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

• 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
• 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' 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

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）预后极差，5年生存率仅为6%。与许多其他癌症不同，目前的策略并不针对PDA的遗传特征。在某种程度上，这是因为PDA被认为是一种由KRAS主导的致癌驱动因素。因此，对PDA的治疗不是基于生物标志物的靶向性，化疗是治疗的主要手段。为了确定治疗PDA的新方法，我们通过外显子组测序对bb100例PDA病例进行了遗传分析。这些数据揭示了多种通路的畸变。特别是，在75%的病例中观察到染色体稳定过程或细胞周期控制的改变。这些途径是相互关联的，尽管存在共同的问题，但仍有望保持可操作性

项目成果

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

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
• 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

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