Tuesday, May 7, 2013

DON'T BEAT YOURSELF, THE WORK HAS BEEN DONE BY VON HOFF ET AL!

TARGET TESTED BY IHC                    DRUG PROPOSED AS INTERACTING WITH TARGET

1.EGFR..................................................CETUXIMAB,ERLOTINIB,GEFITINIB
2.SPARC................................................ABRAXANE
3.c-KIT...................................................IMATINIB,SUNITINIB,SORAFENIB
4.ER........................................................TAMOXIFEN,AROMATASE INHIBITOR,TOREMIFENE,
................................................................PROGESTATIONAL AGENT
5.PR........................................................(SAME AS ER) ADD GOSERELIN
6.ANDROGEN RECEPTOR..................FLUTAMIDE,ABARELIX,BICALUTAMIDE,LEUPROLIDE,
................................................................GOSERELIN
7.PGP......................................................DOXORUBICIN,ETOPOSIDE,DOCETAXEL,VINORELBINE
................................................................PLEASE AVOID NATURAL PRODUCT
8.HER-2/NEU.........................................TRASTUZUMAB
9.PDGFR.................................................SUTENT,GLEEVEC,SORAFENIB (NEXAVAR)
10. CD52.................................................ALEMTUZUMAB
11.CD25..................................................DENILEUKIN DIFTITOX
12.HSP90................................................GELDANAMYCIN, CNF2024
13.TOP2A...............................................DOXORUBICIN, EPIRUBICIN, ETOPOSIDE

THIS WAS PUBLISHED THROUGH ASCO

Comments

We can now go wild testing gene on our specimen.  Basically after failure of standard of care, re-biopsy and adjust the attack using these agents!

Geldanamycin is a benzoquinone ansamycin antibiotic that binds to Hsp90 (Heat Shock Protein 90) and inhibits its function. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.

Hsp90-geldanamycin complex. PDB 1yet[1]
Geldanamycin induces the degradation of proteins that are mutated in tumor cells such as v-Src, Bcr-Abl and p53 preferentially over their normal cellular counterparts. This effect is mediated via HSP90. Despite its potent antitumor potential, geldanamycin presents several major drawbacks as a drug candidate (namely, hepatotoxicity) that have led to the development of geldanamycin analogues, in particular analogues containing a derivatisation at the 17 position: (wikipedia)

Conceptually, this drug should be tested in triple negative breast cancer where receptors will fail  stressing the cell to amplify HSP90.   As a matter of facts, this drug should most likely be used widely given the importance of cellular stress in Neoplasia (including leukemia).

Invivo gene reports:

"Hsp90 is a ubiquitous molecular chaperone critical for the folding, assembly and activity of multiple mutated and overexpressed signaling proteins that promote the growth and/or survival of tumor cells. Hsp90 client proteins include mutated p53, Raf-1, Akt, ErbB2 and hypoxia-inducible factor 1a (HIF-1a) [1]. Binding of GA to Hsp90 causes the destabilization and degradation of its client proteins [2]."    So disease where mutations of HSP90 "clients appear to be a driver mutation, should have Geldamycin theoritically !

"However due to poor aqueous solubility and liver toxicity, GA has not moved forward in clinical trials. To overcome these undesirable properties, numerous GA analogs have been synthesized which differ only in their 17-substituent. These include 17-allylamino-demethoxygeldamycin (17-AAG) and 17-dimethylamino- geldanamycin (17-DMAG) that have completed phase I and are currently entering phase II clinical trials."
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