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Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer Christopher C

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Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer Christopher C Published OnlineFirst November 2, 2017; DOI: 10.1158/0008-5472.CAN-17-2066 Cancer Review Research Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer Christopher C. Mills1, EA. Kolb2, and Valerie B. Sampson2 Abstract This review describes the pivotal roles of cell-cycle and check- MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib), and tubu- point regulators and discusses development of specific cell-cycle lin (taxanes, vinca alkaloids), are presented. The design of mech- inhibitors for therapeutic use for pediatric cancer. The mechanism anism-based combinations that exploit the cross-talk of signals of action as well as the safety and tolerability of drugs in pediatric activated by cell-cycle arrest, as well as pediatric-focused drug patients, including compounds that target CDK4/CDK6 (palbo- development, are critical for the advancement of drugs for rare ciclib, ribociclib, and abemaciclib), aurora kinases (AT9283 and childhood diseases. Cancer Res; 77(23); 6489–98. Ó2017 AACR. Introduction of DNA damage, epigenetics, metabolism, proteolytic degra- dation, stem cell self-renewal, neuronal functions, and sper- Recent preclinical and clinical studies of highly selective matogenesis (2). agents that target various regulators of the mammalian cell Selective members of the CDK family of protein kinases act as cycle demonstrate cell-cycle arrest, inhibition of transcription, oncogenic stimuli in several types of cancer (e.g., CDK1 in breast and apoptotic cell death in models of human cancer. The cell- cancer and colon cancer (3, 4), CDK4 in familial melanoma (5), cycle drives proliferation of cells by the duplication of chromo- and CDK6 in MLL-rearranged leukemia (6). Abnormal activity somes and their distribution to a pair of genetically identical is associated with the malignant transformation of cells, inhi- daughter cells. The fidelity of these processes relies on a series of bition of DNA transcription and low response to standard drug ordered and highly regulated steps that control the transition of treatment (7). Pharmacological inhibition of CDKs typically cells through DNA synthesis (S-phase) and cell division (M- results in cell cycle arrest, apoptosis, and transcriptional repres- phase), which are separated by gap phases G and G . Activa- 1 2 sion to provide the rationale for therapeutically targeting tion of cyclin-dependent kinases (CDK) and association with CDKs in cancer. This review focuses on the cell-cycle inhibitors regulatory cyclins enable successful progression through the that have entered clinical trials for development against child- cell cycle. Nine CDKs regulate different processes in the cell- hood cancer. cycle machinery, through formation of specialized and tissue- specific cyclin/CDK complexes (1). Association of cyclin D1 Cyclin-dependent kinase 4/6 inhibition with CDK4 and CDK6 drives progression through G1 stage, Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have cyclin E and cyclin A bind CDK2 to regulate centrosome emerged as promising cell-cycle therapeutics. The CDK4 and duplication and also to target helicases and polymerases during CDK6 genes encode the CDK4 and CDK6 cyclin-dependent – G1 S and S-phase, and cyclin A/cyclin B/CDK1 complexes serine-threonine kinases (CDK 4/6), respectively. Mitogenic – regulate the G2 M checkpoint (1). stimuli (e.g., estrogen and human epidermal growth factor Inhibitory proteins further regulate activity of cyclin/CDK receptor) and pro-proliferative factors (e.g., oncogenic MYC complexes. p27 (CDKN1B gene), p21 (CDKN1A gene), and and RAS) trigger quiescent cells to express D-type cyclins and CDKN1C p57 ( gene) block the interaction of G1-phase CDKs enter the cell cycle (8). These stimulate formation of CDK4/6 (CDK4 and CDK6) with their respective targets. In addition, complexes with cyclins D1-D3, leading to phosphorylation and the family of Ink4 proteins (inhibitors of kinase 4), p15 activation of the retinoblastoma tumor suppressor gene prod- (CDKN2B gene), and p16 (CDKN2A gene) bind CDK4 and uct (Rb). Rb protein phosphorylation releases E2F transcription CDK6 and control mid-G1 stage by decreasing the phosphor- factors that regulate genes that are required for G0 or G1 phase ylation of target proteins. Over 30 cyclin/CDK/Inhibitors are transition (pre-DNA synthesis) to S phase, in which DNA implicated in cellular functions regulating transcription, repair synthesis occurs (9). CDK4/6 signaling also has roles indepen- dent of cell-cycle regulation. These include senescence suppres- sion via regulation of the FOXM1 transcription factor (10) and 1University of Delaware, Newark, Delaware. 2Nemours Center for Cancer and transcriptioninhematopoieticcells(1).HighexpressionofD- Blood Disorders, Nemours/Alfred I. duPont Hospital for Children, Wilmington, type cyclins, genetic mutations or amplification of the CDK4 Delaware. and CDK6 loci, or loss of the p16Ink4A inhibitory protein that Corresponding Author: Valerie B. Sampson, Nemours/A.I. duPont Hospital for regulates cyclin D/CDK4/6 complexes, are associated with Children, 1701 Rockland Road, Wilmington, DE 19803. Phone: 302-651-4832; Fax: unrestricted cancer cell growth. In addition, deletion of RB1 301-651-4827; E-mail: [email protected] occurs in many tumors and accelerates proliferation indepen- doi: 10.1158/0008-5472.CAN-17-2066 dently of cyclin D–CDK4/6 activity. This suggests that activa- Ó2017 American Association for Cancer Research. tion of the cyclin D/CDK4/CDK6/Rb axis is a molecular www.aacrjournals.org 6489 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst November 2, 2017; DOI: 10.1158/0008-5472.CAN-17-2066 Mills et al. hallmark of cancer (11). Currently, three selective CDK4/6 ALL mouse models in combination therapy with corticosteroids inhibitors are approved: palbociclib (PD-0332991), ribociclib and mTOR inhibitors (18). Dual inhibition of MEK1/2 (binime- (LEE011), and abemaciclib (LY2835219). tinib) and CDK4/6 (ribociclib) achieved preclinical synergy (19), as well as ALK (ceritinib) and CDK4/6 (ribociclib; ref. 20) in Palbociclib (PD-0332991). Palbociclib (Pfizer) is developed for neuroblastoma. treatment of ER-positive and HER2-negative breast cancer. Estro- Ribociclib was assessed in one pediatric phase I study for 32 gen receptor (ER) pathway activation induces cyclin D1 and patients with malignant rhabdoid tumors (MRT) and neuroblas- combining aromatase inhibition with CDK4/6 inhibition signif- toma. Results demonstrated acceptable safety and pharmacoki- icantly reduces cyclin D–CDK4/6 activity (11). Palbociclib shows netics (21). Patients received escalating once-daily oral doses 2 selective potency against CDK4 and CDK 6 (IC50 9–11 nmol/L (3-weeks-on/1-week-off). The MTD was 470 mg/m and RP2D and 15 nmol/L, respectively) in comparison with a range of other was 350 mg/m2. These values were similar to those in adults. The kinases (12). Preclinical studies indicate palbociclib shows anti- most common grade 3 DLTs were fatigue (280 mg/m2; n ¼ 1) tumor activity in pediatric malignancies. Barton and colleagues and thrombocytopenia (470 mg/m2; n ¼ 2). There were several (13) demonstrated that a single dose of gamma radiotherapy adverse grade-3/4 hematologic events, including neutropenia followed by daily treatment with palbociclib increased survival in (63%), leukopenia (38%), anemia (3%), thrombocytopenia genetically engineered brainstem glioma mouse models by 19% (28%), and lymphopenia (19%) and fatigue (3%). Observations in comparison with radiotherapy alone. In another investigation, of prolonged stable disease in a subset of patients with neuro- palbociclib plus PLX4720, an inhibitor against v-raf murine blastoma (n ¼ 7) and primary CNS MRT (n ¼ 2) support further sarcoma viral oncogene homolog B1 (BRAF) extended survival clinical evaluation of combination therapies to optimize CDK4/6 in pediatric malignant astrocytoma, relative to either monother- targeting in neuroblastoma and MRT. An integrated analysis of apy (14). Response was specific for a subset of pediatric astrocy- ribociclib-induced cellular senescence could help to identify tomas with BRAF (V600E) mutation and CDKN2A (encoding unresponsive tumors, and may have potentially important ther- cyclin-dependent kinase inhibitor 2A) deficiency. apeutic implications. Two phase-I clinical trials are ongoing to test palcociclib in Rb-positive solid tumors and leukemia. Investigation of the Abemaciclib (LY2835219). Abemaciclib (Eli Lilly and Company) maximum tolerated dose (MTD)/phase II recommended dose is an ATP-competitive, reversible kinase inhibitor with break- as well as toxicities of palcociclib in children with Rb-positive through therapy designation for patients with refractory hor- þ recurrent, progressive or refractory primary central nervous mone-receptor–positive (HR ) advanced or metastatic breast system (CNS) tumors is planned (NCT02255461). One clinical cancer. Abemaciclib shows potency against CDK4, CDK6 and study for adults with various advanced solid tumors, reported CDK9 at 2, 10, and 57 nmol/L, respectively (22). One area of dose-limiting toxicities (DLT) in patients were grade 3 neutro- clinical study is the ability of abemaciclib to penetrate the blood– penia (12%), anemia (7%), and leukopenia (2%). Other com- brain barrier (23). This agent has entered clinical evaluation for mon adverse events included fatigue, nausea, and diarrhea newly diagnosed diffuse intrinsic pontine glioma (DIPG) and (15). For the planned
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