来自宾夕法尼亚大学的科学家在JAMA Oncology杂志上发表了最新的研究成果，他们发现，一种可以治疗乳腺癌及同内分泌疗法进行结合治疗的药物Palbociclib(帕博西尼)或许可以潜在抵御其它类型的癌症。Palbociclib可以通过抑制CDK4和CDK6的酶类活性来靶向作用肿瘤细胞的快速分裂，同时还会促进细胞分裂并且增加癌细胞繁殖的速度，而目前该药物也是作为首个CDK4/6抑制剂治疗乳腺癌的药物。
研究人员Amy S. Clark说道，所有的活细胞都会经历细胞分裂，而Palbociclib可以有效抑制细胞的分裂过程，而将Palbociclib同其它抗癌疗法比如内分泌疗法、化疗及其它靶向疗法结合就可以对多种类型的癌症产生一种强大的治疗效应；比如其可以高效抑制黑色素瘤和食管癌中CDK4的效应。
靶向疗法可以利用多种药物和其它干预措施来准确地鉴别并且攻击癌细胞，同时并不会对正常细胞产生损伤，Peter J. O'Dwyer博士表示，除了中性粒细胞外，Palbociclib对正常细胞的效应也较小，而在肿瘤中该药物可以有效抑制肿瘤的生长，随着我们发现靶点CDK4/6的新功能，我们或将开发新型的药物组合来作为新兴的抗癌制剂。
对130项相关的论文进行分析评估后，研究人员发现，药物Palbociclib除了可以帮助有效安全地抵御特定类型的乳腺癌外，该药物的早期临床试验结果还揭示了其对淋巴瘤、肉瘤、畸胎瘤等肿瘤的效力。随后研究者对17名患外套细胞淋巴瘤的患者进行2期临床试验，结果发现，Palbociclib会产生一种完全的反应和两种部分的效应，尽管患者的中位无进展生存期仅为4个月，而其中5位患者的生存期超过了1年；另一项对29名肉瘤患者的2期临床试验结果表明，药物Palbociclib可以使得66%的患者的中位无进展生存期达到12周。
研究者表示，将Palbociclib同其它抗癌制剂相结合是可行的，而且对骨髓瘤和其它实体瘤的早期试验结果发现组合疗法或许可以带来较好的疗效。在乳腺癌和其它癌症的临床试验中，每日服用一次Palbociclib是安全的，而且该药物的主要副作用可以对嗜中性白血球减少症进行逆转，嗜中性白血球减少症即中性白细胞数量异常性降低，该细胞数量的减少会使得患者对感染性疾病更加易感，患者出现的其它副作用还包括疲劳、恶心、腹泻、便秘等。
doi:10.1001/jamaoncol.2015.4701
PMC:
PMID:
Palbociclib (PD0332991)-a Selective and Potent Cyclin-Dependent Kinase Inhibitor: A Review of Pharmacodynamics and Clinical Development.
Clark AS1, Karasic TB2, DeMichele A3, Vaughn DJ1, O'Hara M1, Perini R4, Zhang P5, Lal P5, Feldman M5, Gallagher M6, O'Dwyer PJ1.
IMPORTANCE: Palbociclib (PD0332991) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive, ERBB2-negative (formerly HER2 or HER2/neu) breast cancer in the first-line metastatic setting. OBJECTIVE: Herein we describe the preclinical and translational data and early- and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types. We discuss the pharmacodynamics, pharmacokinetics, toxic effects, and clinical response rates. EVIDENCE REVIEW: On March 1, 2015, we conducted a review of the literature describing the development of palbociclib. We used the PubMed search terms "PD0332991," "palbociclib," and "CDK4/6 inhibitor" to find all published articles of interest, without limitation as to publication date. FINDINGS: Palbociclib is a potent and specific oral cyclin-dependent kinase (CDK) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein-expressing tumors. Phase 1 trials have demonstrated safety, and phase 2 trials have shown single-agent activity in mantle-cell lymphoma, breast cancer, liposarcoma, and teratoma with reversible neutropenia as the main toxic effect. Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-nave and endocrine therapy-resistant metastatic settings. CONCLUSIONS AND RELEVANCE: Palbociclib is well tolerated and has therapeutic potential for multiple cancers, including breast cancer, where its efficacy has been demonstrated alone and in combination with endocrine therapy. Additional combinations of palbociclib with endocrine therapy, chemotherapy, and targeted therapy have potential in various tumors, and phase 3 trials are under way.
