, colon, lung, ovary and kidney showed especially high frequencies with a high degree of MAP kinase activation, while those derived from brain, esophagus, stomach, liver and of hematopoietic origin showed low frequencies with a limited degree of MAP kinase activation. We also detected constitutive activation of the 41-/43-kDa MAP kinases in a relatively large number of primary human tumors derived from kidney, colon and lung tissues but not from liver tissue. Many tumor cells, in which point mutations of ras genes were detected, showed constitutive activation of MAP kinases, however, there were also many exceptions to this observation. In contrast, the activation of the 41-/43-kDa MAP kinases was accompanied by the activation of Raf-1 in the majority of tumor cells and was completely associated with the activation of MEK and p90rsk in all the tumor cells examined. These results suggest that the constitutive activation of 41-/43-kDa MAP kinases in tumor cells is not due to the disorder of MAP kinases themselves, but is due to the disorder of Raf-1, Ras, or some other signaling molecules upstream of Ras.<< PRs related to Bay 43-9006 mention that 90% of pancreatic cancers have this raf kinase upregulation issue, but doesn't assign a number to kidney cancers. I've had trouble finding anything specific how about how widely overexpressed raf kinase is in kidney cancer; Ill gladly accept help. Why results in colon cancer have been more disappointing is not clear to me; perhaps an alternate pathway for cell growth is available for those cell lines. Some more color on the results and trial design: eurekalert.org pennhealth.com The molecule hasn't seen a lot of discussion on the ONXX thread; maybe elsewhere such as in the Indications -- Cancer thread, but the SI search engine is challenged to find anything. The thread itself is not active or easy to find, so here's the link: Subject 9228 Despite Miljenko's reservations, I'm not inclined to short this now, until I can find support for those reservations. Cheers, Tuck

To: tuck who wrote (617)	12/2/2003 7:16:28 PM
From: Miljenko Zuanic	Read Replies (1) \| Respond to of 897

Tuck, <<Well, this is an interesting question. The degree of involvement of Raf-1 in kidney cancer appears to be hit or miss depending on your genetic makeup and degree of disease progression.>> Ras-Raf-MEK activation and over-activity is not ONLY RCC characteristic. It is active in many cancer type (for instance colorectal as one with higher percentage), so my concern is why 9006 is active for RCC and not for CRC. IF it is anti-angiogeneic component (latest hype from EORC) that potentate 9006 activity than it should be active in CRC (like Avastin was). So, my concern is about Pts’s genetic-makeup and RCC type (clear cells carcinoma) that was enrolled, and how they were selected. Second, DNA Avastin RCC pivotal PIII trial is against inf-alpha2b (second most common immuno-based cancer agent for advance RCC): cancer.gov It is interesting that they did not included IL-2 based arm. ONXX PIII is against placebo for (???) end-stage RCC. This agent should work much better in combination (based on the action mode that ONXX is promoting), but I guess toxicity of the agent itself is problem here. <<And if this is the case, then Onyx probably is a good short.>> Recently I was short (@25) ONXX. Covered my short with small loss. Current positive spin from EORC and PR is too high to accommodate real view and compound value. I will be following story closely, and maybe in time again short stock. I am not against ONXX or 9006, but market value may incorporate perceptions that were hard to achieve even if 9006 prove to be effective for RCC. Miljenko