This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Targeted cancer therapy has the potential benefit of affecting tumor cell pathways more specifically than normal tissues by utilizing agents with selectivity for those pathways activated in tumors. Since multiple growh regulatory pathways are altered in the common solid tumors, it follows that combinations of agents which can regulate common targets of those pathways, or agents that modulate distinct pathways, will likely comprise the combination chemotherapy regimens of the future. This protocol proposes to study one combination of such targeted therapies. 17-AAG is a benzoquinoid ansamycin antibiotic with antiproliferative activity for eucaryotic cells as well. Its parent compound, geldanamycin, showed promising anti-tumor activity in preclinical studies, but 17-AAG proved to be less hepatotoxic and more amenable to intravenous formulation. Both compounds act by binding to the ATP/ADP binding site on the heat shock protein 90 (Hsp90). Hsp90 is known to be critical for the normal folding and subsequnt localization to intracellular compartments and function of numerous regulators of cell proliferation including the Akt, Raf, erbB family, and CDK4 protein kinases, the hypoxia inducible factor (HIF1), and certain steroid hormone receptors including the androgen and estrogen receptors, among others. Inhibition of the the Hsp90 interaction with these Hsp90 'client' proteins results in their improper folding and subsequent degradation in the proteosome. The Raf family of kinases is particularly important in cellular proliferation. Rafs phosphorylate and activate Mek-1, which in turn phosphorylates and activates the exctracellular signal related kinases (Erks). Erk activation leads to activation and stimulation of a variety of anti-cell death and cell cycle activation pathways. Raf receives input from the erB2 family of tyrosine kinase and ras oncogene-related signaling pathways. Raf therefore sits at the center of numeropus regulatory pathways important in cellular proliferation. BAY 43-9006 (also known as sorafenib) is a small molecule that was specifically selected to have potent ability to interfere with Ras signaling. Subsequently, it was found to directly interact and inhibit the function of Raf, which is downstream of ras signaling. In addition, it has noteworthy activity against the Vascular Endothelial Growth Factoir (VEGF) receptor kinases, and therefore could portentially act to inhibit both proliferative and angiogenic pathways stimulating tumor growth. The combination of 17-AAG and BAY 43-9006 is particularly appealing to consider. 17-AAG is envisoned to able to down-regulate tyrosine kinase and raf by its Hsp-90 directed effects. BAY 43-9006 is envisioned to directly inhibit raf signaling. Therefore the combination of 17-AAG and BAY 43-9006 has the poitential to down-reguilate more efficiently proliferative signals acting through RAF and also affect VEGF -related pathways. The later result would be achieved gy 17-AAG modulation of HIF-1, and direct action of BAY-43-9006 on the VEGF-R. The trial proposed here would be a 'first in humans' combination study of 17-AAG and BAY- 43-9006. We will score the adverse events, and define evidence of pharmacological interaction of the combination, as well as observe any evidence oif anti-tumor activity. In addition to these convential Phase I goals, we will define in all patients evidence of changes in the vascular permeability of the tumor by NMR techniques, as well as score effects of the combination on molecular targets of 17-AAG and /or BAY-43-9006 in peripheral blood mononuclear cells. Under a separate informed consent in patients with easily accessible tumor to needle biopsy, we will seek to define evidence of combined drug effect on relevant molecular markers in the tumoral compartment. Participation in tumor biopsies will not, however, be a requirement and patients can still participate in the protocol if they decline the biopsies.
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