Common Genetically Altered Pathways as Targets for Therapy in Pancreatic Cancer

常见的基因改变途径作为胰腺癌治疗的目标

基本信息

批准号：
10088419
负责人：
Erik Knudsen
金额：
$ 39.3万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10088419
关键词：
BRCA2 gene Biological Biological Markers CDK4 gene CDKN2A gene Cell Cycle Cell Cycle Arrest Cell Cycle Inhibition Cell Cycle Regulation Cell Death Chromosomal Instability Chromosomal Stability Chromosome Cohesion Chromosomes Clinical Combined Modality Therapy Complex Data Defect Disease Disease Progression Drug Screening Event Evolution Exhibits FANCD2 protein FRAP1 gene Fanconi&apos s Anemia Genes Genetic Genome Genome Stability Individual KRAS2 gene Lead Legal patent MEKs Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Modeling Mutation Oncogenic Other Genetics Outcome Output PALB2 gene Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phase III Clinical Trials Pre-Clinical Model Process Prognosis Repair Complex Resistance Signal Transduction Specimen Testing Therapeutic Therapeutic Agents Tissues Traction Tumor Suppressor Proteins Work base cancer cell chemotherapy chromosome loss disorder control exome sequencing functional group genetic analysis genome integrity inhibitor/antagonist mTOR inhibition novel therapeutic intervention pancreatic cancer model pancreatic ductal adenocarcinoma model patient derived xenograft model phase III trial protein function repaired response senescence targeted treatment therapeutic target treatment strategy tumor

项目摘要

Pancreatic ductal adenocarcinoma (PDA) has an exceedingly poor prognosis with a 5-year survival of only ~6%. Unlike many other cancers, current strategies do NOT target genetic features of PDA. In part, this is because PDA is viewed as a disease that is dominated by KRAS as the oncogenic driver. As a result, therapies delivered to PDA are not targeted based on biomarkers, and chemotherapy is the mainstay for treatment. To define new means to treat PDA, we performed genetic analysis of >100 PDA cases by exome sequencing. These data revealed aberrations in multiple pathways. In particular, alterations in chromosome stability processes or cell cycle control were observed in >75% of cases. These pathways are inter-related, and would be expected to remain actionable in spite of the common deregulated KRAS signaling in PDA. Genetic alterations can lead to tumor-specific vulnerabilities that can be exploited for treatment. Here we will approach rational targeting of genetic events in PDA using two complementary efforts. First, we have defined loss/mutation of multiple pathways associated with chromosome-fidelity. These events individually are rare, but when coalesced into pathways/functional groups represent >30% of PDA patents. Our group and others have found that a specific subset of genetic events represent vulnerabilities that can be selectively targeted. Most notably germline BRCA/PALB2 mutations are the basis of the only active Phase III trial for patients with PDA. However, whether other pathways associated with chromosomal instability can be effectively targeted is unknown. These findings provide the impetus for a detailed analysis of the confluence of loss of genes involved in genome stability, resultant biological output in PDA, and selective therapeutic sensitivities. Second, therapeutic strategies can re-instate tumor suppressor activities that have been disrupted in PDA and limit proliferation to control disease. Loss of cell cycle regulatory control over CDK4/6 occurs frequently in >50% of PDA cases through loss of p16ink4a. Therefore, CDK4/6 inhibition would be expected to be exceedingly effective in PDA treatment. However, the response to CDK4/6 inhibitors is variable and cell cycle regulatory networks in PDA are particularly complex suggesting that other genetic events impinge on the efficacy of CDK4/6 inhibition. These findings provide the basis for defining the determinants of durable response to CDK4/6 inhibitors, delineating successful combination therapies, and defining the utility of such agents in disease relevant models of PDA. In total, these studies interrogate the hypothesis that therapeutic approaches targeting genetic features of PDA controlling genome stability and cell cycle control will provide critical advances to treatment.

胰腺导管腺癌 (PDA) 的预后极差，5 年生存率仅为 6% 左右。与许多其他癌症不同，目前的策略并不针对 PDA 的遗传特征。部分原因是 PDA 被视为一种以 KRAS 为致癌驱动因素的疾病。因此，针对 PDA 的治疗并非基于生物标志物，化疗是主要治疗方法。为了确定治疗 PDA 的新方法，我们通过外显子组测序对超过 100 例 PDA 病例进行了遗传分析。这些数据揭示了多个途径的畸变。特别是，在 > 75% 的病例中观察到染色体稳定性过程或细胞周期控制的改变。这些途径是相互关联的，尽管存在共同点，但预计仍可采取行动 PDA 中 KRAS 信号传导失调。基因改变可能导致肿瘤特异性的脆弱性，可用于治疗。这里我们将通过两项互补的努力来合理定位 PDA 中的遗传事件。首先，我们有与染色体保真度相关的多个途径的定义丢失/突变。这些事件分别是很少见，但当合并为途径/功能组时，占 PDA 专利的比例超过 30%。我们组和其他人发现，遗传事件的特定子集代表了可以选择性地修复的脆弱性有针对性。最值得注意的是种系 BRCA/PALB2 突变是唯一活跃的 III 期试验的基础患有PDA的患者。然而，与染色体不稳定相关的其他途径是否可以有效的目标尚不清楚。这些发现为对融合的详细分析提供了动力涉及基因组稳定性的基因丢失、PDA 中的生物输出以及选择性治疗敏感性。其次，治疗策略可以恢复已经被抑制的肿瘤抑制活性。破坏 PDA 并限制增殖以控制疾病。失去对 CDK4/6 的细胞周期调控由于 p16ink4a 缺失，>50% 的 PDA 病例中经常发生这种情况。因此，CDK4/6 抑制是预计在 PDA 治疗中非常有效。然而，对 CDK4/6 抑制剂的反应是可变的 PDA 中的细胞周期调控网络特别复杂，表明其他遗传事件影响 CDK4/6 抑制的功效。这些发现为定义决定因素提供了基础对 CDK4/6 抑制剂的持久反应，描绘成功的联合疗法，并定义其效用 PDA 疾病相关模型中的此类药物。总的来说，这些研究质疑了以下假设：针对控制基因组稳定性和细胞周期的 PDA 遗传特征的治疗方法控制将为治疗提供关键进展。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities.

DOI：
10.1016/j.celrep.2020.107793
发表时间：
2020-07-07
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Franco, Jorge;Balaji, Uthra;Freinkman, Elizaveta;Witkiewicz, Agnieszka K.;Knudsen, Erik S.
通讯作者：
Knudsen, Erik S.

The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies.

DOI：
10.1016/j.trecan.2016.11.006
发表时间：
2017-01
期刊：
Trends in cancer
影响因子：
18.4
作者：
Knudsen ES;Witkiewicz AK
通讯作者：
Witkiewicz AK

A Phase I Study of Ribociclib Plus Everolimus in Patients with Metastatic Pancreatic Adenocarcinoma Refractory to Chemotherapy.

Ribociclib 加依维莫司治疗化疗难治性转移性胰腺癌患者的 I 期研究。

DOI：
10.1089/pancan.2020.0005
发表时间：
2020
期刊：
Journal of pancreatic cancer
影响因子：
2
作者：
Weinberg,BenjaminA;Wang,Hongkun;Witkiewicz,AgnieszkaK;Marshall,JohnL;He,AiwuR;Vail,Paris;Knudsen,ErikS;Pishvaian,MichaelJ
通讯作者：
Pishvaian,MichaelJ

Stratification of Pancreatic Ductal Adenocarcinoma: Combinatorial Genetic, Stromal, and Immunologic Markers.

DOI：
10.1158/1078-0432.ccr-17-0162
发表时间：
2017-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Knudsen ES;Vail P;Balaji U;Ngo H;Botros IW;Makarov V;Riaz N;Balachandran V;Leach S;Thompson DM;Chan TA;Witkiewicz AK
通讯作者：
Witkiewicz AK