PDX Trial Center for Breast Cancer Therapy

PDX 乳腺癌治疗试验中心

• 批准号: 10732947
• 负责人: Michael T. Lewis
• 金额: $ 118.71万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732947
• 关键词: Algorithms; Animals; Bioinformatics; Biometry; Breast; Breast Cancer Patient; Breast Cancer therapy; Cancer Biology; Cancer Etiology; Cellular biology; Cessation of life; Chemoresistance; Clinical Trials; Clinical Trials Network; Collaborations; Collection; Combined Modality Therapy; Communication; Data; Development; Disease; Drug Combinations; Early treatment; Elements; Evolution; Fostering; Funding; Future; Generations; Genomics; Goals; Human; Huntsman Cancer Institute at the University of Utah; Institution; Investigational Therapies; Investments; Malignant Neoplasms; Mammary Neoplasms; Medicine; Metastatic/Recurrent; Modeling; Molecular; Molecular Genetics; Molecular Profiling; National Cancer Institute; Neoplasm Metastasis; Organoids; Pathology; Patient-derived xenograft models of breast cancer; Pharmaceutical Preparations; Pharmacotherapy; Pilot Projects; Preclinical Drug Evaluation; Recurrence; Recurrent Malignant Neoplasm; Recurrent disease; Regimen; Reproducibility; Research; Research Project Grants; Resistance; Sampling; Structure; Testing; Therapeutic; Treatment Protocols; Veterinary Medicine; Woman; advanced breast cancer; cancer clinical trial; cancer recurrence; care outcomes; chemotherapy; cohort; college; combat; data visualization; design; drug testing; effective therapy; ethnic minority; experience; improved; improved outcome; innovation; inter-institutional; interactive tool; malignant breast neoplasm; multidisciplinary; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; patient population; pre-clinical; pre-clinical research; preclinical trial; prevent; racial minority; response; standard of care; synergism; targeted treatment; therapeutic evaluation; treatment strategy; triple-negative invasive breast carcinoma; tumor; web-based tool

Project Summary The scientific premise of this Center is that breast cancer patient-derived xenograft (PDX) and organoid models represent the diversity of human breast tumors, and can be feasibly utilized to test new drugs and drug combinations to find therapeutic approaches that match with molecular features of various tumor types. Our PDTC is focused on identifying new treatment strategies for breast cancer, which remains the 2nd leading cause of cancer death in women. We will conduct preclinical evaluation of drugs and drug combinations in models selected from our large collection of 261 breast PDX models and >100 stable PDxO lines representing primary, metastatic, and treatment-resistant breast cancers from diverse patient populations (25% of the collection is from racial/ethnic minorities, with plans to increase that proportion in Aim 1 of both research projects). The Center comprises two highly integrated Research Projects that are designed together to combat the two most difficult problems contributing to breast cancer deaths: breast cancer recurrence, and treatment of recurrent/metastatic disease. More than 90% of breast cancer deaths are attributed to disease recurrence as incurable metastatic disease. Project 1 is focused on improving therapy for early-stage triple negative breast cancer (TNBC), to prevent recurrence and achieve durable cures by identifying optimal chemotherapy and targeted therapy combinations based on molecular features of tumors. Project 2 aims to identify more effective regimens in disease that does recur (treatment-resistant, metastatic disease) by utilizing our unique collection of PDX and PDxO from metastatic samples. These two complementary research projects will be supported by a PDX Core, a Bioinformatics Core, a Pilot Projects and Trans-Network Activities Core that fosters exploration of new ideas within the PDTC and in collaboration with the PDXNetwork (PDXNet), and an Administrative Core that provides project oversight and management, and facilitates effective communication within the PDTC and the PDXNet. The overarching goal of our PDX Development and Trials Center (PDTC) is to obtain preclinical data that will facilitate prioritization of drugs to be tested in breast cancer clinical trials at the National Cancer Institute (NCI).

项目概要 该中心的科学前提是乳腺癌患者来源的异种移植物（PDX）和类器官模型 代表了人类乳腺肿瘤的多样性，可用于新药和新药的测试 组合来寻找与各种肿瘤类型的分子特征相匹配的治疗方法。我们的 PDTC 致力于确定乳腺癌的新治疗策略，乳腺癌仍然是第二大病因 女性癌症死亡的情况。我们将在模型中对药物和药物组合进行临床前评价 从我们大量的 261 个乳腺 PDX 模型和超过 100 个稳定的 PDxO 系中选出，代表初级、 来自不同患者群体的转移性和难治性乳腺癌（收集的 25% 来自 种族/族裔少数群体，并计划在两个研究项目的目标 1 中增加这一比例）。中心 包括两个高度集成的研究项目，旨在共同应对两个最困难的问题 导致乳腺癌死亡的问题：乳腺癌复发以及复发/转移性乳腺癌的治疗 疾病。超过 90% 的乳腺癌死亡归因于作为无法治愈的转移性疾病的疾病复发。 项目 1 的重点是改善早期三阴性乳腺癌 (TNBC) 的治疗，以预防 通过确定最佳化疗和靶向治疗组合来预防复发并实现持久治愈 基于肿瘤的分子特征。项目 2 旨在确定更有效的治疗方案 通过利用我们独特的 PDX 和 PDxO 集合来治疗复发（难治性转移性疾病） 转移样本。这两个互补的研究项目将得到 PDX Core 的支持， 生物信息学核心，一个试点项目和跨网络活动核心，促进新想法的探索 在 PDTC 内并与 PDXNetwork (PDXNet) 合作，以及一个管理核心，该核心提供 项目监督和管理，并促进 PDTC 和 PDXNet 内的有效沟通。 我们的 PDX 开发和试验中心 (PDTC) 的首要目标是获取临床前数据，以便 促进国家癌症研究所 (NCI) 乳腺癌临床试验中待测试药物的优先顺序。

项目成果

Dll1-Mediated Notch Signaling Drives Tumor Cell Cross-talk with Cancer-Associated Fibroblasts to Promote Radioresistance in Breast Cancer.

• DOI: 10.1158/0008-5472.can-21-1225
• 发表时间: 2022-10-17
• 期刊: Cancer research
• 影响因子: 11.2

In Vivo Modeling of Human Breast Cancer Using Cell Line and Patient-Derived Xenografts.

使用细胞系和患者衍生的异种移植物对人乳腺癌进行体内模型。

• DOI: 10.1007/s10911-022-09520-y
• 发表时间: 2022-06
• 期刊: JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA
• 影响因子: 2.5
• 作者: Souto, Eric P.;Dobrolecki, Lacey E.;Villanueva, Hugo;Sikora, Andrew G.;Lewis, Michael T.
• 通讯作者: Lewis, Michael T.

RANK is a poor prognosis marker and a therapeutic target in ER-negative postmenopausal breast cancer.

• DOI: 10.15252/emmm.202216715
• 发表时间: 2023-04-11
• 期刊: EMBO MOLECULAR MEDICINE
• 影响因子: 11.1
• 作者: Ciscar, Marina;Trinidad, Eva M.;Perez-Chacon, Gema;Alsaleem, Mansour;Jimenez, Maria;Jimenez-Santos, Maria J.;Perez-Montoyo, Hector;Sanz-Moreno, Adrian;Vethencourt, Andrea;Toss, Michael;Petit, Anna;Soler-Monso, Maria T.;Lopez, Victor;Gomez-Miragaya, Jorge;Gomez-Aleza, Clara;Dobrolecki, Lacey E.;Lewis, Michael T.;Bruna, Alejandra;Mouron, Silvana;Quintela-Fandino, Miguel;Al-Shahrour, Fatima;Martinez-Aranda, Antonio;Sierra, Angels;Green, Andrew R.;Rakha, Emad;Gonzalez-Suarez, Eva
• 通讯作者: Gonzalez-Suarez, Eva

Transferred mitochondria accumulate reactive oxygen species, promoting proliferation.

• DOI: 10.7554/elife.85494
• 发表时间: 2023-03-06
• 期刊: eLife
• 影响因子: 7.7
• 作者: Kidwell CU;Casalini JR;Pradeep S;Scherer SD;Greiner D;Bayik D;Watson DC;Olson GS;Lathia JD;Johnson JS;Rutter J;Welm AL;Zangle TA;Roh-Johnson M
• 通讯作者: Roh-Johnson M

Toward improved models of human cancer.

• DOI: 10.1063/5.0030534
• 发表时间: 2021-03
• 期刊: APL bioengineering
• 影响因子: 6
• 作者: Welm BE;Vaklavas C;Welm AL
• 通讯作者: Welm AL