Biomarkers of response to Hsp90 inhibitors in triple-negative breast cancer

描述（由申请人提供）：背景：TNBC未满足的医疗需求：三阴性乳腺癌（TNBC），一种缺乏雌激素受体（ER）、孕酮受体（PR）和HER 2表达的乳腺癌亚型，提出了特别困难的治疗挑战，因为这种表型的特征在于其侵袭性和相对缺乏靶向策略。其特征在于其独特的分子谱和独特的转移模式。流行病学研究表明，年轻妇女和非洲裔妇女中三阴性乳腺癌的发病率很高。虽然最初对化疗敏感，但早期复发是常见的，并且已经描述了内脏转移的偏好。在这种癌症亚群中缺乏肿瘤特异性治疗方案，这强调了更好地了解这种疾病的生物学以及推进这些患者的治疗策略的迫切需要。 背景资料：Hsp 90作为TNBC中的有效靶标：我们最近已经表明，Hsp 90在这种侵袭性和异质性乳腺癌亚型中是特别有希望的靶标，并且已经提出在这些女性的治疗中使用Hsp 90抑制剂（Caldas等人，PNAS 2009）。由于目前有几种Hsp 90抑制剂处于临床研究中，因此，在TNBC中评价Hsp 90抑制剂是一个及时的建议。 假设：靶向治疗最好在适当的分子背景下使用。尽管如此，大多数随机III期试验-监管批准的定义性障碍-仍然是针对糖尿病患者人群设计的。除了在分子定义明确的疾病中的少数靶向药物（例如，伊马替尼在具有激活KIT突变的胃肠道间质瘤中）外，靶向治疗的临床试验结局充其量是适度的，这可能反映了迄今为止缺乏基于分子改变的个体化治疗方法。因此，对于Hsp 90抑制剂的合理和生物标志物驱动的临床策略，我们假设有必要开发和实施用于患者选择和试验富集前景的预测性生物标志物。 方法：个体癌症可能具有不同的生物驱动因素，可以通过适当的靶向药物进行治疗。使用一种新的化学生物学/蛋白质组学方法，我们确定在TNBC中，Hsp 90调节p-Akt和Bcl-xL，并且已经表明它们的表达可能预测对Hsp 90抑制的高凋亡响应。我们假设这些抗凋亡驱动因子在选择更可能受益于Hsp 90治疗的TNBC患者中是有用的生物标志物。为了证明这一假设，我们的申请旨在建立TNBC肿瘤对Hsp 90抑制剂的离体敏感性与这些选择的生物标志物的表达之间的相关关系。为此，它将使用新鲜的患者样本：目标1。离体测试患者TNBC肿瘤样本对Hsp 90抑制剂（Hsp 90 i）的敏感性。 目标2.通过免疫组织化学（IHC）和蛋白质印迹（WB）检查生物标志物的表达，评分并建立生物标志物表达和Hsp 90 i敏感性之间的相关性。肿瘤敏感性与生物标志物谱的探索性相关性分析将提供TNBC肿瘤对Hsp 90 i的预测反应的评分系统。该系统将在I期临床试验和更大的II期队列（R21中未涵盖）中进行验证。最终目标是提供一种方法，通过该方法，将在福尔马林固定的石蜡包埋（FFPE）标本或循环肿瘤细胞中常规进行TNBC中未来Hsp 90 i治疗的患者选择。 重要性：所提出的评分系统有可能通过TNBC中的药物开发管道增加Hsp 90抑制剂成功和有效过渡的几率。我们建议将科学和分析验证的生物标志物，如本文所述，纳入合理设计的假设检验临床试验，为TNBC的成功靶向治疗提供了一个有希望的前进方向，并承诺个性化医疗可以在这种情况下成为现实。

DESCRIPTION (provided by applicant): Background: TNBC an unmet medical need: Triple negative breast cancer (TNBC), a subtype of breast cancer that lacks expression of an estrogen receptor (ER), a progesterone receptor (PR), and HER2, presents a particularly difficult therapeutic challenge as this phenotype is characterized by its aggressive nature and relative lack of targeted strategies. It is characterized by its unique molecular profile and distinct pattern of metastasis. Epidemiological studies show a high prevalence of triple negative breast cancer among younger women and those of African descent. Although initially sensitive to chemotherapy, early relapse is common, and a predilection for visceral metastasis has been described. The absence of tumor-specific treatment options in this cancer subset underscores the critical need to develop a better understanding of the biology of this disease, as well as to advance treatment strategies for these patients. Background: Hsp90 as a potent target in TNBC: We have recently shown that Hsp90 is an especially promising target in this aggressive and heterogeneous breast cancer subtype, and have proposed the used of Hsp90 inhibitors in the treatment of these women (Caldas et al, PNAS 2009). With several Hsp90 inhibitors currently in clinical investigation, evaluation of Hsp90 inhibitors in TNBC is thus, a timely proposition. Hypothesis: Targeted therapies are best used in the appropriate molecular context. Despite this, the majority of randomized phase III trials-the defining hurdle for regulatory approval-continue to be designed for unselected patient populations. With the exception of a few targeted agents in molecularly well-defined diseases (eg, imatinib in gastrointestinal stromal tumors with activating KIT mutations), outcomes of clinical trials of targeted therapies have been at best modest, probably reflecting the hitherto lack of individualized, treatment approaches based on molecular alterations. Thus, for a rational and a biomarker-driven clinical strategy for Hsp90 inhibitors, we hypothesize that the development and implementation of predictive biomarkers for patient selection and trial enrichment prospects is necessary. Approach: Individual cancers are likely to have distinct biologic drivers, which can be exploited therapeutically by an appropriate targeted agent. Using a novel chemical biology/proteomics approach, we identified that in TNBC, Hsp90 regulates p-Akt and Bcl-xL, and have shown that their expression is potentially predictive of high apoptotic response to Hsp90 inhibition. We hypothesize here that these anti-apoptotic drivers are useful biomarkers in the selection of TNBC patients more likely to benefit from Hsp90 therapy. To demonstrate this hypothesis, our application aims to establish a correlative relationship between the ex vivo sensitivity of TNBC tumors to Hsp90 inhibitors and the expression of these select biomarkers. To do so, it will use fresh patient samples to: Aim 1. test ex vivo the sensitivity of patient TNBC tumor specimens to Hsp90 inhibitor (Hsp90i). Aim 2. examine the expression of biomarkers by immunohistochemistry (IHC) and Western blot (WB), score and develop a correlative relationship between biomarker expression and Hsp90i sensitivity This exploratory correlation analysis of tumor sensitivity vs biomarker profile will provide a scoring system for predictive response of TNBC tumors to Hsp90i. This system will be validated in a Phase I clinical trial and in a larger Phase II cohort (not covered in the R21). The ultimate goal is to provide a means by which patient selection for future Hsp90i treatment in TNBC would be routinely performed on formalin-fixed paraffin- embedded (FFPE) specimens or in circulating tumor cells. Significance: The proposed scoring system has the potential for increasing the odds for a successful and efficient transition of Hsp90 inhibitors through the drug development pipeline in TNBC. We propose that the incorporation of scientifically and analytically validated biomarkers, as described here, into rationally designed hypothesis-testing clinical trials offers a promising forward direction towards a successful targeted therapy in TNBC, and promises that personalized medicine can be a reality in this setting.