OT, but less so than basketball . . .
All right, why don't I just be upfront about this. Ciphergen is trying to commercialize a diagnostic test for ovarian cancer using their SELDI-TOF/protein chip systems as the platform for the testing. They have said vaguely that they feel their platform is superior to ELISA in this application, but will not give any specific reasons for feeling this way. Peter and I have both wondered why this wouldn't be better commercialized as an ELISA. The following snip hinted at an answer:
>>But here's the SELDI advantage over ELISA as summarized by Petricoin:
"Mass spectroscopy as a clinical analytical method has many unique attributes that no ELISA can achieve at this time. In addition to the speed of mass spectroscopy, ions can be precisely identified without the need for antibody development or a priori amino acid sequencing. This agnostic approach affords the experimentalist an approach to disease detection without bias about the source or identity of the markers. Mass spectroscopy can differentiate clipped or modified versions of molecules with extremely high speed and resolution. If the biomarker were a cleaved version of a larger, abundant protein, it may be nearly impossible to generate antibodies that recognize the cleaved version and do not cross-react with the much more abundant parent species. Consequently, mass spectroscopy is attractive for biomarker discovery as well as routine high-throughput testing."
Emphasis mine.<<
This abstract contains most of what I know about the biomarkers:
>>Cancer Res. 2004 Aug 15;64(16):5882-90.
Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer.
Zhang Z, Bast RC Jr, Yu Y, Li J, Sokoll LJ, Rai AJ, Rosenzweig JM, Cameron B, Wang YY, Meng XY, Berchuck A, Van Haaften-Day C, Hacker NF, de Bruijn HW, van der Zee AG, Jacobs IJ, Fung ET, Chan DW.
Department of Pathology, Biomarker Discovery Center, Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA. zzhang7@jhmi.edu
Early detection remains the most promising approach to improve long-term survival of patients with ovarian cancer. In a five-center case-control study, serum proteomic expressions were analyzed on 153 patients with invasive epithelial ovarian cancer, 42 with other ovarian cancers, 166 with benign pelvic masses, and 142 healthy women. Data from patients with early stage ovarian cancer and healthy women at two centers were analyzed independently and the results cross-validated to discover potential biomarkers. The results were validated using the samples from two of the remaining centers. After protein identification, biomarkers for which an immunoassay was available were tested on samples from the fifth center, which included 41 healthy women, 41 patients with ovarian cancer, and 20 each with breast, colon, and prostate cancers. Three biomarkers were identified as follows: (a) apolipoprotein A1 (down-regulated in cancer); (b) a truncated form of transthyretin (down-regulated); and (c) a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (up-regulated). In independent validation to detect early stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of a multivariate model combining the three biomarkers and CA125 [74% (95% CI, 52-90%)] was higher than that of CA125 alone [65% (95% CI, 43-84%)] at a matched specificity of 97% (95% CI, 89-100%). When compared at a fixed sensitivity of 83% (95% CI, 61-95%), the specificity of the model [94% (95% CI, 85-98%)] was significantly better than that of CA125 alone [52% (95% CI, 39-65%)]. These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer.<<
Emphasis mine again.
I know the the truncated TTR has had ten amino acids lopped off the n-terminal. It's not that large (151 amino acids, I believe), but it's definitely abundant. I know less about the others. However, the amino acid sequence of the ITIH4 cleavage fragment is as follows (obviously in single letter abbreviation format):
mnfrpgvlssrqlglpgppdvpdhaayhpfr
So, is there a better way than SELDI to measure this stuff in a high throughput clinical lab setting? SDS-PAGE/Western blotting is kind of tedious for that, isn't it?
It seems that the predictive power of this test might be good enough to market for high risk women (obviously not good enough for general screening). So, if it is marketed as an ELISA by Ciphergen's partner, Ciphergen just gets low single digit royalties. If it's marketed on the SELDI platform, they get the royalties, plus get to sell machines, chips, and consumables. That's why this is an important question in evaluating CIPH's prospects.
FWIW, I PMed another friend with considerable expertise, and he kind of agreed with Rick, though he made it sound a lot harder. I could probably get permission to share this answer if anyone cares. He seemed to think that much depended on how different those TTR isoforms are from each other. This is probably a key piece of information, and I don't have it at the moment.
Whatever, I'll take opinions Ciphergen's odds here from any who want to share them.
Thanks, and Cheers, Tuck |
