Targeting brain and bone metastases in metastatic breast cancer for improved patient survival

乳腺癌的一个主要临床挑战是预防和治疗转移性疾病。以下两个关键障碍 转移性乳腺癌(MBC)患者的治疗方法是治疗脑转移(BrnMets)和预防 骨转移的进展(BonMets)。化疗药物，包括紫杉烷，仍然是主线 第四期MBC患者的治疗。然而，长期临床使用紫杉烷与 多药耐药、剂量限制的造血毒性和神经毒性的发展。 我们在这一领域的持续努力导致了一种正在研究的新药--沙比布林。萨比布林在临床中的应用 MBC和其他肿瘤模型显示出对原发肿瘤生长和肿瘤转移的抑制，以及 克服紫杉烷耐药性的有效性。由于萨比布林的脑渗透率有限，其进一步 修改导致SB-216的发现，这是一种高度脑穿透的类似物，在多种疾病中具有出色的疗效 紫杉烷耐药肿瘤模型。为了进一步开发用于MBC的SB-216脚手架，本项目的目标是 要：(1)在SB-216脚手架的基础上进行重点结构优化，生产出新的高效、高效的脚手架 可克服紫杉烷耐药的脑透性类似物用于MBC BrnMets管理；以及(2)开发 新型药物与双膦酸偶联物(BisPhos)用于治疗MBC骨代谢。 目的1.在SB-216脚手架的基础上进行重点结构优化，开发新的类似物 具有很高的脑渗透能力。微管蛋白/Sb-216复合体的晶体结构将用于引导聚焦， 迭代领先优化。我们将使用一组MBC细胞系，包括细胞，在体外筛选新的类似物 来源于PDX模型和正常细胞。我们将确定他们的大脑穿透力，选出十个最好的 用于体内疗效研究的化合物。目的2.测定SB-216类似物的体内药效。 抑制MBC BrnMets。我们将首先确定该药的最大耐受量和药代动力学 从目标1中选择SB-216类似物来确定总体上最好的三个类似物，用于体内评估使用多个 特征良好的MBC临床前模型，包括紫杉烷耐药模型，每种模型都已存在 BrnMets因转移进展延迟而得分。目的3.共轭沙比布林、SB-216及其新类似物 用BisPhos更有效地靶向MBC BonMet，使用最好的Sabizulin结合物和紫杉醇 作为参考。SB-216或其新类似物与BisPhos药物的偶联 对骨骼的亲和力将增加治疗BonMet的疗效。因此，我们将优化链接器化学和 评估各种BisPhos药物的偶联作用。结合物将首先在体外进行稳定性和 激活以选择两种最佳结合物，用于使用BonMet临床前模型进行进一步的体内疗效研究。 影响：在现有化疗药物小组中增加新一代微管蛋白抑制剂 可能会改善MBC患者的PFS、OS和QOL。此外，被诊断为其他类型转移的患者 微管蛋白抑制剂目前是标准治疗(SOC)的实体肿瘤也可以从该项目中受益。

A major clinical challenge in breast cancer is to prevent and to treat metastatic disease. Two key hurdles for therapies for metastatic breast cancer (MBC) patients are to treat brain metastases (BrnMets) and to prevent progression of bone metastases (BonMets). Chemotherapeutic drugs, including the taxanes, remain mainline therapies for stage IV patients with MBC. However, prolonged clinical use of taxanes is associated with development of multidrug resistance, dose-limiting hematopoietic toxicity, and neurotoxicity. Our ongoing efforts in this area has led to an investigational new drug, Sabizabulin. Use of Sabizabulin in MBC and other tumor models demonstrated suppression of primary tumor growth and tumor metastasis, and effectiveness in overcoming taxane resistance. Since Sabizabulin has limited brain penetration, its further modification led to the discovery of SB-216, a highly brain penetrable analog that has excellent efficacy in multiple taxane-resistant tumor models. To further develop the SB-216 scaffold for MBC, the goals of this project are to: (1) perform focused structural optimization based on the SB-216 scaffold to produce new potent and high brain penetrable analogs that can overcome taxane resistance for MBC BrnMets management; and (2) develop novel drug conjugates with bisphosphonate (BisPhos) for MBC bone BonMets treatment. AIM 1. Perform focused structure-based optimization based on the SB-216 scaffold to develop new analogs with high brain penetration ability. Crystal structures of tubulin/SB-216 complexes will be used to guide focused, iterative lead optimization. We will screen new analogs in vitro using a panel of MBC cell lines, including cells derived from PDX models, and normal cells. We will determine their brain penetrations to select the ten best compounds for in vivo efficacy studies. AIM 2. Determine the in vivo efficacy of selected SB-216 analogs for suppressing MBC BrnMets. We will first determine the maximum tolerable dose and pharmacokinetics for selected SB-216 analogs from Aim 1 to identify the overall best three analogs for in vivo evaluation using multiple well-characterized, pre-clinical models of MBC, including taxane-refractory models, each with pre-existing BrnMets to score for delay of metastatic progression. AIM 3. Conjugate Sabizabulin, SB-216 and its new analogs with BisPhos for more efficacious targeting of MBC BonMets, using the best Sabizabulin conjugate and paclitaxel as the references. Conjugating Sabizabulin, SB-216, or its new analogs with a BisPhos drug with very high affinity to bones will increase the efficacy of treating BonMets. Thus, we will optimize the linker chemistry and evaluate a variety of BisPhos drugs for conjugation. Conjugates will first be evaluated in vitro for stability and activation to select the two best conjugates for further in vivo efficacy studies using BonMet pre-clinical models. Impact: The addition of a new generation of tubulin inhibitor to the existing panel of chemotherapeutic drugs is likely to improve MBC patient PFS, OS and QOL. In addition, patients diagnosed with other types of metastatic solid tumors in which tubulin inhibitors are currently standard of care (SOC) could also benefit from this project.