Sensitivity of Abi1/Pten null tumors to taxane and anti-androgen receptor therapy

Abi1/Pten 无效肿瘤对紫杉烷和抗雄激素受体治疗的敏感性

基本信息

批准号：
10430168
负责人：
LESZEK KOTULA
金额：
$ 18.56万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10430168
关键词：
1-Phosphatidylinositol 3-Kinase Actins American Anatomy Androgen Antagonists Androgen Receptor Androgens Antiandrogen Therapy Apoptosis Biochemical Biopsy CDH1 gene Cadherins Cancer Etiology Cell Nucleus Cell membrane Cell-Cell Adhesion Cessation of life Clinical Clinical Treatment Complex Data Disease Dissection Down-Regulation Drug usage Epithelial FYN gene FZD2 gene Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Histology Human Immunohistochemistry Indolent Knockout Mice Knowledge Ligands Literature MMP2 gene Malignant Neoplasms Malignant neoplasm of prostate Mediating Mesenchymal Metastatic Prostate Cancer Metastatic to Microdissection Modeling Mus Nonmetastatic Organoids Outcome PTEN gene Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Pharmacotherapy Prostate Prostate Cancer therapy Publishing Quality of life RNA analysis Receptor Inhibition Research Resistance Role STAT3 gene Signal Transduction Small Interfering RNA Survival Rate Therapeutic Treatment Protocols Treatment outcome Tumor Biology Tumor Burden Tumor Markers Tumor Suppressor Genes Tumor Tissue Tumor Weights Up-Regulation WNT5A gene Xenograft Model advanced prostate cancer androgen deprivation therapy base cancer diagnosis candidate marker chemotherapy deprivation docetaxel drug sensitivity enzalutamide human model improved inhibitor male men new therapeutic target novel personalized medicine polymerization precision medicine prostate cancer model prostate cancer progression receptor receptor function response senescence synergism targeted agent targeted cancer therapy taxane therapy resistant transcriptome sequencing translational study treatment strategy tumor tumor growth ultrasound

项目摘要

ABSTRACT Prostate cancer (PCa) is the most frequently diagnosed cancer in American men and the 2nd leading cause of male cancer-related deaths in the U.S. Indolent localized PCa is curable, but metastatic PCa is fatal. Progression to metastatic disease is characterized by reactivation of androgen signaling including androgen receptor (AR) function. This knowledge led to anti-androgen pathway therapy which is a mainstay for treatment of progressive PCa. Unfortunately, patients eventually become resistant to anti-androgen therapy and the benefit of subsequent taxane-based chemotherapy is limited to only extending patient survival for up to a year. An urgent need for identification of novel actionable targets remains. The long-term goal of this project is to develop better treatment strategies and rational drug therapies for precision medicine in advanced PCa. Our previous studies demonstrated ABI1 as a bona fide PCa tumor suppressor gene. ABI1 downregulation promotes epithelial mesenchymal transition (EMT) downstream from activation of the non-canonical WNT- FYN-STAT3 pathway. Our published and preliminary data indicate that ABI1 downregulation, in conjunction with loss of PTEN, is associated with high grade and metastatic PCa in a significant subset of human PCa. Because ABI1 expression is downregulated following androgen deprivation therapy, we hypothesize that anti- AR treatment leads to activation of the WNT-FYN-STAT3 pathway. Moreover, taxane therapies might promote activation of the WNT pathway and potentially cause cross-pathway effects with anti-AR treatment. Our objective is to develop a more comprehensive understanding of the contribution of ABI1 and PTEN on tumor sensitivity to the current treatment regimen of androgen receptor (AR)-targeting agents for both castrate- sensitive (CSPC) and resistant (CRPC) PCa, as well as druggability of the ABI1/PTEN pathway itself. Our central hypothesis is that ABI1-deficient tumors have a low sensitivity to anti-AR agents. In addition, we propose that ABI1-deficient tumors are sensitive to STAT3 pathway inhibitors. We propose that ABI1 is a candidate marker of tumor sensitivity for current treatments of PCa. Using the novel Abi1/Pten null mouse and organoid prostate models, we will assess drug sensitivity and characterize the tumor response in search for treatment resistance targets. We aim to: 1) Determine sensitivity of Abi1/Pten null tumors to AR inhibition (using enzalutamide) or taxane chemotherapy (using cabazitaxel) before and after androgen deprivation; 2) determine sensitivity of Abi1/Pten null tumors to STAT3 inhibition and synergy with AR inhibition (enzalutamide) or taxane (cabazitaxel) chemotherapy. Tumor gene expression patterns will be analyzed by RNA-Seq. Identified drug response-pathways will be studied using organoid and xenograft models of human metastatic PCa lacking ABI1 and PTEN genes. The expected outcome is a better understanding of ABI1 and PTEN involvement in tumor sensitivity to current therapeutics for advanced PCa, the role for STAT3 inhibition in PCa therapy, and identification of potential targets for overcoming treatment resistance.

抽象的前列腺癌 (PCa) 是美国男性中最常诊断出的癌症，也是导致前列腺癌的第二大原因。美国男性癌症相关死亡惰性局部前列腺癌是可以治愈的，但转移性前列腺癌是致命的。进展为转移性疾病的特征是雄激素信号传导重新激活，包括雄激素受体（AR）功能。这些知识催生了抗雄激素途径疗法，这是治疗的支柱进行性 PCa。不幸的是，患者最终会对抗雄激素治疗产生耐药性，并且随后基于紫杉烷的化疗的益处仅限于将患者的生存期延长一年。仍然迫切需要确定新的可操作目标。该项目的长期目标是为晚期前列腺癌的精准医疗制定更好的治疗策略和合理的药物疗法。我们的先前的研究证明 ABI1 是真正的 PCa 肿瘤抑制基因。 ABI1 下调促进非经典 WNT-激活下游的上皮间质转化 (EMT) FYN-STAT3 途径。我们发布的初步数据表明 ABI1 下调，结合 PTEN 缺失与人类 PCa 的一个重要子集中的高级别和转移性 PCa 相关。由于雄激素剥夺治疗后 ABI1 表达下调，我们假设抗 AR 治疗导致 WNT-FYN-STAT3 通路激活。此外，紫杉烷疗法可能会促进 WNT 通路的激活，并可能与抗 AR 治疗产生交叉通路效应。我们的目的是更全面地了解 ABI1 和 PTEN 对肿瘤的贡献对当前雄激素受体（AR）靶向药物治疗方案的敏感性敏感 (CSPC) 和耐药 (CRPC) PCa，以及 ABI1/PTEN 通路本身的成药性。我们的中心假设是 ABI1 缺陷的肿瘤对抗 AR 药物的敏感性较低。此外，我们提出 ABI1 缺陷的肿瘤对 STAT3 通路抑制剂敏感。我们建议 ABI1 是当前 PCa 治疗的肿瘤敏感性候选标志物。使用新颖的 Abi1/Pten 空鼠和类器官前列腺模型，我们将评估药物敏感性并表征肿瘤反应以寻找治疗抵抗目标。我们的目标是： 1) 确定 Abi1/Pten 无效肿瘤对 AR 抑制的敏感性雄激素剥夺前后（使用恩杂鲁胺）或紫杉烷化疗（使用卡巴他赛）； 2）确定 Abi1/Pten 无效肿瘤对 STAT3 抑制的敏感性以及与 AR 抑制的协同作用（恩杂鲁胺）或紫杉烷（卡巴他赛）化疗。肿瘤基因表达模式将通过以下方式进行分析 RNA测序。将使用人类的类器官和异种移植模型来研究已确定的药物反应途径缺乏 ABI1 和 PTEN 基因的转移性 PCa。预期结果是更好地理解 ABI1 和 PTEN 参与肿瘤对当前晚期 PCa 疗法的敏感性，以及 STAT3 抑制的作用 PCa 治疗，并确定克服治疗耐药性的潜在目标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Breast Cancer Treatment: To tARget or Not? That Is the Question.

乳腺癌治疗：有目标还是无目标？这就是问题所在。

DOI：
10.3390/cancers15235664
发表时间：
2023-11-30
期刊：
CANCERS
影响因子：
5.2
作者：
Stone, Alexandra;Lin, Kevin M.;Ghelani, Ghanshyam H.;Patel, Sanik;Benjamin, Sam;Graziano, Stephen;Kotula, Leszek
通讯作者：
Kotula, Leszek

Novel Target Opportunities in Non-Metastatic Castrate Resistant Prostate Cancer.

DOI：
10.3390/cancers13102426
发表时间：
2021-05-17
期刊：
Cancers
影响因子：
5.2
作者：
Gleicher S;Porter BA;Nath D;Li G;Khanna R;Goldberg H;Kortylewski M;Bratslavsky G;Kotula L
通讯作者：
Kotula L

In Vivo Models for Prostate Cancer Research.