Drugs Targeting Dormant Tumors as Anti-Metastatic Agents

描述(申请人提供)：大多数实体瘤患者死于肿瘤在同一部位复发或转移到远端部位。复发和转移的中间步骤是称为肿瘤休眠的阶段，在这个阶段，癌细胞被正常的细胞外基质(ECM)和其他机制抑制。这样的细胞在组织病理学上看起来是正常的，因此可以逃脱检测。像转移和复发肿瘤一样，休眠细胞对传统疗法具有抵抗力。乳腺癌，尤其是三阴性乳腺癌(TNBC)和基底细胞样癌(BLBC)，是一种低分化、高侵袭性(复发/转移)、治疗难治的肿瘤，在BC患者缓解多年后发现了潜伏的肿瘤细胞。有时，这些受抑制的细胞会重新激活并开始活跃生长，形成转移或局部复发。DormaTarg，Inc.开发了一种新型药物测试平台，用于模拟正常ECM的抑制作用(美国专利7,575,926)。我们已经使用这个模型来筛选化合物库中能够优先杀死休眠癌细胞的化合物，以努力针对以前未开发的点，休眠或抑制的肿瘤微转移的转移和复发。在我们对2,300种化合物的第一次筛选中，鉴定出三种先导化合物，分别命名为DT-310、DT-320和DT-330。在这项SBIR建议的第一阶段，这些化合物在肿瘤休眠的体内模型(正在申请专利)和已建立的转移性原位基底样乳腺癌(BLBC)模型中进行了评估。在这些模型中，与标准药物阿霉素(DOX)和吉西他滨(GEM)相比，化合物DT-320具有更好的抗肿瘤效果和低毒。这项第二阶段应用研究的目标是完成对DT-320的良好实验室操作规范(Pre-GLP)前评估，以支持DormaTarg公司在FDA的IND中取得这一第一类治疗药物。目的1确定DT-320体内抗肿瘤作用的ODSE升级性、时序性和可逆性。目的2扩大DT-320在体内对乳腺肿瘤的抗癌作用。目的评价DT-320在体内的药代动力学参数。目的4研究DT-320肿瘤杀伤机制的特点。 公共卫生相关性：三阴性乳腺癌(TNBC)和基底细胞样癌(BLBC)通常具有高度侵袭性(复发/转移)。虽然有几种治疗TNBC/BLBC的方法，但这些癌症的存活率仍然很低。该项目测试了一种治疗TNBC/BLBC的新方法，即攻击休眠肿瘤。

DESCRIPTION (provided by applicant): Most patients with solid tumors die of tumor recurrence at the same site or metastasis of the tumor to distal sites. An intermediate step in both recurrence and metastasis is a stage called tumor dormancy, where the cancer cells are suppressed by a normal extracellular matrix (ECM) and by other mechanisms. Such cells can appear histopathologically normal and therefore escape detection. Like metastases and recurrent tumors, dormant cells are resistant to traditional therapeutics. Breast cancer, in particularly triple negative breast cancer (TNBC) and basal like breast cancer (BLBC), are poorly differentiated, highly aggressive (recurrent/metastatic), refractory to treatment and dormant tumor cells have been found years after remission in BC patients. Sometimes, these suppressed cells will reactivate and begin actively growing, forming either a metastasis or a local recurrence. DormaTarg, Inc. has developed a novel drug testing platform to model suppression by the normal ECM (U.S. Patent 7,575,926). We have used this model to screen chemical libraries for compounds capable of preferentially killing dormant cancer cells in an effort to target metastasis and recurrence at a previously unexploited point, the dormant or suppressed tumor micrometastasis. In our first screen of 2,300 compounds, three lead compounds were identified, designated DT-310, DT- 320 and DT-330. In the phase I portion of this SBIR proposal, these compounds were evaluated in an in vivo model of tumor dormancy (Patent Pending) and in an established metastatic orthotopic basal- like breast cancer (BLBC) model. It was found that one compound, DT-320, had superior antitumor efficacy and low toxicity in these models as compared to standard agents doxorubicin (DOX) and gemcitabine (GEM). The goal of the studies in this phase II application is to complete pre-good laboratory practices (pre-GLP) evaluation of DT-320 to support DormaTarg, Inc. moving forward with an IND from the FDA for this first in class therapeutic. Aim 1 is to determine the odse escalation, scheduling and reversibility of the antitumor effect of DT-320 in vivo. Aim 2 is to extend the anticancer efficacy of DT- 320 in breast tumors in vivo. Aim 3 evaluates the pharmacokinetic parameters of DT-320 in vivo. Aim 4 characterizes of mechanism of DT-320 tumor kill. PUBLIC HEALTH RELEVANCE: Triple negative breast cancer (TNBC) and basal like breast cancer (BLBC) are often highly aggressive (recurrent/metastatic). While there are several therapies available for TNBC/BLBC, survival rates for these cancers remain low. This project tests a novel approach to treating TNBC/BLBC, attacking dormant tumors.