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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 靶向癌症治疗具有潜在的益处，即通过利用对肿瘤中激活的那些通路具有选择性的药剂，比正常组织更特异性地影响肿瘤细胞通路。由于在常见的实体瘤中多种生长调节途径发生改变，因此可以调节这些途径的共同靶点的药物组合或调节不同途径的药物组合可能会构成未来的联合化疗方案。本方案建议研究此类靶向治疗的一种组合。17-AAG是一种苯醌类安莎霉素抗生素，对真核细胞也具有抗增殖活性。其母体化合物格尔德霉素在临床前研究中显示出有希望的抗肿瘤活性，但17-AAG被证明肝毒性较低，更适合静脉注射制剂。这两种化合物通过结合热休克蛋白90（Hsp 90）上的ATP/ADP结合位点而起作用。已知Hsp 90对于细胞内区室的正常折叠和后续定位以及细胞增殖的许多调节剂的功能是关键的，所述调节剂包括Akt、Raf、erbB家族和CDK 4蛋白激酶、缺氧诱导因子（HIF 1）和某些类固醇激素受体，包括雄激素和雌激素受体等。抑制Hsp 90与这些Hsp 90“客户”蛋白的相互作用导致它们在蛋白体中的不正确折叠和随后的降解。Raf激酶家族在细胞增殖中特别重要。Rafs磷酸化并激活Mek-1，Mek-1又磷酸化并激活细胞外信号相关激酶（Erks）。Erk活化导致多种抗细胞死亡和细胞周期活化途径的活化和刺激。Raf接受来自酪氨酸激酶erB 2家族和ras癌基因相关信号通路的输入。因此Raf位于细胞增殖中重要的数字体调节途径的中心。BAY 43-9006（也称为索拉非尼）是一种小分子，其被特别选择以具有干扰Ras信号传导的有效能力。随后，发现它直接相互作用并抑制Ras信号下游的Raf的功能。此外，它对血管内皮生长因子（VEGF）受体激酶具有显著的活性，因此可能潜在地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信号传导。因此，17-AAG和BAY 43-9006的组合具有更有效地下调通过RAF起作用的增殖信号并且还影响VEGF相关途径的潜力。后者的结果将实现戈伊17-AAG对HIF-1的调节，以及BAY-43-9006对VEGF-R的直接作用。这里提出的试验将是17-AAG和BAY- 43-9006的“首次人体”联合研究。我们将对不良事件进行评分，并确定联合用药的药理学相互作用的证据，以及观察任何抗肿瘤活性的证据。除了这些常规的I期目标外，我们还将通过NMR技术确定所有患者肿瘤血管通透性变化的证据，以及该组合对外周血单核细胞中17-AAG和/或BAY-43-9006分子靶点的评分效应。根据单独的知情同意书，在肿瘤易于穿刺活检的患者中，我们将寻求确定联合药物对肿瘤室中相关分子标志物的影响的证据。然而，参与肿瘤活检将不是一个要求，如果患者拒绝活检，他们仍然可以参加该方案。

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.