Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activit

描述（由申请人提供）：乳腺癌（BCa）仅次于肺癌，是美国女性癌症死亡的主要原因。维持乳腺癌的一个常见机制是内分泌蛋白如雌激素受体（ER）的功能障碍。利用这种蛋白质功能障碍的治疗干预在乳腺癌治疗和/或化学预防中取得了一定的成功。例如，选择性雌激素受体调节剂（SERM）如他莫昔芬是治疗激素依赖性乳腺癌的一线疗法。然而，尽管最初的好处，大多数患者最终复发，由于获得性耐药这些药物。获得性抗性的确切机制尚未完全了解。然而，很明显，耐药肿瘤仍然保持ER表达，要么以ER <$的形式（超过70%的病例），要么上调ER <$（一种密切相关的亚型ER <$）的表达。因此，对于越来越多的选择性和有效的药物来治疗抗性阶段BCa和早期阶段，存在未满足的医学需求。本申请中提出的研究的具体重点是探索肿瘤ER表达状态以实现独立抗肿瘤化学型（在这种情况下为组蛋白脱乙酰酶抑制剂（HDACi））的选择性递送。我们选择HDAC作为治疗靶点是因为HDAC抑制是一种临床验证的抗肿瘤策略，对转化细胞具有选择性细胞毒性。HDACi继续在肿瘤学中激发巨大的兴奋，迄今为止已经启动了近500项临床试验，迄今为止产生了两种临床批准的药物，SAHA（Zolinza”）和FK 228（Istodax”），用于治疗皮肤T细胞淋巴瘤（CTCL）。然而，目前的HDACi由于生物分布差而具有严重的局限性，包括在实体瘤中无效的低浓度和阻碍临床进展的脱靶毒性。该研究解决了两种主流癌症治疗药物的问题-对雌激素受体调节剂的耐药性发展和HDACi缺乏肿瘤积累-以提供一类新型靶向抗BCa药物。如果成功，拟议的研究将导致BCa治疗的突破，并对患者的治疗结果产生积极影响。

DESCRIPTION (provided by applicant): Breast cancer (BCa) ranks second only to lung cancer as the leading cause of US cancer deaths in women. A common mechanism for the sustenance of breast carcinoma is the malfunction of endocrine proteins such as estrogen receptor (ER). Therapeutic interventions that capitalize on such protein malfunction have enjoyed measured success in breast cancer therapy and/or chemo-prevention. For example, selective estrogen-receptor modulators (SERMs) such as tamoxifen are the first-line therapy for treatment of hormone dependent breast cancer. However, despite initial benefits, most patients eventually relapse due to acquired resistance to these drugs. The exact mechanisms of the acquired resistance are not completely understood. It is clear however that resistant tumors still maintain ER expression, either in the form of ER¿ (in more than 70% of the case) or up regulation of the expression of ER¿, a closely related isoform ER¿. Therefore, there is an unmet medical need for increasingly selective and potent drugs to treat the resistant stage BCa and early stage as well. The specific focus of the studies proposed in this application is to explore the tumor ER expression state to effect a selective delivery of an independent anti-tumor chemotype, in this case histone deacetylase inhibitor (HDACi). Our choice of HDAC as a therapeutic target is informed by the fact that HDAC inhibition is a clinically validated anti-cancr strategy that is selectively cytotoxic to transformed cells. HDACi continue to stimulate immense excitement in oncology, with close to 500 clinical trials initiated to date, thus far resulting in wo clinically approved drugs, SAHA (Zolinza") and FK228 (Istodax"), for the treatment of cutaneous T-cell lymphoma (CTCL). However, current HDACi have serious limitations resulting from poor biodistribution, including ineffectively low concentrations in solid tumors and off-target toxicity which is hampering clinical progress. The proposed research solves the problems of two mainstream cancer therapy agents - resistance development to estrogen-receptor modulators and lack of tumor accumulation of HDACi - to furnish a novel class targeted anti-BCa agents. If successful, the proposed research will lead to breakthroughs in BCa therapy and positively impact patients' treatment outcome.