CDK4/6 inhibition: a novel therapeutic strategy for GNAS-mutant gastrointestinal malignancies

CDK4/6抑制：GNAS突变胃肠道恶性肿瘤的新治疗策略

基本信息

批准号：
10513233
负责人：
ANDREW M LOWY
金额：
$ 18.47万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-02 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10513233
关键词：
Abdominal Cavity Affect Appendiceal Neoplasms Behavior Benign Biological Biological Models Biology CDK4 gene CDX2 gene Carcinomatosis Cell Proliferation Cells Cessation of life Clinical Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cytotoxic Chemotherapy Data Data Set Development Disease Disease Progression Doxycycline FDA approved Flow Cytometry GTP-Binding Proteins Gastrointestinal Neoplasms Gastrointestinal tract structure Gene Expression Genome Histology Human Immunohistochemistry Individual Intestinal Cancer Intestinal Obstruction Intestines KRAS2 gene KRASG12D Laboratories MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of appendix Malignant neoplasm of gastrointestinal tract Messenger RNA Modeling Mucinous Mucinous Neoplasm Mucins Mus Mutation Nature Neoplasm Metastasis Oncogenes Operative Surgical Procedures Organoids Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic cystic neoplasia Papillary Pathogenicity Patients Peritoneal Pharmacology Phenocopy Pre-Clinical Model Precision therapeutics Predisposition Protein-Protein Interaction Map Pseudomyxoma Peritonei Quality of life RNA-Binding Proteins Refractory Reporting Research Personnel Signal Transduction Signaling Protein Slice Stable Disease Surface Syndrome System Testing Tetanus Helper Peptide Therapeutic Toxic effect Tumor Debulking Work cancer cachexia chemotherapy clinical phenotype inducible gene expression inhibitor knock-down loss of function multidisciplinary mutant neoplastic cell new therapeutic target novel novel strategies novel therapeutic intervention novel therapeutics pancreatic neoplasm protein activation proteogenomics rare cancer standard of care targeted treatment therapeutic protein tool transcriptome sequencing treatment strategy tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

ABSTRACT Mucinous neoplasms of the appendix (MNA) are rare tumors that may progress from benign to malignant disease and ultimately assume an aggressive biological behavior. The metastatic tumor cells often secrete large quantities of mucin resulting in the clinical syndrome known as pseudomyxoma peritonei (PMP), the vast majority of which originates from the appendix. Once peritoneal metastasis has occurred, disease progression is frequently fatal, often with massive accumulation of tumor masses and mucin that can fill the abdominal cavity, resulting in death from intestinal obstruction and cancer cachexia. While the primary treatment of PMP is surgical, patients with higher-grade mucinous cancers and those with inoperable disease typically receive cytotoxic therapies approved for colorectal cancer (CRC), which generally have limited efficacy. New approaches are clearly needed to elucidate the underlying biology of PMP and to develop new and more effective targeted treatment strategies. Discoveries by the Lowy lab revealed the mutational landscape of PMP (Genome Med. 2014), which is characterized by pathogenic alterations in the KRAS and GNAS oncogenes. The latter has been the focus of the Gutkind lab for many years, who pioneered the study of G proteins in cancer (Nature Rev. Cancer 2010, 2013). Recently our collaborative work has suggested that MNA may be exquisitely sensitive to inhibition of cyclin dependent kinase (CDK) 4/6. Our preliminary data includes treatment of a patient with mucinous carcinomatosis-low grade of appendiceal origin whose disease progressed on standard of care chemotherapy, but who has had stable disease for greater than 6 years on single agent Palbociclib, the first FDA-approved CDK4/6 inhibitor. Recently we have developed further evidence that this sensitivity to CDK4/6 inhibition, may in fact be related to the activation of PKA signaling downstream of GNAS and therefore, we hypothesize that GNAS mutant tumors of the appendix and colon and possibly those of other histology’s (ie- pancreas) may be sensitive to this targeted therapy as well. In this proposal, we will test this hypothesis, explore how CDK4/6 inhibition may modulate the tumor microenvironment to control GNAS mutant tumor progression and explore the underlying mechanisms underpinning this sensitivity.

抽象的阑尾粘液性肿瘤 (MNA) 是一种罕见的肿瘤，可能从良性进展为恶性疾病并最终呈现出侵袭性的生物学行为，转移性肿瘤细胞通常会分泌大量的物质。大量的粘蛋白导致称为腹膜假粘液瘤（PMP）的临床综合征，绝大多数一旦发生腹膜转移，疾病就会进展。通常是致命的，通常伴随着肿瘤块和粘蛋白的大量积累，可以充满腹腔，导致因肠梗阻和癌症恶病质而死亡虽然 PMP 的主要治疗方法是手术，患有高级别粘液癌的患者和患有无法手术的疾病的患者通常会接受细胞毒性治疗批准用于结直肠癌（CRC）的疗法通常疗效有限。显然需要阐明 PMP 的基础生物学并开发新的、更有效的靶向药物 Lowy 实验室的发现揭示了 PMP 的突变情况（Genome Med. 2014），其特征是 KRAS 和 GNAS 癌基因的致病性改变。 Gutkind 实验室多年来一直关注的焦点，他率先研究了癌症中的 G 蛋白（Nature Rev. Cancer 2010, 2013）最近我们的合作工作表明 MNA 可能对以下因素极其敏感。细胞周期蛋白依赖性激酶 (CDK) 4/6 的抑制我们的初步数据包括对患有以下疾病的患者的治疗。粘液性癌病 - 低级别阑尾起源，其疾病在标准护理下进展化疗，但使用单一药物 Palbociclib（第一个药物）病情稳定超过 6 年 FDA 批准的 CDK4/6 抑制剂最近我们开发了进一步的证据证明这种对 CDK4/6 的敏感性。抑制，实际上可能与 GNAS 下游 PKA 信号通路的激活有关，因此，我们发展出阑尾和结肠的 GNAS 突变肿瘤，也可能是其他组织学的肿瘤（即- 胰腺）也可能对这种靶向治疗敏感。在本提案中，我们将测试这个假设，探索。 CDK4/6 抑制如何调节肿瘤微环境以控制 GNAS 突变肿瘤进展并探索支撑这种敏感性的潜在机制。