0458GCC: A PHASE I DOSE ESCALATION STUDY OF INTRAVENOUS 17-AAG

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 靶向癌症治疗的潜在好处是，通过利用对肿瘤中激活的途径具有选择性的药物，比正常组织更具体地影响肿瘤细胞途径。由于多个Growh调节通路在常见实体肿瘤中发生改变，因此可以调节这些通路的共同靶点的药物组合，或调节不同途径的药物组合，很可能构成未来的联合化疗方案。该方案建议研究这种靶向疗法的一种组合。17-AAG是一种苯喹类阿萨霉素类抗生素，对真核细胞也具有抗增殖活性。它的母体化合物格尔达那霉素在临床前研究中显示出良好的抗肿瘤活性，但17-AAG被证明肝毒性较小，更容易静脉注射。这两种化合物都通过与热休克蛋白90(Hsp90)上的ATP/ADP结合位点结合来发挥作用。已知HSP90对多种细胞增殖调节因子的正常折叠和亚序列定位及其功能至关重要，其中包括Akt、Raf、erbB家族和CDK4蛋白激酶、低氧诱导因子(HIF1)以及某些类固醇激素受体，包括雄激素和雌激素受体等。抑制Hsp90与这些Hsp90“客户”蛋白的相互作用会导致它们不正确的折叠，从而导致蛋白质小体的降解。Raf蛋白家族在细胞增殖中起着特别重要的作用。RAF磷酸化并激活MEK-1，而MEK-1又磷酸化并激活细胞外信号相关激酶(ERK)。ERK的激活导致多种抗细胞死亡和细胞周期激活通路的激活和刺激。RAF从酪氨酸激酶和ras癌基因相关信号通路的ERB2家族接受输入。因此，RAF位于在细胞增殖中重要的Migopus调控通路的中心。Bay 43-9006(也称为sorafenib)是一种专门选择的小分子，具有强大的干扰RAS信号的能力。随后，人们发现它直接相互作用并抑制ras信号下游的Raf的功能。此外，它还具有显著的抗血管内皮细胞生长因子(VEGF)受体激酶的活性，因此可以抑制刺激肿瘤生长的增殖和血管生成途径。17-AAG和Bay 43-9006的组合特别值得考虑。17-AAG被认为能够通过其HSP-90的定向作用下调酪氨酸激酶和RAF。BAY 43-9006被设想为直接抑制RAF信号。因此，17-AAG和Bay 43-9006联合使用可能下调通过RAF作用的更有效的增殖信号，并影响血管内皮生长因子相关通路。后者可能通过17-AAG对HIF-1的调控和Bay-43-9006对血管内皮细胞生长因子受体的直接作用来实现。这里提出的试验将是17-AAG和Bay-43-9006的“首次人类”联合研究。我们将对不良事件进行评分，确定联合用药的药理相互作用的证据，并观察任何抗肿瘤活性的证据。除了这些常规的第一阶段目标外，我们还将通过核磁共振技术在所有患者中确定肿瘤血管渗透性变化的证据，以及联合使用对外周血单核细胞中17-AAG和/或Bay-43-9006分子靶标的评分影响。根据单独的知情同意，对于容易接受针吸活检的肿瘤患者，我们将寻求确定联合药物对肿瘤间隔区相关分子标志物影响的证据。然而，参与肿瘤活组织检查不是必须的，如果患者拒绝活组织检查，他们仍然可以参与该方案。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.