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https://www.readbyqxmd.com/read/28438180/recent-advances-of-highly-selective-cdk4-6-inhibitors-in-breast-cancer
#1
REVIEW
Hanxiao Xu, Shengnan Yu, Qian Liu, Xun Yuan, Sridhar Mani, Richard G Pestell, Kongming Wu
Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219)...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28432176/a-phase-i-study-of-the-cdk4-6-inhibitor-ribociclib-lee011-in-pediatric-patients-with-malignant-rhabdoid-tumors-neuroblastoma-and-other-solid-tumors
#2
Birgit Geoerger, Franck Bourdeaut, Steven G DuBois, Matthias Fischer, James I Geller, Nicholas G Gottardo, Aurélien Marabelle, Andrew D J Pearson, Shakeel Modak, Thomas Cash, Giles W Robinson, Marlyane Motta, Alessandro Matano, Suraj G Bhansali, Jason R Dobson, Sudha Parasuraman, Susan N Chi
Purpose: The cyclin-dependent kinase (CDK) 4/6 inhibitor, ribociclib (LEE011), displayed preclinical activity in neuroblastoma and malignant rhabdoid tumor (MRT) models. In this phase I study, the maximum tolerated dose (MTD) and recommended phase II dose (RP2D), safety, pharmacokinetics (PK), and preliminary activity of single-agent ribociclib were investigated in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors.Experimental Design: Patients (aged 1-21 years) received escalating once-daily oral doses of ribociclib (3-weeks-on/1-week-off)...
April 21, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28359238/hr-her2-advanced-breast-cancer-and-cdk4-6-inhibitors-mode-of-action-clinical-activity-and-safety-profiles
#3
Sarah L Sammons, Donna L Topping, Kimberly L Blackwell
Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapies have shown great promise in improving clinical outcomes for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Addition of a CDK4/6 inhibitor to endocrine therapy increases efficacy and delays disease progression. Successful use of CDK4/6 inhibitor-based therapies in the clinic requires insight into the unique side-effect profiles of this class of agents and effective patient monitoring...
March 30, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28351928/ribociclib-lee011-mechanism-of-action-and-clinical-impact-of-this-selective-cyclin-dependent-kinase-4-6-inhibitor-in-various-solid-tumors
#4
Debu Tripathy, Aditya Bardia, William R Sellers
The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which was granted priority review by the US Food and Drug Administration in November 2016, and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib...
March 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28286417/molecular-mechanism-of-g1-arrest-and-cellular-senescence-induced-by-lee011-a-novel-cdk4-cdk6-inhibitor-in-leukemia-cells
#5
Yan-Fang Tao, Na-Na Wang, Li-Xiao Xu, Zhi-Heng Li, Xiao-Lu Li, Yun-Yun Xu, Fang Fang, Mei Li, Guang-Hui Qian, Yan-Hong Li, Yi-Ping Li, Yi Wu, Jun-Li Ren, Wei-Wei Du, Jun Lu, Xing Feng, Jian Wang, Wei-Qi He, Shao-Yan Hu, Jian Pan
BACKGROUND: Overexpression of cyclin D1 dependent kinases 4 and 6 (CDK4/6) is a common feature of many human cancers including leukemia. LEE011 is a novel inhibitor of both CDK4 and 6. To date, the molecular function of LEE011 in leukemia remains unclear. METHODS: Leukemia cell growth and apoptosis following LEE011 treatment was assessed through CCK-8 and annexin V/propidium iodide staining assays. Cell senescence was assessed by β-galactosidase staining and p16(INK4a) expression analysis...
2017: Cancer Cell International
https://www.readbyqxmd.com/read/28226315/the-novel-cyclin-dependent-kinase-4-6-inhibitor-ribociclib-lee011-alone-and-in-dual-targeting-approaches-demonstrates-antitumoral-efficacy-in-neuroendocrine-tumors-in-vitro
#6
Elke Tatjana Aristizabal Prada, Svenja Noelting, Gerald Spoettl, Julian Maurer, Christoph Joseph Auernhammer
No abstract text is available yet for this article.
February 23, 2017: Neuroendocrinology
https://www.readbyqxmd.com/read/28151717/synergistic-drug-combinations-with-a-cdk4-6-inhibitor-in-t-cell-acute-lymphoblastic-leukemia
#7
Yana Pikman, Gabriela Alexe, Giovanni Roti, Amy Saur Conway, Andrew Furman, Emily S Lee, Andrew E Place, Sunkyu Kim, Chitra Saran, Rebecca Modiste, David M Weinstock, Marian Harris, Andrew L Kung, Lewis B Silverman, Kimberly Stegmaier
Purpose: Although significant progress has been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL), many patients will require additional therapy for relapsed/refractory disease. Cyclin D3 (CCND3) and CDK6 are highly expressed in T-ALL and have been effectively targeted in mutant NOTCH1-driven mouse models of this disease with a CDK4/6 small-molecule inhibitor. Combination therapy, however, will be needed for the successful treatment of human disease.Experimental Design: We performed preclinical drug testing using a panel of T-ALL cell lines first with LEE011, a CDK4/6 inhibitor, and next with the combination of LEE011 with a panel of drugs relevant to T-ALL treatment...
February 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28092667/oncogenic-braf-fusions-in-mucosal-melanomas-activate-the-mapk-pathway-and-are-sensitive-to-mek-pi3k-inhibition-or-mek-cdk4-6-inhibition
#8
H S Kim, M Jung, H N Kang, H Kim, C-W Park, S-M Kim, S J Shin, S H Kim, S G Kim, E K Kim, M R Yun, Z Zheng, K Y Chung, J Greenbowe, S M Ali, T-M Kim, B C Cho
Despite remarkable progress in cutaneous melanoma genomic profiling, the mutational landscape of primary mucosal melanomas (PMM) remains unclear. Forty-six PMMs underwent targeted exome sequencing of 111 cancer-associated genes. Seventy-six somatic nonsynonymous mutations in 42 genes were observed, and recurrent mutations were noted on eight genes, including TP53 (13%), NRAS (13%), SNX31 (9%), NF1 (9%), KIT (7%) and APC (7%). Mitogen-activated protein kinase (MAPK; 37%), cell cycle (20%) and phosphatidylinositol 3-kinase (PI3K)-mTOR (15%) pathways were frequently mutated...
January 16, 2017: Oncogene
https://www.readbyqxmd.com/read/27542767/a-phase-i-study-of-the-cyclin-dependent-kinase-4-6-inhibitor-ribociclib-lee011-in-patients-with-advanced-solid-tumors-and-lymphomas
#9
Jeffrey R Infante, Philippe A Cassier, John F Gerecitano, Petronella O Witteveen, Rashmi Chugh, Vincent Ribrag, Abhijit Chakraborty, Alessandro Matano, Jason R Dobson, Adam S Crystal, Sudha Parasuraman, Geoffrey I Shapiro
PURPOSE: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb(+)). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb(+) advanced solid tumors or lymphomas. EXPERIMENTAL DESIGN: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous)...
December 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27493615/clinical-development-of-the-cdk4-6-inhibitors-ribociclib-and-abemaciclib-in-breast-cancer
#10
REVIEW
Romualdo Barroso-Sousa, Geoffrey I Shapiro, Sara M Tolaney
Clinical and preclinical data support a significant role for inhibitors of the cyclin-dependent kinases (CDKs) 4 and 6 in the treatment of patients with breast cancer. Recently, based on data showing improvement in progression-free survival, the use of palbociclib (Ibrance; Pfizer, Inc.) in combination with endocrine agents was approved to treat patients with hormone receptor-positive advanced disease. Importantly, 2 other CDK4/6 inhibitors, abemaciclib (LY2835219; Lilly) and ribociclib (LEE011; Novartis), are in the late stage of clinical development...
June 2016: Breast Care
https://www.readbyqxmd.com/read/27336726/ribociclib-plus-letrozole-in-early-breast-cancer-a-presurgical-window-of-opportunity-study
#11
RANDOMIZED CONTROLLED TRIAL
G Curigliano, P Gómez Pardo, F Meric-Bernstam, P Conte, M P Lolkema, J T Beck, A Bardia, M Martínez García, F Penault-Llorca, S Dhuria, Z Tang, N Solovieff, M Miller, E Di Tomaso, S A Hurvitz
OBJECTIVES: Cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitor of CDK4/6-retinoblastoma (Rb) pathway hyperactivation is associated with hormone receptor-positive (HR+) breast cancer (BC). This study assessed the biological activity of ribociclib (LEE011; CDK4/6 inhibitor) plus letrozole compared with single-agent letrozole in the presurgical setting. MATERIALS AND METHODS: Postmenopausal women (N = 14) with resectable, HR+, human epidermal growth factor receptor 2-negative (HER2-) early BC were randomized 1:1:1 to receive 2...
August 2016: Breast: Official Journal of the European Society of Mastology
https://www.readbyqxmd.com/read/27267837/bez235-pik3-mtor-inhibitor-overcomes-pazopanib-resistance-in-patient-derived-refractory-soft-tissue-sarcoma-cells
#12
Hee Kyung Kim, Sun Young Kim, Su Jin Lee, Mihyeon Kang, Seung Tae Kim, Jiryeon Jang, Oliver Rath, Julia Schueler, Dong Woo Lee, Woong Yang Park, Sung Joo Kim, Se Hoon Park, Jeeyun Lee
BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients...
June 2016: Translational Oncology
https://www.readbyqxmd.com/read/27017286/targeting-cdk4-6-in-patients-with-cancer
#13
REVIEW
Erika Hamilton, Jeffrey R Infante
The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway controls cell cycle progression by regulating the G1-S checkpoint. Dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway results in increased proliferation, and is frequently observed in many types of cancer. Pathway activation can occur through a variety of mechanisms, including gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components...
April 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/26995305/cyclin-dependent-protein-kinase-inhibitors-including-palbociclib-as-anticancer-drugs
#14
REVIEW
Robert Roskoski
Cyclins and cyclin-dependent protein kinases (CDKs) are important regulatory components that are required for cell cycle progression. The levels of the cell cycle CDKs are generally constant and their activities are controlled by cyclins, proteins whose levels oscillate during each cell cycle. Additional CDK family members were subsequently discovered that play significant roles in a wide range of activities including the control of gene transcription, metabolism, and neuronal function. In response to mitogenic stimuli, cells in the G1 phase of the cell cycle produce cyclins of the D type that activate CDK4/6...
May 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/26642065/cyclin-dependent-kinase-pathways-as-targets-for-women-s-cancer-treatment
#15
REVIEW
Gottfried E Konecny
PURPOSE OF REVIEW: In this article, we not only review the preclinical and clinical studies of cyclin-dependent kinase (CDK) 4/6 inhibitors in breast cancer, liposarcoma, mantel cell lymphoma, melanoma and germ cell tumors, but also examine promising preclinical data in glioblastoma, renal and ovarian cancer models that may provide directions for future development. RECENT FINDINGS: Targeting CDKs has been the focus of considerable basic science and clinical research...
February 2016: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/26390342/chemoproteomics-reveals-novel-protein-and-lipid-kinase-targets-of-clinical-cdk4-6-inhibitors-in-lung-cancer
#16
Natalia J Sumi, Brent M Kuenzi, Claire E Knezevic, Lily L Remsing Rix, Uwe Rix
Several selective CDK4/6 inhibitors are in clinical trials for non-small cell lung cancer (NSCLC). Palbociclib (PD0332991) is included in the phase II/III Lung-MAP trial for squamous cell lung carcinoma (LUSQ). We noted differential cellular activity between palbociclib and the structurally related ribociclib (LEE011) in LUSQ cells. Applying an unbiased mass spectrometry-based chemoproteomics approach in H157 cells and primary tumor samples, we here report distinct proteome-wide target profiles of these two drug candidates in LUSQ, which encompass novel protein and, for palbociclib only, lipid kinases...
December 18, 2015: ACS Chemical Biology
https://www.readbyqxmd.com/read/26303211/cyclin-dependent-kinase-4-6-inhibitors-for-the-treatment-of-breast-cancer-a-review-of-preclinical-and-clinical-data
#17
REVIEW
Neelima Vidula, Hope S Rugo
For millions of women, breast cancer remains a potentially life-endangering diagnosis. With advances in research, new therapies targeted to tumor biology are emerging to treat the most common form of this disease. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of therapeutic agents that have the potential to improve the outcomes of patients with hormone receptor-positive (HR(+)) breast cancer. Three CDK 4/6 inhibitors have been investigated for the treatment of HR(+) breast cancer, including palbociclib (PD 0332991), ribociclib (LEE011), and abemaciclib (LY2835219)...
February 2016: Clinical Breast Cancer
https://www.readbyqxmd.com/read/25914884/targeting-cell-cycle-regulators-in-hematologic-malignancies
#18
REVIEW
Eiman Aleem, Robert J Arceci
Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair...
2015: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/25876993/the-role-of-cdk4-6-inhibition-in-breast-cancer
#19
REVIEW
Conleth G Murphy, Maura N Dickler
Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib)...
May 2015: Oncologist
https://www.readbyqxmd.com/read/25852058/cdkn2a-p16-loss-implicates-cdk4-as-a-therapeutic-target-in-imatinib-resistant-dermatofibrosarcoma-protuberans
#20
Grant Eilers, Jeffrey T Czaplinski, Mark Mayeda, Nacef Bahri, Derrick Tao, Meijun Zhu, Jason L Hornick, Neal I Lindeman, Ewa Sicinska, Andrew J Wagner, Jonathan A Fletcher, Adrian Mariño-Enriquez
Dermatofibrosarcoma protuberans (DFSP) is an aggressive PDGFB-dependent cutaneous sarcoma characterized by infiltrative growth and frequent local recurrences. Some DFSP progress to a higher-grade fibrosarcomatous form, with rapid growth and increased risk of metastasis. Imatinib provides clinical benefit in approximately 50% of patients with unresectable or metastatic DFSP. However, efficacious medical therapies have not been developed for imatinib-resistant DFSP. We established a model of imatinib-resistant DFSP and evaluated CDK4/6 inhibition as a genomically credentialed targeted therapy...
June 2015: Molecular Cancer Therapeutics
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