ERBB1 AND ERBB2 BLOCKADE IN ADVANCED BREAST CANCER

晚期乳腺癌中的 ERBB1 和 ERBB2 阻断

• 批准号: 6867516
• 负责人: CHRIS H. TAKIMOTO
• 金额: $ 26.41万
• 依托单位: CANCER THERAPY AND RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-23 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867516
• 关键词: angiogenesis inhibitors; apoptosis; biopsy; breast neoplasms; cell differentiation; cell proliferation; clinical research; clinical trial phase I; combination chemotherapy; drug administration rate /duration; drug screening /evaluation; epidermal growth factor; growth factor receptors; human subject; human therapy evaluation; immunocytochemistry; metastasis; neoplasm /cancer blood supply; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; paclitaxel; patient oriented research; protooncogene; quinazolines; receptor expression

DESCRIPTION (provided by applicant): HER2 signaling inhibition increases the antitumor effects of paclitaxel increasing survival in patients with metastatic breast cancer (MBC). EGFR blockade enhances the antitumor activity of HER2 inhibition. EGFR is expressed in 48% of MBC, its expression like HER2, correlating with poor prognosis. HER2 overexpression increases EGFR signaling, and transgenic mice overexpressing HER2 in mammary tissue develop mammary tumors with increased EGFR signaling. OSI-774 is an oral quinazoline inhibitor of EGFR tyrosine kinase and downstream signaling that also inhibits HER2 signaling through receptor heterodimerization. HYPOTHESIS: ErbB 1 blockade by OSI-774 potentiates the antitumor activity of trastuzumab and paclitaxel induces increased apoptosis, differentiation, and inhibition of proliferation and angiogenesis in MBC. SPECIFIC AIMS: 1. To characterize, in a phase I study, the safety of continuous oral OSI-774 and a weekly regimen of trastuzumab and paclitaxel and to recommend a dose for subsequent studies. 2. To determine the importance of EGFR signaling in HER2+ and HER2- disease and to assess in phase II studies whether the anticancer activity of this regimen in HER2+ EGFR+ MBC warrants evaluation in phase III studies. 3. To explore the biologic effects of concomitant EGFR and HER2 blockade in MBC amenable to serial tumor biopsies. STUDY DESIGN: This investigator-initiated, NCI-CTEP sponsored, phase I study will evaluate the safety, dose-limiting toxicities, and maximum tolerated dose of weekly paclitaxel and trastuzumab with oral once daily OSI-774. A non-randomized phase II study will then be performed in two separate cohorts of patients with HER2 and EGFR expressing MBC. Patients untreated in the metastatic setting will be treated using a single stage accrual design. Patients with taxane and trastuzumab refractory disease will be treated utilizing a two-stage design to determine whether EGFR blockade can alter resistance to treatment. Corroborative biological studies will be pursued in 30 patients treated on these studies, who have disease safely amenable to serial biopsy. The agents will be introduced sequentially in the first course of treatment only, trastuzumab being commenced on day 1, oral OSI-774 on day 15, and weekly paclitaxel on day 29. Serial tumor biopsies will be obtained on days 0, 14 and 28 in course 1 to evaluate the effects of HER2 blockade on EGFR expression and signaling, and of combined HER2 and EGFR blockade on tumor proliferation, apoptosis, differentiation (hormone receptor expression) and angiogenesis. RELEVANCE: If these results are favorable, a phase III study of trastuzumab and paclitaxel with or without OSI-774 in patients with MBC is planned.

描述（由申请人提供）：HER2 信号传导抑制可增强紫杉醇的抗肿瘤作用，从而提高转移性​​乳腺癌 (MBC) 患者的生存率。 EGFR 阻断增强 HER2 抑制的抗肿瘤活性。 EGFR 在 48% 的 MBC 中表达，其表达与 HER2 类似，与不良预后相关。 HER2 过度表达会增加 EGFR 信号传导，而乳腺组织中过度表达 HER2 的转基因小鼠会出现 EGFR 信号传导增加的乳腺肿瘤。 OSI-774 是一种口服喹唑啉 EGFR 酪氨酸激酶和下游信号传导抑制剂，还通过受体异二聚化抑制 HER2 信号传导。 假设：OSI-774 阻断 ErbB 1 可增强曲妥珠单抗和紫杉醇的抗肿瘤活性，从而诱导 MBC 中细胞凋亡、分化增加以及增殖和血管生成的抑制。 具体目标： 1. 在 I 期研究中表征连续口服 OSI-774 以及每周一次曲妥珠单抗和紫杉醇治疗方案的安全性，并为后续研究推荐剂量。 2. 确定 EGFR 信号传导在 HER2+ 和 HER2- 疾病中的重要性，并在 II 期研究中评估该方案在 HER2+ EGFR+ MBC 中的抗癌活性是否值得在 III 期研究中进行评估。 3. 探讨联合 EGFR 和 HER2 阻断对适合连续肿瘤活检的 MBC 的生物学效应。 研究设计：这项由研究者发起、NCI-CTEP 赞助的 I 期研究将评估每周一次紫杉醇和曲妥珠单抗口服每日一次 OSI-774 的安全性、剂量限制毒性和最大耐受剂量。然后将在两个单独的 HER2 和 EGFR 表达 MBC 患者队列中进行非随机 II 期研究。在转移环境中未经治疗的患者将使用单阶段应计设计进行治疗。患有紫杉烷和曲妥珠单抗难治性疾病的患者将采用两阶段设计进行治疗，以确定 EGFR 阻断是否可以改变治疗耐药性。将对 30 名接受这些研究治疗的患者进行确凿的生物学研究，这些患者的疾病可以安全地进行连续活检。这些药物将仅在第一个疗程中依次引入，第1天开始曲妥珠单抗，第15天开始口服OSI-774，第29天每周服用紫杉醇。将在第1疗程的第0、14和28天获得连续肿瘤活检，以评估HER2阻断对EGFR表达和信号转导的影响，以及联合HER2和EGFR阻断对肿瘤增殖的影响。 细胞凋亡、分化（激素受体表达）和血管生成。 相关性：如果这些结果良好，则计划对 MBC 患者进行曲妥珠单抗和紫杉醇联合或不联合 OSI-774 的 III 期研究。

项目成果

Second-Generation HSP90 Inhibitor Onalespib Blocks mRNA Splicing of Androgen Receptor Variant 7 in Prostate Cancer Cells.

• DOI: 10.1158/0008-5472.can-15-2186
• 发表时间: 2016-05-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Ferraldeschi R;Welti J;Powers MV;Yuan W;Smyth T;Seed G;Riisnaes R;Hedayat S;Wang H;Crespo M;Nava Rodrigues D;Figueiredo I;Miranda S;Carreira S;Lyons JF;Sharp S;Plymate SR;Attard G;Wallis N;Workman P;de Bono JS
• 通讯作者: de Bono JS

Characterizing CDK12-Mutated Prostate Cancers.

表征CDK12突变的前列腺癌。

• DOI: 10.1158/1078-0432.ccr-20-2371
• 发表时间: 2021-01-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Rescigno P;Gurel B;Pereira R;Crespo M;Rekowski J;Rediti M;Barrero M;Mateo J;Bianchini D;Messina C;Fenor de la Maza MD;Chandran K;Carmichael J;Guo C;Paschalis A;Sharp A;Seed G;Figueiredo I;Lambros M;Miranda S;Ferreira A;Bertan C;Riisnaes R;Porta N;Yuan W;Carreira S;de Bono JS
• 通讯作者: de Bono JS