China
Africa
Explore chapters and articles related to this topic
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Polo-like kinase 1 (PLK1) facilitates mitotic entry and exit. Overexpression leads to aneuploidy, chromosomal instability, and neoplastic transformation [99]. Likewise, a small molecule inhibitor of PLK1 (BI 2536) suppressed colony and tumor sphere formation, inhibited cell growth, and increased apoptosis in vitro; moreover, PLK1 inhibition enhanced radiosensitivity of high-MYC expressing medulloblastoma cell lines [100]. Finally, the CDK4/6 inhibitor, palbociclib, was shown to decrease tumor cell proliferation, to increase apoptosis, and to improve survival in an orthotopic mouse model of MYC-overexpressing Group 3 MB [101].
Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
A study published in the journal Cell Chemical Biology has suggested that patients taking a combination of palbociclib (IbranceTM) and letrozole (FemaraTM) (see Chapters 6 and 8, respectively), a popular drug combination for treating breast cancer, should avoid foods rich in xenoestrogens (i.e., estrogen-mimicking compounds). Palbociclib was developed by Pfizer for the treatment of ER-positive/HER2-negative breast cancer, and is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. Letrozole is an aromatase inhibitor used in the treatment of hormonally responsive breast cancer after surgery. The research showed that two common dietary xenoestrogens, genistein (Figure 12.14) and zearalenone (Figure 12.19), which are found in many different plant-based foods, appear to potently reverse the effects of palbociclib/letrozole in tumor cells growing in vitro. Structure of zearalenone.
Hormone Receptors and Endocrine Therapy in Breast Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Nancy E. Davidson
Currently, three selective CDK4/6 inhibitors—palbociclib, ribociclib, and abemaciclib—are in advanced stages of clinical development and/or in post market surveillance. All three are approved by the FDA in combination with an anti-estrogen agent for the treatment of patients with HR+/HER2-advanced or metastatic breast cancer as first-line therapy and following progression on endocrine therapy.
Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition
Published in Expert Opinion on Investigational Drugs, 2022
Xianan Guo, Huihui Chen, Yunxiang Zhou, Lu Shen, Shijie Wu, Yiding Chen
CDK4 and CDK6 are well-known as CDKs associated with cell cycle, which are activated by binding to D-type cyclins including cyclin D1, cyclin D2, and cyclin D3 [13,14]. The CDK4/6-retinoblastoma protein (RB1) axis is a signaling pathway with a major role in the transition from the G1 to S phase of cell cycle [15]. RB1 is a vital cell cycle suppressor that is active when unphosphorylated in the G1 phase [16]. Either active CDK4 or CDK6 can facilitate the deactivating phosphorylation of RB1, which results in release of adenoviral early region 2 binding factor (E2F) to drive the expression of its transcriptional targets such as cyclin E [16,17]. The synthesis of the cyclin E-CDK2 complex can further phosphorylate RB1 and thereby promote the E2F transcriptional program and in turn catalyze the G1-S transition [18–21]. Simultaneously, the cyclin D-CDK4/6 complex enhances the activity of the cyclin E-CDK2 complex via sequestration of the CIP/KIP proteins [20]. Furthermore, a number of cell proliferation-related proteins have been reported to be regulated by CDK4/6, including forkhead box protein M1 (FOXM1), small mothers against decapentaplegic 3 (SMAD3), fizzy-related protein homolog (FZR1), tuberous sclerosis 2 (TSC2), and protein arginine methyltransferase 5 (PRMT5)/methylosome protein 50 (MEP50) [22]. Collectively, these findings indicate a particularly pivotal role of CDK4/6 in several cellular processes.
Advances in cyclin-dependent kinase inhibitors for the treatment of melanoma
Published in Expert Opinion on Pharmacotherapy, 2021
Maximilian Julve, James J. Clark, Mark P. Lythgoe
The first licensed CDK inhibitor was palbociclib (PD-0332991), an oral reversible selective small-molecule inhibitor of CDK4 and CDK6 developed by Pfizer and licensed in estrogen receptor-positive (ER+) breast cancer [48]. Parallel drug discovery at Novartis and Eli Lilly has led to the licensing of two further CDK4/6i ribociclib (LEE011) and abemaciclib (LY-2835219) respectively, also in ER+ breast cancer [64]. All three licensed CDK4/6i have a similar mechanism of action but differ in pharmacokinetic properties (Table 2). The successful development of selective inhibitors of CDK4/6 has markedly changed the perception of CDK inhibition as a therapeutic target in cancer. These compounds are now under further investigation in a range of cancers including pancreatic, head & neck, ovarian and melanoma [44].
Cyclin-dependent kinase 4/6 inhibitors for cancer therapy: a patent review (2015 – 2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Peng-Fei Wang, Han-Yue Qiu, Yun He, Hai-Liang Zhu
Unlike many other kinases in cancers, e.g., B-RAF, MEK, and EGFR, CDKs are rarely mutated in the pathogenesis of malignancies [19–22]. Instead, overexpression and/or hyperactivation of CDK4/6 are common features and key factors in many human tumors, e.g. ovary cancers, lung cancers, osteosarcoma, lymphomas, sarcoma, glioma, and malignant melanoma [23]. Especially in hormone receptor-positive breast cancers, estrogen induces the over-expression of cyclin D1, which activates CDK4/6 to further form the cyclin D1-CDK4/6-RB complex. The complex in turn functions as the major mediator in estrogen signaling to promote the cell cycle. While the other way around, reducing the signal transduction of estrogen pathway in cancer cells has proven to cause G0 and G1 cell-cycle arrest by cutting down cyclin-CDK complexing [24]. Hence CDK4/6 inhibitors (CDK4/6Is) are highly effective in this kind of breast cancer by interfering with the dysregulated CDK4/6. Other CDK4/6-involving oncology mechanisms, including negative regulatory factors loss, epigenetic modifications, mutations in other pathway components, and gene rearrangement or less common amplification, have also been elucidated [25]. Understandings of the mechanisms in detail shall help to extend the application of CDK4/6Is in other cancer therapies.