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Blocking tumor progression in therapy-responsive RET aberration-associated cancer

阻断治疗反应性 RET 畸变相关癌症的肿瘤进展

基本信息

批准号：
10615797
负责人：
Blaine H. M. Mooers
金额：
$ 38.22万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615797
关键词：
3-Dimensional Animals Biological Bypass Cancer Patient Cells Clinic Clinical Complex Data Databases Development Disease Disease Management Disease Progression Drug Tolerance Drug resistance Foundations Generations Genes Goals Human Knowledge Laboratories Learning Link Lung Neoplasms Malignant Neoplasms Malignant neoplasm of thyroid Maps Methods Mission Modeling Molecular Biology Molecular Conformation Mutation National Cancer Institute Non-Small-Cell Lung Carcinoma Oncogenes Outcome PTK2 gene Patients Pharmaceutical Preparations Phosphotransferases Plasma Cells Pre-Clinical Model Protein Tyrosine Kinase Proteins RET gene Recurrent tumor Residual Neoplasm Residual state Resistance Resistance development Roentgen Rays Signal Transduction Solid Neoplasm Structure Study models System Testing Transfection Transgenic Mice Tumor Promotion Tumor Suppression Tumor-Derived Tyrosine Kinase Inhibitor United States Food and Drug Administration Validation Variant base cancer therapy cell free DNA clinical development design drug sensitivity drug structure effectiveness evaluation experience improved in vivo in vivo evaluation inhibitor insight mutant neoplastic cell novel personalized management pharmacologic resistance mutation response targeted cancer therapy targeted treatment translational impact treatment response tumor tumor progression

项目摘要

The rearranged during transfection (RET) gene encodes a protein tyrosine kinase (PTK). RET aberrations are found in various types of human cancer. Highly potent and selective RET protein tyrosine kinase inhibitors (TKIs) are in the later stage of clinical development for precision cancer treatment. A lesson learned from the previous experience is that the PTK-targeted cancer therapy often fails because of adaptive resistance evolved from the drug-tolerant, residual tumors. Results of our preliminary studies indicate that the RET-targeted cancer treatment is no exception to this rule. To prolong the suppression of tumors and the lives of patients, we must eliminate the residual tumor cells, identify target mutations that cause drug resistance, find or develop drugs effective against different drug-resistant mutants, and discover alternative signaling mechanisms that promote tumor progression. The overall goal of this project is to improve the targeted therapy for RET aberration- associated cancer. The objectives of this project are to map the landscape of drug-resistant RET kinase mutations, identify drugs effective against mutant RET, determine the structures of RET kinase variants, characterize the structural bases of interaction between RET and its inhibitors, and evaluate a method to minimize the residual lung tumors. Specific Aim 1 is to identify and characterize RET mutations resistant to selective RET TKIs in preclinical models and cancer patients, and find potential secondary drugs. Specific Aim 2 is to determine the crystal structures of drug-resistant RET mutant proteins and RET-inhibitor complexes. Specific Aim 3 is to test RET mutant-sensitive TKIs in vivo and evaluate a method for reducing the residual fibrotic stroma and the associated residual tumor cells. Taken together, this study will provide a RET mutation- TKI toolkit for precision management of RET-aberrant cancers to maximize the benefit of RET-targeted cancer therapy, lay the foundation for developing a continuous pipeline of mutant-effective RET TKIs, and find a method to reduce the residual drug-tolerant tumors to delay tumor recurrence. The outcomes of this project will have positive translational impact on prolonging the survival of patients with cancer.

转染期间重排 (RET) 基因编码蛋白酪氨酸激酶 (PTK)。 RET像差存在于各种类型的人类癌症中。高效、选择性 RET 蛋白酪氨酸激酶抑制剂（TKI）正处于精准癌症治疗临床开发的后期阶段。从中吸取的教训以往的经验是，PTK靶向癌症治疗常常因适应性耐药的进化而失败来自耐药的残留肿瘤。我们的初步研究结果表明，RET 靶向癌症治疗也不例外。为了延长肿瘤的抑制和患者的生命，我们必须消除残留的肿瘤细胞，识别导致耐药性的靶点突变，寻找或开发药物有效对抗不同的耐药突变体，并发现促进的替代信号机制肿瘤进展。该项目的总体目标是改进 RET 畸变的靶向治疗—— 相关癌症。该项目的目标是绘制耐药 RET 激酶的概况突变，识别有效对抗突变 RET 的药物，确定 RET 激酶变体的结构，描述 RET 及其抑制剂之间相互作用的结构基础，并评估一种方法尽量减少残留的肺部肿瘤。具体目标 1 是识别和表征 RET 突变的抗性在临床前模型和癌症患者中选择性 RET TKI，并寻找潜在的辅助药物。具体目标图2是确定耐药RET突变蛋白和RET抑制剂复合物的晶体结构。具体目标 3 是体内测试 RET 突变敏感 TKI 并评估减少残留的方法纤维化基质和相关的残留肿瘤细胞。总而言之，这项研究将提供 RET 突变—— 用于精确管理 RET 异常癌症的 TKI 工具包，以最大限度地发挥 RET 靶向癌症的益处疗法，为开发突变有效的 RET TKI 的连续管道奠定基础，并找到方法减少肿瘤残留耐药性，延缓肿瘤复发。该项目的成果将有对延长癌症患者的生存期产生积极的转化影响。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sequencing PEComas: Viewing Unicorns through the Molecular Looking Glass.

PEComas 测序：通过分子镜子观察独角兽。

DOI：
10.1159/000510650
发表时间：
2021
期刊：
Oncology
影响因子：
3.5
作者：
Groisberg,Roman;Subbiah,Vivek
通讯作者：
Subbiah,Vivek

Translating immuno-onco-microbiome-based therapeutics: precision bugs for immune checkpoint drugs!

转化基于免疫肿瘤微生物组的疗法：免疫检查点药物的精确缺陷！

DOI：
10.1016/j.annonc.2023.03.002
发表时间：
2023
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
0
作者：
Subbiah,V;Pant,S
通讯作者：
Pant,S

Simulations of Promising Indolizidine-α6-β2 Nicotinic Acetylcholine Receptor Complexes.

DOI：
10.3390/ijms22157934
发表时间：
2021-07-25
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Acquah FA;Paramel M;Kuta A;Hussaini SR;Wallace DR;Mooers BHM
通讯作者：
Mooers BHM

Tissue-Agnostic Activity of BRAF plus MEK Inhibitor in BRAF V600-Mutant Tumors.

DOI：
10.1158/1535-7163.mct-21-0950
发表时间：
2022-06-01
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Adashek JJ;Menta AK;Reddy NK;Desai AP;Roszik J;Subbiah V
通讯作者：
Subbiah V

Validation of prognostic scoring systems for patients with metastatic renal cell carcinoma enrolled in phase I clinical trials.

DOI：
10.1136/esmoopen-2020-001073
发表时间：
2020-11
期刊：
ESMO open
影响因子：
7.3
作者：
Hahn AW;Alhalabi O;Msaouel P;Meric-Bernstam F;Naing A;Jonasch E;Piha-Paul S;Hong D;Pant S;Yap T;Campbell E;Le H;Tannir NM;Roszik J;Subbiah V
通讯作者：
Subbiah V