CDK4/6 inhibition: a novel therapeutic strategy for GNAS-mutant gastrointestinal malignancies

摘要 摘要阑尾粘液性肿瘤(MNA)是一种罕见的可由良性病变进展为恶性病变的肿瘤。 并最终表现出一种攻击性的生物学行为。转移的肿瘤细胞通常分泌大量的 大量的粘蛋白导致临床综合征称为腹膜假性粘液瘤(PMP)，绝大多数 其中的一个起源于阑尾。一旦发生腹膜转移，疾病的进展是 常常是致命的，通常伴随着大量的肿块和粘液堆积，可以填满腹腔， 导致肠梗阻和癌症恶病质死亡。虽然PMP的主要治疗方法是外科手术， 级别较高的粘液性癌和无法手术的疾病的患者通常会接受细胞毒 被批准用于结直肠癌(CRC)的治疗方法，通常疗效有限。新的方法是 显然需要阐明PMP的潜在生物学，并开发新的、更有效的靶向 治疗策略。洛伊实验室的发现揭示了PMP(基因组医学)的突变图景。 2014年)，其特点是KRAS和GNAS癌基因的致病性变化。后者一直是 古特金德实验室多年来一直关注的焦点，他开创了癌症中G蛋白的研究(自然修订版)。 癌症2010、2013)。最近我们的合作工作表明，MNA可能对 细胞周期蛋白依赖性激酶(CDK)4/6的抑制。我们的初步数据包括一例 粘液性癌病-阑尾起源的低级别，其疾病在治疗标准上进展 化疗，但谁已经病情稳定超过6年的单一药物帕博西利，第一次 FDA批准的CDK4/6抑制剂。最近，我们发现了更多的证据表明这种对CDK4/6的敏感性 抑制，实际上可能与GNAS下游PKA信号的激活有关，因此，我们 假设GNAS突变的阑尾和结肠肿瘤，以及可能的其他组织学肿瘤(即- 胰腺)可能也对这种靶向治疗敏感。在这个提案中，我们将检验这一假设，探索 CDK4/6抑制如何调节肿瘤微环境控制GNAS突变型肿瘤进展 并探索支撑这种敏感性的潜在机制。

ABSTRACT Mucinous neoplasms of the appendix (MNA) are rare tumors that may progress from benign to malignant disease and ultimately assume an aggressive biological behavior. The metastatic tumor cells often secrete large quantities of mucin resulting in the clinical syndrome known as pseudomyxoma peritonei (PMP), the vast majority of which originates from the appendix. Once peritoneal metastasis has occurred, disease progression is frequently fatal, often with massive accumulation of tumor masses and mucin that can fill the abdominal cavity, resulting in death from intestinal obstruction and cancer cachexia. While the primary treatment of PMP is surgical, patients with higher-grade mucinous cancers and those with inoperable disease typically receive cytotoxic therapies approved for colorectal cancer (CRC), which generally have limited efficacy. New approaches are clearly needed to elucidate the underlying biology of PMP and to develop new and more effective targeted treatment strategies. Discoveries by the Lowy lab revealed the mutational landscape of PMP (Genome Med. 2014), which is characterized by pathogenic alterations in the KRAS and GNAS oncogenes. The latter has been the focus of the Gutkind lab for many years, who pioneered the study of G proteins in cancer (Nature Rev. Cancer 2010, 2013). Recently our collaborative work has suggested that MNA may be exquisitely sensitive to inhibition of cyclin dependent kinase (CDK) 4/6. Our preliminary data includes treatment of a patient with mucinous carcinomatosis-low grade of appendiceal origin whose disease progressed on standard of care chemotherapy, but who has had stable disease for greater than 6 years on single agent Palbociclib, the first FDA-approved CDK4/6 inhibitor. Recently we have developed further evidence that this sensitivity to CDK4/6 inhibition, may in fact be related to the activation of PKA signaling downstream of GNAS and therefore, we hypothesize that GNAS mutant tumors of the appendix and colon and possibly those of other histology’s (ie- pancreas) may be sensitive to this targeted therapy as well. In this proposal, we will test this hypothesis, explore how CDK4/6 inhibition may modulate the tumor microenvironment to control GNAS mutant tumor progression and explore the underlying mechanisms underpinning this sensitivity.