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Targeting the colchicine binding site in tubulin for cancer therapy

靶向微管蛋白中的秋水仙碱结合位点进行癌症治疗

基本信息

批准号：
10298280
负责人：
WEI LI
金额：
$ 40.33万
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：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298280
关键词：
ABCG2 gene Address Affinity Allergic Androgens Binding Binding Sites Cancer Patient Cell Line Clinical Clinical Management Clinical Trials Colchicine Crystallization DU145 Data Daughter Development Disease Dose Dose-Limiting Drug Kinetics Drug resistance Drug usage FDA approved FOLH1 gene Fracture Frequencies Funding Future Generations Goals Grant Hematopoietic Hybrids Immunotherapy In Vitro Indium-111 Lead Length Malignant Neoplasms Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Neoplasm Metastasis Neutropenia Oral Pain Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Phase II Clinical Trials Property Prostate Cancer therapy Prostatic Neoplasms Quality of life Resistance Resolution Roentgen Rays Site Solubility Structure Therapeutic Index Toxic effect Tubulin X-Ray Crystallography Xenograft Model acquired drug resistance analog anti-cancer aqueous base bisphosphonate bone cancer therapy cancer type chemotherapeutic agent chemotherapy clinical candidate clinical efficacy design docetaxel drug candidate efficacious treatment efficacy study improved in vivo in vivo Model inhibitor/antagonist mortality nerve damage neurotoxicity next generation novel therapeutics overexpression patient derived xenograft model phase II trial phase III trial prostate cancer cell line prostate cancer metastasis prostate cancer model pyrrolidin-3-yl-methanesulfonic acid resistance mechanism scaffold side effect spinal cord compression success surfactant targeted agent targeted treatment taxane triple-negative invasive breast carcinoma tumor

项目摘要

Despite recent advances in both targeted therapy and immunotherapy, the overall survival (OS) for metastatic prostate cancer (PCa) remains low. This renewal application is to continue our productive efforts to develop a new tubulin inhibitor that can overcome drug resistance associated with FDA approved tubulin inhibitors, and will therefore, increase OS in PCa and other types of cancers where anti-tubulin drugs are used. The support from the previous periods of funding has resulted in a new drug candidate, Veru-111, which is under Phase 2 clinical trials for metastatic PCa. While Veru-111 is on a promising path to gain future FDA approval, there are significant room for improvement. The goals of this renewal are: (1) to develop the next generation of Veru-111 to proactively address its anticipated drug resistance; and (2) to develop targeted Veru- 111 drug conjugates to increase drug accumulation in prostate tumors and to target PCa bone metastasis. Aim 1. Develop a new generation of Veru-111, that can overcome both taxane resistance and the anticipated Veru-111 resistance. Preliminary data: We have discovered a hybrid scaffold based on Veru-111 and Azixa, represented by SHIP-216, that can overcome resistances to both taxanes and Veru-111. Approaches: Guided by high-resolution X-ray crystal structures, we will optimize the SHIP-216 scaffold to further improve its potency and drug-like properties. New analogs will be evaluated against a panel of PCa cell lines, including both taxane- and Veru-111-resistant cell lines to select the best five analogs for in vivo efficacy studies in Aim 3. Aim 2. Conjugate Veru-111 with PSMA targeting moieties to increase drug accumulation in PCa tumors and conjugate Veru-111 with bisphosphonates for more efficacious targeting of bone metastasis. Preliminary data: we have demonstrated Veru-111 itself can significantly reduce bone metastasis in a PDX model. We have also developed linkers for conjugating Veru-111 with PSMA targeting moieties or bisphosphonates. Approaches: we will optimize the length and composition of the linkers to PSMA targeting moieties and use different bisphosphonates in conjugation, to generate focused sets of Veru-111 drug conjugates. These conjugates will be first evaluated in vitro for stability and activation to select the best four conjugates (two in PMSA and two in bisphosphonates conjugates) for further in vivo efficacy studies in Aim 3. Aim 3. We will determine the maximum tolerable dose (MTD), pharmacokinetics (PK), and in vivo efficacy of the selected nine compounds from Aims 1-2 in both PCa cell line models and a PDX model to select the overall best compound to support subsequent clinical trials in the Veru-111 portfolio. Preliminary data: we have already shown that SHIP-216 as a new Veru-111 analog is highly efficacious against multiple xenograft models, including the 22Rv1 PCa and the Veru-111 resistant DU-145/VxR PCa models. Approaches: We will evaluate all selected new compounds for their designed ability to treat prostate tumors using both cell line and PDX models in vivo.

尽管最近在靶向治疗和免疫治疗方面都取得了进展，但治疗的总生存期（OS）