Inhibition of P13k and MEK Pathways in the Treatment of Lung Cancer

抑制 P13k 和 MEK 通路治疗肺癌

• 批准号: 7699517
• 负责人: Jeffrey A. Engelman
• 金额: $ 43.45万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7699517
• 关键词: 1-Phosphatidylinositol 4-Kinase; Address; Affect; Apoptosis; Cell Survival; Cells; Chemicals; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Disease; Disease remission; Effectiveness; Engineering; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Extracellular Signal Regulated Kinases; Foundations; Gefitinib; Genetic; Genetically Engineered Mouse; Grant; Growth; Human; IGF1R gene; KRAS2 gene; Lead; Learning; Longevity; Lung; Lung Adenocarcinoma; MAP3K3 gene; MEK inhibition; MEKs; MET Oncogene; Malignant Neoplasms; Malignant neoplasm of lung; Mammals; Mitogen-Activated Protein Kinases; Modeling; Molecular Biology; Mus; Mutant Strains Mice; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oncogene Activation; Oncogenic; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Positioning Attribute; Process; Receptor Signaling; Resistance; Resistance development; Role; STK11 gene; Signal Pathway; Signal Transduction; TP53 gene; Treatment Efficacy; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; cancer therapy; cancer type; cell growth; effective therapy; follow-up; in vivo; inhibitor/antagonist; insight; mouse model; mutant; mutant mouse model; novel therapeutics; overexpression; prevent; public health relevance; research study; resistance mechanism; response; therapy resistant; treatment strategy; tumor

DESCRIPTION (provided by applicant): Although there has been substantial progress in the understanding of the molecular biology and genetics of non-small cell lung cancer (NSCLC) over the last several years, metastatic NSCLC remains incurable, and patients suffering from this disease have a median survival of ~12 months. Recently, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have demonstrated clinical activity in patients with NSCLC. A small subset of patients has activating mutations in the EGFR kinase domain. In these patients, TKIs can produce dramatic responses. In such situations, the cancer is "addicted" to EGFR signaling. Such addicted cancers are unique in that the critical intracellular survival and growth signaling pathways such as phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) are solely regulated by EGFR. Thus, when the cancer is treated with the EGFR TKI, both PI3K and ERK signaling are turned off and the cells undergo apoptosis and cell growth arrest. Although cancers with activating EGFR mutations often have dramatic responses to EGFR TKIs, these cancers invariably develop resistance (acquired resistance), thereby limiting the clinical benefit from these drugs. Recently, we and others have identified how some NSCLCs become resistant to EGFR inhibitors. These include a secondary mutation in EGFR, T790M, amplification of the MET oncogene, and activation of IGF1R. Interestingly, regardless of the specific mechanism, when the cancer becomes resistant to EGFR TKIs, there is re-activation of these critical downstream signaling pathways in the presence of the EGFR TKI. In contrast to the subset of NSCLCs with activating EGFR mutations, most NSCLCs do not demonstrate any initial response to EGFR TKIs (de novo or primary resistance). In particular, NSCLCs with KRAS mutations are especially resistant to EGFR TKIs. In these cancers, treatment with an EGFR TKI (or any TKI) does not lead to loss of PI3K and ERK signaling, and there is no detrimental affect on cell viability or growth. Furthermore, mutations in KRAS are the most common oncogenic mutations in NSCLCs (~25% of lung adenocarcinomas), and currently, there are no targeted therapies for this subset of cancers. However, in an effort to mirror the effects of a successful TKI treatment in these KRAS mutant cancers, we have been implementing a strategy that centers on simultaneously inhibiting PI3K and MEK by combining specific chemical inhibitors of each of these kinases. We have observed dramatic effects using this combination in vivo on genetically engineered mouse models of mutant Kras and EGFR driven lung cancers. Our preliminary data suggest that successful concomitant targeting of the PI3K and MEK pathways is feasible in mammals, and leads to dramatic tumor regression in mouse models of mutant KRas and EGFR driven lung cancers. This grant centers on developing this combination therapy using genetically engineered mouse models. We also aim to learn how cancers will become resistant to this therapy so we can proactively identify strategies to increase its efficacy and prolong benefit. We are hopeful that the studies proposed in this grant will serve as the foundation for successful clinical trials implementing this treatment strategy for patients with NSCLC. PUBLIC HEALTH RELEVANCE: Understanding the roles of PI3K and MEK signaling pathways in the growth and survival of Kras and EGFR mutant lung cancers provide unique opportunities to identify rational combination targeted therapies for the treatment of this deadly disease and other types of cancer. Our proposal aims to characterize and evaluate the impact of novel therapeutic strategies that inhibit both the PI3K and MEK pathways in genetically defined de novo murine lung cancers. Results from the experiments proposed will help guide the clinical development of these combination therapies for patients with lung cancers and other cancer types.

描述（由申请人提供）：尽管在过去几年中，对非小细胞肺癌（NSCLC）的分子生物学和遗传学的理解取得了长足的进步，但转移性NSCLC仍然无法治愈，患有这种疾病的患者中间存活率约为12个月。最近，表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIS），例如吉非替尼和厄洛替尼，在NSCLC患者中表现出临床活性。一小部分患者在EGFR激酶结构域中具有激活突变。在这些患者中，TKI可以产生戏剧性的反应。在这种情况下，癌症“上瘾”了EGFR信号传导。这种上瘾的癌症是独一无二的，因为关键的细胞内存活和生长信号通路，例如磷酸肌醇3-激酶（PI3K）和细胞外信号调节激酶（ERK）仅受EGFR的调节。因此，当用EGFR TKI处理癌症时，PI3K和ERK信号都被关闭，细胞会凋亡和细胞生长停滞。尽管激活EGFR突变的癌症通常对EGFR TKI具有巨大的反应，但这些癌症总是会产生耐药性（获得的抗药性），从而限制了这些药物的临床益处。最近，我们和其他人已经确定了某些NSCLC如何对EGFR抑制剂具有抗性。其中包括EGFR中的继发突变，T790M，MET癌基因的扩增以及IGF1R的激活。有趣的是，无论特定机制如何，当癌症对EGFR TKI具有抵抗力时，在EGFR TKI存在下，这些关键的下游信号通路会重新激活。与激活EGFR突变的NSCLC子集相反，大多数NSCLC并未证明对EGFR TKI（从头或原发性抗性）的初始响应。特别是，具有KRAS突变的NSCLC对EGFR TKI尤其具有抵抗力。在这些癌症中，用EGFR TKI（或任何TKI）的治疗不会导致PI3K和ERK信号的损失，并且对细胞活力或生长没有有害影响。此外，KRAS中的突变是NSCLC中最常见的致癌突变（占肺腺癌的25％），目前，该子集的癌症尚无靶向疗法。但是，为了反映这些KRAS突变癌中成功的TKI治疗的影响，我们一直在实施一种策略，该策略通过结合每种激酶的特定化学抑制剂来同时抑制PI3K和MEK。我们已经使用这种组合在体内观察到了突变KRAS和EGFR驱动的肺癌的基因工程小鼠模型的戏剧性效应。我们的初步数据表明，在哺乳动物中，成功的靶向PI3K和MEK途径是可行的，并且导致突变体KRAS和EGFR驱动的肺癌的小鼠模型中的巨大肿瘤回归。该赠款以使用基因工程的小鼠模型来开发这种组合疗法。我们还旨在了解癌症将如何对这种疗法具有抵抗力，以便我们可以主动确定提高其疗效并延长收益的策略。我们希望这笔赠款中提出的研究将成为成功为NSCLC患者实施这种治疗策略的成功临床试验的基础。公共卫生相关性：了解PI3K和MEK信号通路在KRAS和EGFR突变肺癌的生长和生存中的作用提供了独特的机会，可以鉴定有理组合的靶向靶向疗法，以治疗这种致命的疾病和其他类型的癌症。我们的建议旨在表征和评估新型治疗策略的影响，这些治疗策略抑制了遗传定义的从头鼠肺癌中PI3K和MEK途径。提出的实验的结果将有助于指导肺癌和其他癌症类型患者这些联合疗法的临床发展。