PTEN公司
帕博西利布
脊索瘤
医学
PI3K/AKT/mTOR通路
癌症研究
CDKN2A
蛋白激酶B
肿瘤科
依维莫司
内科学
癌症
病理
乳腺癌
生物
细胞凋亡
转移性乳腺癌
生物化学
作者
Carolin Seeling,Elena Mosca,Eva Mantel,Peter Møller,Thomas Barth,Kevin Mellert
出处
期刊:Cancers
[MDPI AG]
日期:2023-03-26
卷期号:15 (7): 1977-1977
被引量:2
标识
DOI:10.3390/cancers15071977
摘要
Chordomas are rare bone tumors arising along the spine. Due to high resistance towards chemotherapy, surgical resection-often followed by radiation therapy-is currently the gold standard of treatment. So far, targeted systemic therapies have not been approved. The most frequent molecular alterations include the loss of PTEN and CDKN2A (encoding p16), being associated with poor prognoses in chordoma patients. Specific inhibitors of the PI3K/AKT/mTOR pathway as well as CDK4/6 have shown antitumor activity in preclinical studies and have recently been under investigation in phase II clinical trials; however, the clinical impacts and therapeutic consequences of concomitant PTEN and p16 deficiency have not yet been investigated in chordomas. In a cohort of 43 chordoma patients, 16% of the cases were immunohistochemically negative for both markers. The simultaneous loss of PTEN and p16 was associated with a higher KI-67 index, a tendency to metastasize, and significantly shorter overall survival. Additionally, 30% of chordoma cell lines (n = 19) were PTEN-/p16-negative. Treating these chordoma cells with palbociclib (CDK4/6 inhibitor), rapamycin (mTOR inhibitor) or the pan-PI3K inhibitor buparlisib significantly reduced cell viability. Synergistic effects were observed when combining palbociclib with rapamycin. In conclusion, we show that patients with PTEN-/p16-negative chordomas have poor prognoses and provide strong preclinical evidence that these patients might benefit from a Palbociclib/rapamycin combination treatment.
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