Histone Deacetylase Inhibitors Equipped with Estrogen Receptor Modulation Activit

描述(申请人提供)：乳腺癌(BCA)是美国女性癌症死亡的第二大原因，仅次于肺癌。乳腺癌的一种常见的生存机制是内分泌蛋白功能失调，如雌激素受体(ER)。利用这种蛋白质故障的治疗干预在乳腺癌治疗和/或化学预防方面取得了一定的成功。例如，选择性雌激素受体调节剂(SERM)，如他莫昔芬，是治疗激素依赖型乳腺癌的一线药物。然而，尽管最初有好处，但由于对这些药物的获得性耐药性，大多数患者最终会复发。获得性抗性的确切机制尚不完全清楚。然而，很明显，耐药肿瘤仍然保持ER的表达，要么以ER？的形式(在70%以上的病例中)，要么上调ER？的表达，ER？是一种密切相关的亚型ER？因此，对于治疗耐药阶段BCA和早期BCA的药物，有越来越多的选择性和强效药物的医学需求尚未得到满足。在这一应用中提出的研究的具体重点是探索肿瘤ER的表达状态，以影响选择性地输送一种独立的抗肿瘤化学类型，在这种情况下，组蛋白去乙酰酶抑制物(HDACi)。我们选择HDAC作为治疗靶点是因为HDAC抑制是一种经过临床验证的抗癌策略，对转化的细胞具有选择性的细胞毒作用。HDACi继续刺激肿瘤学的巨大兴奋，迄今已启动近500项临床试验，迄今已产生两种临床批准的药物，SAHA(佐林扎)和FK228(Istodax)，用于治疗皮肤T细胞淋巴瘤(CTCL)。然而，由于生物分布不佳，目前的HDACi具有严重的局限性，包括实体瘤中低浓度的药物和非靶点毒性，这阻碍了临床的进展。这项研究解决了两种主流癌症治疗药物对雌激素受体调节剂的耐药性和HDACi缺乏肿瘤蓄积的问题，提供了一类新型的靶向抗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.