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

乳腺癌的主要临床挑战是预防和治疗转移性疾病。两个关键障碍， 转移性乳腺癌（MBC）患者的治疗是治疗脑转移（BrnMets）和预防脑转移（BrnMets）。 骨转移进展（BonMets）。包括紫杉烷类在内的化疗药物仍然是主要的治疗药物， IV期MBC患者的治疗。然而，长期临床使用紫杉烷类药物与 多药耐药性、剂量限制性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研究性新药Sabizabulin。沙比珠布林的用途 MBC和其他肿瘤模型显示了原发性肿瘤生长和肿瘤转移的抑制， 有效克服紫杉烷耐药性。由于Sabizabulin具有有限的脑渗透，其进一步 修改导致SB-216的发现，SB-216是一种高度脑渗透的类似物，在多种疾病中具有优异的疗效。 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 （1）基于SB-216支架进行重点结构优化，以产生新的强效和高效的 脑渗透类似物，可以克服紫杉烷耐药性的MBC BrnMets管理;和（2）开发 用于MBC骨BonMets治疗的具有双膦酸盐（BisPhos）的新型药物缀合物。 AIM 1.基于SB-216支架进行重点结构优化，开发新的类似物 具有很强的大脑穿透能力。微管蛋白/SB-216复合物的晶体结构将用于引导聚焦， 迭代引导优化。我们将在体外使用一组MBC细胞系筛选新的类似物， 来源于PDX模型和正常细胞。我们将决定他们的大脑渗透率，以选出十个最好的 用于体内功效研究的化合物。AIM 2.测定所选SB-216类似物用于治疗糖尿病的体内功效。 抑制MBC BrnMets。我们将首先确定最大耐受剂量和药代动力学 从Aim 1中选择SB-216类似物，以鉴定总体上最好的三种类似物，用于使用多个 充分表征的MBC临床前模型，包括紫杉烷难治性模型，每种模型均预先存在 BrnMets评分转移进展延迟。AIM 3.结合物Sabizabulin，SB-216及其新类似物 与BisPhos联合使用，可更有效地靶向MBC BonMets，使用最佳的萨比布林结合物和紫杉醇 作为参考。将Sabizabulin、SB-216或其新类似物与具有非常高的生物活性的BisPhos药物缀合 对骨的亲和力将增加治疗BonMets的功效。因此，我们将优化接头化学， 评估各种用于缀合的BisPhos药物。首先在体外评价结合物的稳定性， 活化以选择两种最佳缀合物用于使用BonMet临床前模型的进一步体内功效研究。 影响：在现有化疗药物组合中添加新一代微管蛋白抑制剂 可能改善MBC患者的PFS、OS和QOL。此外，诊断为其他类型转移性肿瘤的患者 微管蛋白抑制剂目前是标准治疗（SOC）的实体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.