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

背景：三阴性乳腺癌（TNBC）是一种缺乏雌激素受体（ER）、孕激素受体（PR）和HER2表达的乳腺癌亚型，由于其侵袭性和相对缺乏靶向策略的特点，呈现出特别困难的治疗挑战。其特点是其独特的分子特征和独特的转移模式。流行病学研究表明，三阴性乳腺癌在年轻妇女和非洲人后裔中发病率很高。虽然最初对化疗敏感，但早期复发是常见的，并且有内脏转移的倾向。在这种癌症亚群中缺乏肿瘤特异性治疗方案，这强调了对这种疾病生物学的更好理解以及对这些患者推进治疗策略的迫切需要。背景：Hsp90是TNBC的有效靶点：我们最近发现，在这种侵袭性异质性乳腺癌亚型中，Hsp90是一个特别有希望的靶点，并建议使用Hsp90抑制剂治疗这些女性（Caldas等，PNAS 2009）。目前有几种Hsp90抑制剂正在临床研究中，因此评估Hsp90抑制剂在TNBC中的作用是一个及时的建议。假设：靶向治疗在适当的分子环境下使用效果最好。尽管如此，大多数随机III期试验——监管机构批准的决定性障碍——仍然是为未选择的患者群体设计的。除了在分子定义明确的疾病中使用少数靶向药物（例如，伊马替尼用于激活KIT突变的胃肠道间质肿瘤）外，靶向治疗的临床试验结果充其量是适度的，这可能反映了迄今为止缺乏基于分子改变的个性化治疗方法。因此，对于Hsp90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预测性生物标志物来选择患者和丰富试验前景。方法：个体癌症可能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，我们发现在TNBC中，Hsp90调节p-Akt和Bcl-xL，并表明它们的表达可能预测对Hsp90抑制的高凋亡反应。我们假设这些抗凋亡驱动因子在选择更有可能从Hsp90治疗中获益的TNBC患者时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Hsp90抑制剂的体外敏感性与这些选定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来：目的1。体外测试患者TNBC肿瘤标本对Hsp90抑制剂（Hsp90i）的敏感性。目标2。通过免疫组织化学（IHC）和Western blot （WB）检测生物标志物的表达，对生物标志物表达与Hsp90i敏感性进行评分并建立相关关系。这种对肿瘤敏感性与生物标志物谱的探索性相关性分析将为预测TNBC肿瘤对Hsp90i的反应提供评分系统。该系统将在I期临床试验和更大的II期队列中进行验证（未包括在R21中）。最终目标是提供一种方法，通过这种方法，在三阴癌中选择未来治疗Hsp90i的患者，将常规地在福尔马林固定石蜡包埋（FFPE）标本或循环肿瘤细胞中进行。意义：提出的评分系统有可能增加Hsp90抑制剂通过TNBC药物开发管道成功和有效过渡的几率。我们建议，如本文所述，将经过科学和分析验证的生物标志物纳入合理设计的假设检验临床试验中，为TNBC成功的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. PUBLIC HEALTH RELEVANCE: Despite of the large number of potential new agents entering clinical evaluation every year, only 5% to 8% ever reach registration. Of particular concern is the high rate of failures in Phase 3, where an estimated 50% of oncology agents are stopped in development. Such failures are especially expensive and deprive many patients of potentially more effective treatments. These dire statistics clearly speak for the need to discover and implement predictive biomarkers for patient selection and trial enrichment. What have we learned from the results obtained in the last years with targeted agents? When a new drug has been administered, either as a single agent or in addition to chemotherapy in a study population not selected by any biomarker, most trials have produced negative results, while in a small minority of cases a statistically significant benefit has been demonstrated. This benefit, however, consisted -- at best -- of a small or moderate absolute prolongation of overall survival. On the other hand, examples of a greater absolute benefit obtained with the use of targeted agents based on a biomarker-driven patient selection are constantly increasing. Biomarkers provide the possibility to use tumor and patient characteristics to integrate an accurate predictor of efficacy with a specific mechanism based therapy, guiding the selection of treatment for each individual patient. In particular, a validated predictive marker can prospectively identify individuals who are likely to have a positive clinical outcome from a specific treatment. Our study recognizes these issues and proposes to develop and validate biomarkers for a biomarker- driven patient selection and trial enrichment in the implementation of Hsp90 inhibitors into the treatment of women with triple-negative breast cancers.