Drugs Targeting Dormant Tumors as Anti-Metastatic Agents

描述（由申请人提供）：大多数实体瘤患者死于同一部位的肿瘤复发或肿瘤转移至远端部位。复发和转移的中间步骤是称为肿瘤休眠的阶段，其中癌细胞被正常细胞外基质（ECM）和其他机制抑制。这些细胞在组织病理学上表现正常，因此无法被检测到。与转移瘤和复发性肿瘤一样，休眠细胞对传统疗法有抵抗力。乳腺癌，特别是三阴性乳腺癌（TNBC）和基底样乳腺癌（BLBC），是低分化的、高度侵袭性的（复发性/转移性的）、对治疗难治的，并且在BC患者缓解后数年发现休眠的肿瘤细胞。有时，这些被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公司已经开发了一种新的药物测试平台来模拟正常ECM的抑制（美国专利7，575，926）。我们已经使用这种模型来筛选能够优先杀死休眠癌细胞的化合物的化学文库，以在以前未开发的点（休眠或抑制的肿瘤微转移）靶向转移和复发。在我们对2，300种化合物的首次筛选中，确定了三种先导化合物，命名为DT-310，DT- 320和DT-330。在该SBIR提案的第一阶段部分中，在肿瘤休眠的体内模型（专利申请中）和已建立的转移性原位基底样乳腺癌（BLBC）模型中评估了这些化合物。发现一种化合物DT-320在这些模型中与标准药剂多柔比星（DOX）和吉西他滨（GEM）相比具有上级抗肿瘤功效和低毒性。 本II期申请中研究的目标是完成DT-320的药物非临床研究质量管理规范（GLP）前评价，以支持DormaTarg，Inc.。FDA正在为这种一流的治疗药物申请IND。目的1是确定DT-320体内抗肿瘤作用的剂量递增、时间表和可逆性。目的2是延长DT- 320在体内乳腺肿瘤中的抗癌功效。目的3评价DT-320的体内药动学参数。目的4研究DT-320的肿瘤杀伤机制。 公共卫生相关性：三阴性乳腺癌（TNBC）和基底样乳腺癌（BLBC）通常具有高度侵袭性（复发/转移）。虽然有几种疗法可用于TNBC/BLBC，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，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.