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。这在一定程度上是因为PDA被视为一种由KRAS主导的疾病，是致癌的驱动因素。因此，提供给PDA的治疗没有基于生物标志物的靶向，而化疗是治疗的主要手段。为了确定治疗PDA的新方法，我们用外显子组测序对100例PDA患者进行了基因分析。这些数据揭示了多种途径的异常。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，尽管有共同之处，但预计仍可采取行动 解除对PDA中KRAS信号的管制。 基因改变可能导致肿瘤特有的脆弱性，可以利用这些脆弱性进行治疗。这里 我们将使用两个互补的努力来实现PDA中基因事件的合理靶向。首先，我们有 明确了与染色体保真度相关的多条途径的丢失/突变。这些事件分别是 很少见，但当结合成路径/官能团时，占PDA专利的30%。我们的团队和 其他人发现，遗传事件的特定子集代表了可以选择性地 有针对性的。最值得注意的是，生殖系BRCA/PALB2突变是唯一有效的III期试验的基础 患有PDA的患者。然而，其他与染色体不稳定相关的途径是否可以 有效的靶向是未知的。这些发现为详细分析两国之间的融合提供了动力 与基因组稳定性有关的基因丢失、在PDA中产生的生物输出和选择性治疗 敏感度。其次，治疗策略可以恢复肿瘤抑制因子的活性。 破坏了PDA，并限制了增殖以控制疾病。CDK4/6的细胞周期调控失控 P16INK4a基因缺失常发生在50%的PDA病例中。因此，CDK4/6的抑制将是 预计在PDA治疗中将非常有效。然而，对CDK4/6抑制剂的反应是不同的 而PDA中的细胞周期调控网络特别复杂，这表明其他遗传事件 影响CDK4/6的抑制作用。这些发现为确定以下因素提供了基础 对CDK4/6抑制剂的持久反应，描述成功的联合治疗，并确定 这类药物可用于疾病相关的PDA模型。总而言之，这些研究质疑了这样一种假设 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的进展。

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