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

针对转移性乳腺癌的脑和骨转移，提高患者生存率

基本信息

批准号：
10564604
负责人：
WEI LI
金额：
$ 61.49万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-20 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10564604
关键词：
ABCG2 gene Affinity Area Binding Binding Sites Biological Availability Brain Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Breast cancer metastasis Bypass COVID-19 Cancer Patient Cell Line Cells Chemistry Clinic Clinical Colchicine Complex Computer Assisted Development Diagnosis Disease Disseminated Malignant Neoplasm Dose Dose Limiting Drug Design Drug Kinetics Drug resistance ERBB2 gene Effectiveness FDA approved Generations Goals Hematopoietic Human In Vitro Investigational Drugs Lead Lung Malignant Bone Neoplasm Malignant Neoplasms Metabolic Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Liver Metastatic breast cancer Metastatic malignant neoplasm to brain Modeling Modification Multi-Drug Resistance Mus Neoplasm Metastasis Neurologic Neuropathy Neutropenia No Evidence of Disease Normal Cell Oral Paclitaxel Patient-derived xenograft models of breast cancer Patients Penetration Peripheral Nervous System Diseases Pharmaceutical Preparations Pre-Clinical Model Primary Neoplasm Progression-Free Survivals Property Proteins Quality of life Refractory Resistance Resolution Roentgen Rays Site Solid Neoplasm Structure Survival Rate Therapeutic Therapeutic Index Toxic effect Treatment Protocols Tubulin Tumor-Derived X-Ray Crystallography advanced prostate cancer analog anti-cancer bisphosphonate bone chemotherapy clinical candidate clinical efficacy docetaxel effective therapy efficacy study improved in vivo in vivo evaluation inhibitor invention lead optimization malignant breast neoplasm mortality neurotoxicity next generation novel novel therapeutics overexpression patient derived xenograft model phase II trial phase III trial prevent resistance mechanism scaffold standard of care targeted treatment taxane triple-negative invasive breast carcinoma tumor tumor growth

ABCG2 gene Affinity Area Binding Binding Sites Biological Availability Brain Breast Cancer Model Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line Breast Cancer therapy Breast cancer metastasis Bypass COVID-19 Cancer Patient Cell Line Cells Chemistry Clinic Clinical Colchicine Complex Computer Assisted Development Diagnosis Disease Disseminated Malignant Neoplasm Dose Dose Limiting Drug Design Drug Kinetics Drug resistance ERBB2 gene Effectiveness FDA approved Generations Goals Hematopoietic Human In Vitro Investigational Drugs Lead Lung Malignant Bone Neoplasm Malignant Neoplasms Metabolic Metastatic Neoplasm to the Bone Metastatic Neoplasm to the Liver Metastatic breast cancer Metastatic malignant neoplasm to brain Modeling Modification Multi-Drug Resistance Mus Neoplasm Metastasis Neurologic Neuropathy Neutropenia No Evidence of Disease Normal Cell Oral Paclitaxel Patient-derived xenograft models of breast cancer Patients Penetration Peripheral Nervous System Diseases Pharmaceutical Preparations Pre-Clinical Model Primary Neoplasm Progression-Free Survivals Property Proteins Quality of life Refractory Resistance Resolution Roentgen Rays Site Solid Neoplasm Structure Survival Rate Therapeutic Therapeutic Index Toxic effect Treatment Protocols Tubulin Tumor-Derived X-Ray Crystallography advanced prostate cancer analog anti-cancer bisphosphonate bone chemotherapy clinical candidate clinical efficacy docetaxel effective therapy efficacy study improved in vivo in vivo evaluation inhibitor invention lead optimization malignant breast neoplasm mortality neurotoxicity next generation novel novel therapeutics overexpression patient derived xenograft model phase II trial phase III trial prevent resistance mechanism scaffold standard of care targeted treatment taxane triple-negative invasive breast carcinoma tumor tumor growth

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项目摘要

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.

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）患者的疗法是治疗脑转移（BRNMET）并防止骨转移的进展（BONMETS）。化学治疗药物（包括紫杉虫）仍然是主线 IV期MBC患者的疗法。但是，长期临床使用群属与多药耐药性，限制剂量的造血毒性和神经毒性的发展。我们在这一领域正在进行的努力导致了一种调查新药Sabizabulin。使用sabizabulin MBC和其他肿瘤模型表现出抑制原发性肿瘤生长和肿瘤转移的抑制作用，以及克服紫杉烷抵抗的有效性。由于Sabizabulin的大脑渗透率有限，因此修改导致发现SB-216，这是一种高度可渗透的类似物，在多个中具有极好的功效抗紫杉烷的肿瘤模型。为了进一步开发MBC的SB-216脚手架，该项目的目标是至：（1）基于SB-216脚手架进行重点的结构优化，以产生新的有效和高可以克服MBC BRNMETS管理的大脑渗透类似物；（2）发展新型药物与双膦酸盐（双膦酸盐）进行MBC骨bon骨治疗。 AIM 1。基于SB-216支架进行基于重点的基于结构的优化以开发新的类似物具有高脑穿透能力。微管蛋白/SB-216复合物的晶体结构将用于引导聚焦，迭代铅优化。我们将使用一系列MBC细胞系在体外筛选新的类似物，包括细胞源自PDX模型和正常细胞。我们将确定他们的大脑穿透以选择十个最好的体内功效研究的化合物。 AIM 2。确定选定的SB-216类似物的体内功效抑制MBC BRNMET。我们将首先确定最大耐受剂量和药代动力学来自AIM 1的选定SB-216类似物，以确定使用多个体内评估的总体最佳三个类似物特征良好的MBC的临床前模型，包括紫杉烷 - 侵犯模型，每个模型都有预先存在 BRNMET得分为转移性进展的延迟。 AIM 3。结合Sabizabulin，SB-216及其新类似物使用Bisphos，可以使用最佳的sabizabulin conjugate和Paclitaxel对MBC Bonmets进行更有效的靶向靶向作为参考。共轭Sabizabulin，SB-216或其新的类似物与具有很高的双Bisphos药物对骨骼的亲和力将提高治疗锁骨的功效。因此，我们将优化接头化学和评估各种双Bisphos药物进行结合。偶联物将在体外首先进行稳定和激活使用BONMET临床前模型选择两个最佳结合物，以进一步进行体内疗效研究。影响：将新一代的微管蛋白抑制剂添加到现有的化学治疗药物面板中可能会改善MBC患者PFS，OS和QOL。此外，被诊断为其他类型转移性的患者微管蛋白抑制剂目前是护理标准（SOC）的实体瘤也可以从该项目中受益。