A Novel Treatment of Vasomotor Symptoms in Prostate Cancer Patients

 描述（由申请方提供）：由于前列腺癌在早期阶段是一种雄激素依赖性恶性肿瘤，因此雄激素耗竭治疗（ADT）已被证明在疾病过程中及时给药可有效改善生存率。另一方面，这些好处可能会被严重的神经系统症状（主要是潮热）所抵消。由于ADT消耗雌激素生物合成所需的底物，并且睾酮替代绝对禁忌用于前列腺癌患者，因此合成雌激素主要用于治疗ADT相关的神经和精神症状。然而，这种治疗方法会导致女性化（最突出的是男性乳房发育），深静脉血栓形成和随后的肺栓塞的风险很高。由于基于当前的临床实践，只有雌激素可以提供足够的潮热缓解，因此对于有效且安全的干预以缓解影响接受ADT的前列腺癌患者的血管扩张症状的医疗需求尚未得到满足。该I期SBIR资助申请的总体假设是，用10β，17β-二羟基雌甾-1，4-二烯-3-酮（DHED）（一种17β-雌二醇的创新性脑选择性生物前体前药）治疗将缓解ADT相关的潮热，而没有伴随当前形式雌激素治疗的外周副作用。在我们的第一个具体目标中，我们将为拟议的评估提供足够数量的DHED。在第二个具体目标中，我们将在去势（RDX）雄性大鼠中进行临床前药代动力学、分布和生物利用度研究，以支持我们的假设，即DHED治疗限制了17β-雌二醇在大脑中的形成。在第三个具体目标中，我们的具体假设是，口服DHED治疗将防止雄性大鼠（一种成熟的潮热临床前模型）中的RDX诱导的尾部皮肤温度升高。此外，我们将通过显示雌激素诱导的基因表达仅在大脑中被触发，而不是在垂体和前列腺中，来寻找DHED衍生的17β-雌二醇的脑特异性作用的证据。使用RDX无胸腺裸鼠，我们还将证实DHED治疗不会诱导癌性前列腺细胞（LNCaP）异种移植物的增殖。我们的目标与这些系列的临床前研究是支持第二阶段SBIR赠款申请继续追求DHED的治疗用途，以补救血管紧张素转换酶-重点是患者患有前列腺癌和接受ADT。AgyPharma获得了DHED从实验室到床边开发的独家许可，其方法得到了令人鼓舞的初步结果的支持，这不仅提供了一个独特的“利基”，而且还承诺了业务发展的高度竞争地位。由于地理位置和独特的基础设施而提供的支持环境进一步增强了公司的地位，使其在开发创新候选药物方面取得潜在突破，用于治疗影响接受ADT的前列腺癌患者的血管舒缩症状。

 DESCRIPTION (provided by applicant): Because prostate cancer is an androgen-dependent malignancy in the early stages, androgen depletion therapy (ADT) has been shown to be effective in improving survival when administered timely in the course of the disease. On the other hand, the benefits may be offset by severe neurological symptoms primarily hot flushes. Since ADT depletes the substrate necessary for estrogen biosynthesis and testosterone replacement is absolutely contraindicated for prostate cancer patients, synthetic estrogens have been used primarily to treat ADT-associated neurological and psychiatric symptoms. However, this remedy causes feminization (most prominently gynecomastia) with high risks for deep vein thrombosis and subsequent pulmonary embolism. Because only estrogens can provide adequate relieve from hot flushes based on current clinical practices, there is an unmet medical need for an effective and, in addition, safe intervention to alleviate vasomotor symptoms that affect prostate cancer patients undergoing ADT. The overall hypothesis of this Phase I SBIR grant application is that treatment with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), an innovative brain- selective bioprecursor prodrug of 17β-estradiol, will alleviate ADT-associated hot flushes without peripheral side-effects accompanying the current forms of estrogen therapy. In our first specific aim, we will produce sufficient quantity of DHED for the proposed assessments. In the second specific aim, we will perform preclinical pharmacokinetics, distribution and bioavailability studies in orchidectomized (ORDX) male rats to support our hypotheses that DHED treatment confines the formation of 17β-estradiol into the brain. In the third specific aim, our specific hypothesis is that oral treatment with DHED will prevent ORDX-induced tail skin temperature elevation in male rats, a well-established preclinical model of hot flushes. In addition, we will seek evidence for the brain-specific action of DHED-derived 17β-estradiol by showing that estrogen-induced gene expressions are triggered only in the brain, but not in the pituitary and prostate. Using ORDX athymic nude mice, we will also confirm that DHED treatment does not induce proliferation in cancerous prostate cell (LNCaP) xenographts. Our goal with these series of preclinical studies is to support a Phase-II SBIR grant application for the continued pursuit of DHED's therapeutic use to remedy vasomotor symptoms-with focus on patients suffering from prostate cancer and undergoing ADT. AgyPharma has secured an exclusive license for the development of DHED from bench to bedside, its approach has been supported by encouraging preliminary results, which provides not only a distinctive 'niche' but also promises a highly competitive position for business development. A supporting environment due to location and unique access to enabling infrastructure further enhance the company's position to achieve potential breakthrough in developing an innovative drug candidate for the treatment of vasomotor symptom affecting prostate cancer patients receiving ADT.