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

摘要 摘要阑尾黏液性肿瘤是一种罕见的肿瘤，可由良性发展为恶性 最终呈现出攻击性的生物行为。转移性肿瘤细胞经常分泌大量的 大量的粘蛋白导致称为腹膜假粘液瘤（PMP）的临床综合征，绝大多数 其中一种来源于阑尾。一旦发生腹膜转移， 常常是致命的，常常伴随着肿瘤块和粘蛋白的大量积累，可以填充腹腔， 导致肠梗阻和癌症恶病质死亡。虽然PMP的主要治疗是手术， 高级别粘液癌患者和不能手术的患者通常接受细胞毒性药物 已批准用于结直肠癌（CRC）的治疗，其通常具有有限的功效。新的方法 显然需要阐明PMP的潜在生物学，并开发新的更有效的靶向药物。 治疗策略。洛伊实验室的发现揭示了PMP的突变景观（基因组医学。 2014），其特征在于KRAS和GNAS癌基因的致病性改变。危险工作据 Gutkind实验室多年来的重点，他是癌症G蛋白研究的先驱（Nature Rev. Cancer 2010，2013）。最近，我们的合作工作表明，MNA可能对 抑制细胞周期蛋白依赖性激酶（CDK）4/6。我们的初步数据包括对一名患有 粘液性癌病-低级别的阑尾源性，其疾病在标准治疗中进展 化疗，但在单药Palbociclib治疗超过6年的稳定疾病， FDA批准的CDK 4/6抑制剂。最近，我们有进一步的证据表明，这种敏感性CDK 4/6 抑制，事实上可能与激活PKA信号下游的GNAS，因此，我们 假设阑尾和结肠GNAS突变型肿瘤以及可能的其他组织学的肿瘤（即， 胰腺）也可能对这种靶向治疗敏感。在本提案中，我们将测试这一假设，探索 CDK 4/6抑制如何调节肿瘤微环境以控制GNAS突变体肿瘤进展 并探索这种敏感性背后的潜在机制。

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.