NF-KB MEDIATED DRUG RESISTANCE IN OVARIAN CANCER

这一建议的实验假设是，核因子-kB DNA结合的激活是卵巢癌获得性顺铂耐药的共同特征。在这项建议中，我们在体外和体内检查了核因子-kB的激活及其药理抑制，将实验室研究(目标1和3)与临床研究(目标2和4)与实验室的相关性联系起来。将检测核因子-kappaB的激活对顺铂紫杉醇、马法兰、阿霉素、拓扑替康等药物耐药的影响。我们将描述与获得性顺铂耐药/敏感性相关的生物学事件以及与核因子-kappaB激活的关系。通过转基因实验，我们将检测转录激活物--核因子-kappaB及其对化疗药物敏感性和耐药性的影响(阳性和阴性)。这些观察结果将通过研究安沙霉素抗生素、MSKCC正在开发的一类新药物和蛋白酶体抑制剂PS-341来扩展到新药开发中。提出了将抑制剂的作用与药物反应联系起来的机制研究，这些作用将与研究性药物治疗后患者来源组织的研究联系起来。具体目标为：具体目标1：研究核因子-kB在获得性化疗耐药中的作用，包括耐药谱、激活过程和核因子-kB活性升高的细胞后果。具体目的2：探讨卵巢癌患者体内IKB/IKB激酶与顺铂耐药组织的相关性。具体目的3：探讨两种潜在的核因子-kB激活的临床抑制剂(除草剂A和PS-341)对体外化疗敏感性的影响及其机制。具体目的4：对两种新药PS-341和17烯丙基氨基凝胶进行临床试验，研究卵巢癌患者体内核因子-kB活性升高、IKB水平降低与顺铂耐药的关系。这一建议代表着一个独特的机会，可以将对核因子-kB介导的获得性耐药的实验室研究与两种新药物的初步临床研究结合起来，这两种新药可能很好地克服晚期癌症患者的这种耐药机制。

The experimental hypothesis of this proposal is that the activation of NF-kB DNA binding is a common feature of acquired CDDP resistance in ovarian cancer. In this proposal, we examine NF-kB activation and its pharmacologic inhibition, both in vitro and in vivo, linking laboratory studies (aims 1 and 3) to clinical studies (aims 2 and 4) with laboratory correlates. The effect of NF-kappaB activation on resistance to the cytotoxicity of CDDP paclitaxel, melphalan, doxorubicin, topotecan and other agents will be examined. We will delineate the related biologic events associated with acquired CDDP resistance / sensitivity and the association to NF-kappaB activation. Through transfection experiments, we will examine the transcriptional activator, NF-kappaB and its effects (positive and negative) on chemotherapy drug sensitivity and resistance. These observations will be extended into new drug development through investigations of the ansamycin antibiotics, a novel class of agents under development at the MSKCC and the proteosome inhibitor PS-341. Mechanistic studies relating the effect of the inhibitors to drug response are proposed and these effects will be linked to studies of patient derived tissues after investigational drug treatment. The detailed objectives are: Specific Aim 1: To examine the role of NF-kB in acquired chemotherapy resistance in vitro, including the spectrum of resistance, the activation process and the cellular consequences of increased NF-kB activity. Specific Aim 2: To explore the in vivo association between the IkB / IkB kinase and CDDP resistance tissues from patients with ovarian cancer. Specific Aim 3: To explore the effect and mechanism of two potential clinical inhibitors of NF-kB activation (Herbimycin A and PS-341) on chemotherapy sensitivity in vitro. Specific Aim 4: To perform clinical trials of two new agents PS-341 and 17 allylaminogeldanamycin and examine the association between increased NF-kB activity, decreased IkB levels and CDDP resistance in vivo for women with ovarian cancer. This proposal represents a unique opportunity to integrate laboratory studies of NF-kB mediated acquired drug resistance with the initial clinical studies of two new agents which may very well overcome this mechanism of resistance in patients with advanced cancer.