METHOD FOR EVALUATING WHETHER AN INDIVIDUAL WITH CANCER IS SUITABLE FOR TREATMENT WITH A CDK INHIBITOR

專利類型

發明

專利國別 (專利申請國家)

美國

專利申請案號

16/451,942

專利證號

US 11,761,044 B2

專利獲證名稱

METHOD FOR EVALUATING WHETHER AN INDIVIDUAL WITH CANCER IS SUITABLE FOR TREATMENT WITH A CDK INHIBITOR

專利所屬機關 (申請機關)

長庚大學

獲證日期

2023/09/19

技術說明

正常人類體細胞內染色體皆為雙套(diploid)，除了性染色體上的基因，其它對偶(allele)基因其拷貝數(copy number)應為二。但在癌細胞中某些基因的拷貝數會有擴增(amplification) (拷貝數>2)或缺失(deletion) (拷貝數<2)現象。癌細胞的重要特徵是不斷生長而不受調控，其原因之一是調控細胞週期的基因拷貝數變異(copy number variation, CNV)，癌細胞中常有CNV變異的基因，有促進細胞生長cyclin D1 (CCND1)基因的擴增和抑制細胞生長cyclin-dependent kinase inhibitor 2A/ p16 (CDKN2A/p16)基因的缺失。已知在癌症病人的周邊血可偵測到癌細胞的游離DNA (cell free DNA, cfDNA)，這些癌細胞cfDNA往往帶有特定DNA的突變，作為鑑別癌症的指標。我們從鼻咽癌(NPC)病人取得血漿檢體，萃取其中游離cfDNA，並以定量PCR (Q-PCR)測定包括EB病毒量(EBV是屬於致癌皰疹DNA病毒並與鼻咽癌高度相關)及CCND1和CDKN2A之個別CNV，可分別成為鼻咽癌和癌細胞增生的指標。由於CCND1和CDKN2A均參與調控細胞週期，目前已有主要用於轉移乳癌的許可標靶藥物palbociclib (CDK4/6抑制劑) 和其它CDK抑制劑，針對於轉移乳癌病患使用，以達抑制癌細胞生長。為了更精準及快速篩選適合鼻咽癌病使用此類癌症標靶藥物，我們透過Q-PCR測定“EB病毒量”及cfDNA中“CCND1和CDKN2A其CNV比值”，以作為palbociclib和其它CDK抑制劑藥物新穎和精準的個人用藥建議評估。 關鍵字：鼻咽癌、EBV、CNV、CCND1、CDKN2A、血漿檢體、cfDNA、生物指標、CDK抑制劑 There are two sets of chromosomes (diploid) in every normal human somatic cell. Except for the genes on sex chromosomes, the copy number of each gene allele should be equal to two. However, in cancer cells some genes may undergo amplification (copy number>2) or deletion (copy number<2). Uncontrolled cell growth is an important trait of cancer cells; and one of the reasons for this is the cell cycle regulated genes have copy number variation (CNV). Amplification of gene promoting cell proliferation, cyclin D1 (CCND1), and deletion of gene suppressing cell growth, cyclin-dependent kinase inhibitor 2A/ p16 (CDKN2A/p16), are often detected in cancer cells. It has been known that tumor cell free DNA (cfDNA) can be isolated from the cancer patients’ peripheral blood. These cfDNA contain specific DNA mutations that may serve as cancer biomarkers. We extracted cfDNA from the nasopharyngeal carcinoma (NPC) patients’ plasma and detected the amount of Epstein Barr virus (EBV), an oncogenic DNA herpesvirus associated with NPC, and the copy number of CCND1 and CDKN2A, respectively, by quantitative PCR (Q-PCR). We found that “EBV load” and “CNV of CCND1 and CDKN2A” in NPC patients’ plasma can be used as the biomarkers for NPC and cancer cell proliferation, respectively. Since CCND1 and CDKN2A are cell cycle regulatory genes, at present the cancer target drug palbociclib (CDK4/6 inhibitor) and other CDK inhibitors are prescribed for metastatic breast cancer patients. To precisely and rapidly evaluate potential suitable NPC patients to have palbociclib treatment, we develop a rapid Q-PCR assays to determine “EBV load” and “CNV ratio between CCND1 and CDKN2A” in NPC plasma. The results of Q-PCR assays can be served as novel and precise personalized drug guidance for the cancer target drug, palbociclib, and other CDK inhibitors. Key words：nasopharyngeal carcinoma (NPC), EBV, CNV, CCND1, CDKN2A, plasma, cfDNA, biomarker, CDK inhibitors

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