Targeting undruggable RAS for cancer treatment

靶向不可成药的 RAS 进行癌症治疗

基本信息

批准号：
10465051
负责人：
CHANNING J. DER
金额：
$ 90万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10465051
关键词：
Adherence Automobile Driving Autophagocytosis Award Biochemistry Biology Cancer Etiology Cessation of life Colorectal Cancer Defect Dependence Development Enzymes Frequencies Fruit Glycolysis Goals Growth Human Impairment KRAS2 gene MYC Family Protein MYC gene Mainstreaming Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Mitochondria Mutation Pancreatic Ductal Adenocarcinoma Play Protein Kinase Research Research Personnel Research Support Resistance Risk Role Signal Transduction Time anticancer research base cancer therapy clinical efficacy high reward high risk member mutant neglect novel ras Oncogene ras Proteins targeted treatment therapeutically effective tumor metabolism

Adherence Automobile Driving Autophagocytosis Award Biochemistry Biology Cancer Etiology Cessation of life Colorectal Cancer Defect Dependence Development Enzymes Frequencies Fruit Glycolysis Goals Growth Human Impairment KRAS2 gene MYC Family Protein MYC gene Mainstreaming Malignant Neoplasms Malignant neoplasm of pancreas Metabolic Mitochondria Mutation Pancreatic Ductal Adenocarcinoma Play Protein Kinase Research Research Personnel Research Support Resistance Risk Role Signal Transduction Time anticancer research base cancer therapy clinical efficacy high reward high risk member mutant neglect novel ras Oncogene ras Proteins targeted treatment therapeutically effective tumor metabolism

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项目摘要

PROJECT SUMMARY/ABSTRACT My Outstanding Investigator Award (OIA) research plan will build on themes developed during my more than three decades of RAS research, pursuing directions generally ignored by the RAS field and by the NCI RAS Initiative, to make “undruggable” RAS druggable. I was a member of the research team that made the initial identification of activated RAS oncogenes in human cancers. Since that discovery, my research has centered on understanding the basic biochemistry, signaling and biology of RAS proteins, with the long-term goal of utilizing that information for the development of anti-RAS cancer therapies. My research focuses on pancreatic ductal adenocarcinoma (PDAC), a cancer where effective targeted therapies remain to be found. With a 95% KRAS mutation frequency and with substantial experimental evidence that “correcting” the KRAS defect will significantly impair PDAC growth, PDAC is arguably the most RAS-addicted cancer. The OIA supports research that “take[s] greater risks, [is] more adventurous”. Based on our unpublished findings from studies initiated 3-4 years ago and just now coming into fruition, I have identified four new high risk / high reward research directions. First, despite the well-established interdependency between the RAS and MYC oncogenes in driving cancer growth, targeting MYC as an anti-KRAS strategy is not widely considered. Our MYC degradation screen identified novel protein kinases that regulate MYC protein stability; we will exploit these to cause MYC loss. Second, we have found that the ERK protein kinases are largely responsible for KRAS-dependent metabolic perturbations (autophagy, glycolysis, macropinocytosis, mitochondrial function). We suggest that targeting ERK, rather than the metabolic enzymes considered by the field, will be a more effective therapeutic strategy to target cancer metabolism. We will pursue an issue still largely neglected, the determination of the key ERK substrates that are critical for ERK-dependent KRAS-mutant PDAC growth. Third, as with other targeted therapies, anti-KRAS therapies will be limited by mechanisms of acquired resistance. While much of the field is focused on YAP1, it is also clear that YAP1-independent mechanisms will also play significant role in how cancers escape KRAS-dependency. We will apply experimental approaches not previously utilized to define these YAP1–independent mechanisms. These findings will be critical for development of anti-KRAS therapies that can achieve long-lasting clinical efficacy. Finally, our surprising finding that one KRAS mutant (G12R) cannot utilize a key RAS effector, PI3K, and drives metabolic activities distinct from the most prevalent KRAS mutations, provides our rationale to pursue outlier mutations in PDAC, to identify mutation-specific vulnerabilities as the basis for development of mutation-selective therapies. In summary, since adherence to long-held dogma has at times stifled progress, less mainstream directions must be taken if we are to finally achieve the breakthroughs needed for development of effective anti-RAS therapies.

项目摘要/摘要我的杰出调查员奖（OIA）研究计划将建立在我在我期间开发的主题上的基础三十年的RAS研究，追求RAS领域和NCI RAS通常忽略的指示倡议，使“不可能”的RAS可吸毒。我是研究团队的成员鉴定人类癌中活化的Ras癌基因。自从发现以来，我的研究集中了了解RAS蛋白的基本生物化学，信号传导和生物学，其长期目标的使用该信息进行抗RAS癌症疗法的发展。我的研究重点是胰腺导管腺癌（PDAC），一种有效靶向疗法的癌症。 95％ KRAS突变频率，并有大量的实验证据表明“纠正” KRAS缺陷将会 PDAC可以显着损害PDAC的增长，可以说是最含有RAS的癌症。 OIA支持研究“承担更大的风险，[]更具冒险性”。根据我们未发表的研究结果我在3 - 4年前开始，刚刚开始流动，我已经确定了四个新的高风险 /高奖励研究方向。首先，努力了RAS和MYC之间建立的相互依存癌基因在驱动癌症生长中，以MYC为抗KRAS策略而被广泛考虑。我们的 MYC降解筛选确定了调节MYC蛋白质稳定性的新型蛋白激酶。我们将利用这些导致MYC损失。其次，我们发现ERK蛋白激酶在很大程度上是造成的 KRAS依赖性代谢扰动（自噬，糖酵解，大型细胞增多症，线粒体功能）。我们建议靶向ERK，而不是该领域考虑的代谢酶，将是更多有效的治疗策略以靶向癌症代谢。我们将追求一个仍然被忽视的问题，确定对ERK依赖性KRAS突变PDAC生长至关重要的关键ERK底物。第三，与其他靶向疗法一样，抗KRAS疗法将受到获得的机制的限制反抗。尽管大部分领域都集中在YAP1上，但也很明显，与YAP1无关的机制将同样在癌症如何逃避KRAS依赖性方面发挥了重要作用。我们将采用实验方法以前没有用于定义这些非依赖性机制。这些发现对于开发可以达到持久临床效率的抗KRAS疗法。最后，我们的惊喜发现一个KRAS突变体（G12R）无法使用键RAS效应器，PI3K并驱动代谢活动与最普遍的KRAS突变不同，为我们在PDAC购买异常突变的基本原理，确定突变特异性脆弱性是突变选择疗法发展的基础。总结，由于遵守长期以来的教条有时会稳定，因此主流方向较少如果我们最终要实现开发有效的抗RAS疗法所需的突破，请采取行动。