17-AAG Tanespimycin (KOS-953)
17-AAG (17-allylamino, 17-demethoxygeldanamycin), now called tanespimycin and KOS-953, is a molecule that inhibits the activity of a protein called HSP90 (heat shock protein 90). HSP90 is one of a class of proteins which are normally in cells and are produced in greater amounts when cells are stressed. In cancer cells, HSP90 in particular has enabled certain such cells to survive and even thrive. For instance, high levels of HSP90 in breast cancer cells is associated with poor prognosis, and HSP90 stabilizes KIT, the protein driving cancer cell survival and division in GIST.
17-AAG or tanespimycin has been in clinical trials since 1999. It is now in phase II trials against melanoma, breast, prostate, and thyroid cancer. This HSP90 inhibitor is a benzoquinone antineoplastic antibiotic derived from the antineoplastic antibiotic geldanamycin. Tanespimycin binds to and inhibits the cytosolic chaperone functions of heat shock protein 90 (HSP90). HSP90 maintains the stability and functional shape of many oncogenic signaling proteins; the inhibition of HSP90 promotes the proteasomal degradation of oncogenic signaling proteins that may be overexpressed by tumor cells.
Tanespimycin is water insoluble, and thus it is administered to patients by intravenous IV using organic solvents such as DMSO. Tanespimycin is structurally related to the water soluble HSP90 inhibitor, retaspimycin (IPI-504, Infinity Pharmaceuticals). In fact, tanespimycin becomes metabolized by enzymes in the body into retaspimycin, which is the actual biologically active form of this class of inhibitor.
Source for the above information: www.cancer.gov
For information at the site of the manufacturer, Kosan Biosciences, link here.
Phase I trial results:
Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer.
Goetz MP, Toft D, Reid J, Ames M, Stensgard B, Safgren S, Adjei AA, Sloan J,
Atherton P, Vasile V, Salazaar S, Adjei A, Croghan G, Erlichman C.
J Clin Oncol. 2005 Feb 20;23(6):1078-87.
Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin
in adult patients with solid tumors.
Grem JL, Morrison G, Guo XD, Agnew E, Takimoto CH, Thomas R, Szabo E,
Grochow L, Grollman F, Hamilton JM, Neckers L, Wilson RH
J Clin Oncol. 2005 Mar 20;23(9):1885-93.
Phase I pharmacokinetic and pharmacodynamic study of 17-allylamino, 17-demethoxygeldanamycin in patients with advanced malignancies.
Banerji U, O'Donnell A, Scurr M, Pacey S, Stapleton S, Asad Y, Simmons
L, Maloney A, Raynaud F, Campbell M, Walton M, Lakhani S, Kaye S,
Workman P, Judson I.
J Clin Oncol. 2005 Jun 20;23(18):4152-61.
17-Allylamino-17-demethoxygeldanamycin (17-AAG) is effective in down-regulating
mutated, constitutively activated KIT protein in human mast cells.
Fumo G, Akin C, Metcalfe DD, Neckers L.
Blood. 2004 Feb 1;103(3):1078-84. (free access in PubMed)
The Hsp90 inhibitor 17-allylamide-17-demethoxygeldanamycin induces
apoptosis and differentiation of Kasumi-1 harboring the Asn822Lys KIT
mutation and down-regulates KIT protein level.
Yu W, Rao Q, Wang M, Tian Z, Lin D, Liu X, Wang J
Leuk Res. 2005 Oct 4; [Epub ahead of print]
STI571 (Glivec) inhibits the interaction between c-KIT and heat shock
protein 90 of the gastrointestinal stromal tumor cell line, GIST-T1.
Nakatani H, Kobayashi M, Jin T, Taguchi T, Sugimoto T, Nakano T, Hamada
S, Araki K.
Cancer Sci. 2005 Feb;96(2):116-9.
Ongoing Clinical Trials
As stated above, once metabolized in the body, tanespimycin becomes the same chemical as retaspimycin (IPI-504), making these two drugs very closely related except for potential differences in administration and absorption.
Researchers have speculated that a combination of a Hsp90 inhibitor plus a KIT inhibitor might have promise in refractory GIST patients, although there are no clinical trials yet addressing this. There is, however, a phase I combination trial of tanespymycin and sorafenib for solid tumors, which offers the potential to inhibit both HSP90 and KIT. Link to clinicaltrials.gov for this trial.
There is also currently a phase I combination trial of Tanespimycin and Bortezomib (a proteasome inhibitor) for solid tumors and lymphoma. The proteasome is the "recycling center" inside the cell; inhibiting it effectively inactivates proteins that require reformulation prior to re-use by the cell. Bortezomib has not been studied as an agent for GIST, although it is an FDA approved drug against multiple myeloma. Theoretically, there might be anti-cancer synergism by inhibiting both HSP90 and the proteasome in some types of cancer, as both HSP90 and the proteasome function in a linked manner to regulate protein levels in a cancer cell. Link to clinicaltrials.gov for this trial.