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Ribociclib

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https://www.readbyqxmd.com/read/29306194/downregulation-of-parp1-transcription-by-cdk4-6-inhibitors-sensitizes-human-lung-cancer-cells-to-anticancer-drug-induced-death-by-impairing-ogg1-dependent-base-excision-repair
#1
Dominika Tempka, Paulina Tokarz, Kinga Chmielewska, Magdalena Kluska, Julita Pietrzak, Żaneta Rygielska, László Virág, Agnieszka Robaszkiewicz
Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB1-E2F1-HDAC1-EZH2 repressive complex to the PARP1 promoter...
December 29, 2017: Redox Biology
https://www.readbyqxmd.com/read/29306020/a-selective-cyclin-dependent-kinase-4-6-dual-inhibitor-ribociclib-lee011-inhibits-cell-proliferation-and-induces-apoptosis-in-aggressive-thyroid-cancer
#2
Hyun Joo Lee, Woo Kyung Lee, Chan Woo Kang, Cheol Ryong Ku, Yoon Hee Cho, Eun Jig Lee
The RB-E2F1 pathway is an important mechanism of cell-cycle control, and deregulation of this pathway is one of the key factors contributing to tumorigenesis. Cyclin-dependent kinases (CDKs) and Cyclin D have been known to increase in aggressive thyroid cancer. However, there has been no study to investigate effects of a selective CDK 4/6 inhibitor, Ribociclib (LEE011), in thyroid cancer. Performing Western blotting, we found that RB phosphorylation and the expression of Cyclin D are significantly higher in papillary thyroid cancer (PTC) cell lines as well as anaplastic thyroid cancer (ATC) cell lines, compared with normal thyroid cell line and follicular thyroid cancer cell line...
January 3, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29283884/a-hypothesis-driven-approach-identifies-cdk4-and-cdk6-inhibitors-as-candidate-drugs-for-treatments-of-adrenocortical-carcinomas
#3
Djihad Hadjadj, Su-Jung Kim, Thomas Denecker, Laura Ben Driss, Jean-Charles Cadoret, Chrystelle Maric, Giuseppe Baldacci, Fabien Fauchereau
High proliferation rate and high mutation density are both indicators of poor prognosis in adrenocortical carcinomas. We performed a hypothesis-driven association study between clinical features in adrenocortical carcinomas and the expression levels of 136 genes involved in DNA metabolism and G1/S phase transition. In 79 samples downloaded from The Cancer Genome Atlas portal, high Cyclin Dependent Kinase 6 (CDK6) mRNA levels gave the most significant association with shorter time to relapse and poorer survival of patients...
December 26, 2017: Aging
https://www.readbyqxmd.com/read/29276273/drug-monographs-avelumab-and-ribociclib
#4
J Aubrey Waddell, Dominic A Solimando
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc, 4201 Wilson Blvd #110-545, Arlington, VA 22203, email: OncRxSvc@comcast...
July 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/29247857/a-highly-potent-cdk4-6-inhibitor-was-rationally-designed-to-overcome-blood-brain-barrier-in-gliobastoma-therapy
#5
Lei Yin, Heng Li, Wenjian Liu, Zhenglin Yao, Zhenzhen Cheng, Huabei Zhang, Hui Zou
Glioblastoma multiforme (GBM) is the most common and deadliest of malignant brain tumors in adults. Disease development is associated with dysregulation of the cyclin D-CDK4/6-INK4-Rb pathway, resulting in increased proliferation; thus, CDK4/6 kinase inhibitors are promising candidates for GBM treatment. The recently developed CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, are effective in subcutaneous glioma models, but their blood-brain barrier (BBB) permeability is poor, limiting drug delivery to the central nervous system...
December 6, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29240261/mitochondrial-dysfunction-rad51-and-ku80-proteolysis-promote-apoptotic-effects-of-dinaciclib-in-bcl-xl-silenced-cells
#6
Daniel R Premkumar, Esther P Jane, Swetha Thambireddy, Philip A Sutera, Jonathon M Cavaleri, Ian F Pollack
In the present study, we investigated the effect of CDK inhibitors (ribociclib, palbociclib, seliciclib, AZD5438 and dinaciclib) on malignant human glioma cells for cell viability, apoptosis, oxidative stress and mitochondrial function using various assays. None of the CDK inhibitors induced cell death at a clinically relevant concentration. However, low nanomolar concentrations of dinaciclib showed higher cytotoxic activity against Bcl-xL silenced cells in a time- and concentration-dependent manner. This effect was not seen with other CDK inhibitors...
December 14, 2017: Molecular Carcinogenesis
https://www.readbyqxmd.com/read/29236940/polyclonal-rb1-mutations-and-acquired-resistance-to-cdk-4-6-inhibitors-in-patients-with-metastatic-breast-cancer
#7
R Condorelli, L Spring, J O'Shaughnessy, L Lacroix, C Bailleux, V Scott, J Dubois, R J Nagy, R B Lanman, A J Iafrate, F Andre, A Bardia
Background: While deregulation of the cyclin D1-CDK4/6-retinoblastoma pathway is common in hormone receptor positive (HR+) breast cancer, Rb is usually intact in HR+ breast cancer, and targeted CDK 4/6 inhibitors that act upstream of Rb, are routinely being utilized in clinical practice. However, factors that can lead to clinical resistance to CDK 4/6 inhibitors are not known. Patients and methods: We identified patients who had pre and post genotyping in tissue and peripheral blood samples after receiving CDK 4/6 inhibitors...
December 11, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29236235/potential-biomarkers-of-cdk4-6-inhibitors-in-hormone-receptor-positive-advanced-breast-cancer
#8
REVIEW
Hehui Fang, Doudou Huang, Fang Yang, Xiaoxiang Guan
PURPOSE: Cyclin D/cyclin-dependent kinase 4/6 (CDK4/6) complex inhibitors have recently been proven effective when combined with endocrine therapy in clinical trials. However, the clinical benefit from CDK4/6 inhibitor varied from different patients. In order to optimize the clinical application of CDK4/6 inhibitors, this review focuses on the potential biomarkers applicable to identify patients who will benefit the most from CDK4/6 inhibition. METHODS: We have summarized the clinical trials about addition of CDK4/6 inhibitors to endocrine therapy and reviewed literature currently available on the potential biomarkers in predicting efficacy of CDK4/6 inhibitors...
December 13, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29229752/ribociclib-extends-survival-in-hr-breast-cancer
#9
(no author information available yet)
Adding the CDK4/6 inhibitor ribociclib to standard first-line endocrine therapy significantly prolonged survival in premenopausal and perimenopausal women with advanced HR-positive, HER2-negative breast cancer enrolled in the MONALEESA-7 trial. This is the first definitive evidence that CDK4/6 inhibitor-based therapy is effective for first-line treatment of premenopausal and perimenopausal women.
December 11, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/29164421/ribociclib-plus-letrozole-versus-letrozole-alone-in-patients-with-de-novo-hr-her2-advanced-breast-cancer-in-the-randomized-monaleesa-2-trial
#10
Joyce O'Shaughnessy, Katarina Petrakova, Gabe S Sonke, Pierfranco Conte, Carlos L Arteaga, David A Cameron, Lowell L Hart, Cristian Villanueva, Erik Jakobsen, Joseph T Beck, Deborah Lindquist, Farida Souami, Shoubhik Mondal, Caroline Germa, Gabriel N Hortobagyi
PURPOSE: Determine the efficacy and safety of first-line ribociclib plus letrozole in patients with de novo advanced breast cancer. METHODS: Postmenopausal women with HR+ , HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase III MONALEESA-2 trial (NCT01958021). Patients were randomized to ribociclib (600 mg/day; 3 weeks-on/1 week-off) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation...
November 21, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29153893/selective-atp-competitive-leads-of-cdk4-discovery-by-3d-qsar-pharmacophore-mapping-and-molecular-docking-approach
#11
Rohini Rondla, Lavanya Souda PadmaRao, Vishwanath Ramatenki, Aboubakr Haredi-Abdel-Monsef, Sarita Rajender Potlapally, Uma Vuruputuri
The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val(96), Arg(101), and Glu(144) residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib...
November 14, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29134635/ribociclib-bioavailability-is-not-affected-by-gastric-ph-changes-or-food-intake-in-silico-and-clinical-evaluations
#12
Tanay S Samant, Shyeilla Dhuria, Yasong Lu, Marc Laisney, Shu Yang, Arnaud Grandeury, Martin Mueller-Zsigmondy, Kenichi Umehara, Felix Huth, Michelle Miller, Caroline Germa, Mohamed Elmeliegy
Ribociclib (KISQALI®), a cyclin-dependent kinase 4/6 inhibitor approved for the first-line treatment of HR+/HER2- advanced breast cancer with an aromatase inhibitor, is administered with no restrictions on concomitant gastric pH-elevating agents or food intake. The influence of proton pump inhibitors (PPIs) on ribociclib bioavailability was assessed using (1) biorelevant media solubility, (2) physiologically based pharmacokinetic (PBPK) modeling, (3) non-compartmental analysis (NCA) of clinical trial data, and (4) population PK (PopPK) analysis...
November 14, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29133594/competitive-kinase-enrichment-proteomics-reveals-that-abemaciclib-inhibits-gsk3%C3%AE-and-activates-wnt-signaling
#13
Emily M Cousins, Dennis Goldfarb, Feng Yan, Jose Roques, David B Darr, Gary L Johnson, Michael B Major
The cellular and organismal phenotypic response to a small-molecule kinase inhibitor is defined collectively by the inhibitor's targets and their functions. The selectivity of small-molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based methodology to define the target landscape of kinase inhibitors. Here, we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells, and treated mice...
November 13, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29125603/cell-cycle-arrest-through-indirect-transcriptional-repression-by-p53-i-have-a-dream
#14
REVIEW
Kurt Engeland
Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements...
November 10, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29119080/metastatic-breast-cancer-endocrine-therapy-landscape-reshaped
#15
REVIEW
Mohamad Adham Salkeni, Samantha June Hall
Endocrine therapy (ET) of hormone receptor (HR)-positive and human epidermal growth factor receptor 2-(HER2)-negative metastatic breast cancer (MBC) historically focused on estrogen deprivation and antagonism. The identification of several intracellular pathways promoting resistance to antiestrogen therapy led to the introduction of novel endocrine drug combinations that reformed treatment schema and expanded therapeutic options. There is no doubt that efforts to overcome or delay resistance to ET are fruiting, particularly with the introduction of cyclin-dependent kinase 4/6 inhibitors such as palbociclib and ribociclib, and mechanistic target of rapamycin inhibitors such as everolimus...
October 2017: Avicenna Journal of Medicine
https://www.readbyqxmd.com/read/29103175/efficacy-and-safety-in-older-patient-subsets-in-studies-of-endocrine-monotherapy-versus-combination-therapy-in-patients-with-hr-her2-%C3%A2-advanced-breast-cancer-a-review
#16
REVIEW
Rachel A Freedman, Sara M Tolaney
PURPOSE: Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population. METHODS: We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with ET ± targeted agents...
November 4, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29097609/recent-advances-of-cell-cycle-inhibitor-therapies-for-pediatric-cancer
#17
REVIEW
Christopher C Mills, E A Kolb, Valerie B Sampson
This review describes the pivotal roles of cell-cycle and checkpoint regulators and discusses development of specific cell-cycle inhibitors for therapeutic use for pediatric cancer. The mechanism of action as well as the safety and tolerability of drugs in pediatric patients, including compounds that target CDK4/CDK6 (palbociclib, ribociclib, and abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib), and tubulin (taxanes, vinca alkaloids), are presented. The design of mechanism-based combinations that exploit the cross-talk of signals activated by cell-cycle arrest, as well as pediatric-focused drug development, are critical for the advancement of drugs for rare childhood diseases...
November 2, 2017: Cancer Research
https://www.readbyqxmd.com/read/29059492/phase-i-study-of-single-agent-ribociclib-in-japanese-patients-with-advanced-solid-tumors
#18
Toshihiko Doi, Becker Hewes, Tomoyuki Kakizume, Takeshi Tajima, Norifumi Ishikawa, Yasuhide Yamada
The cyclin D-CDK4/6-INK4-Rb pathway is frequently dysregulated in cancers. Ribociclib, an orally available, selective CDK4/6 inhibitor, showed preliminary clinical activity in a phase I study in the USA and Europe for patients with solid tumors and lymphomas. The present study aimed to determine the single-agent maximum tolerated dose (MTD) and recommended dose for expansion (RDE) in Japanese patients with advanced solid tumors. Ribociclib safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity were also assessed...
October 23, 2017: Cancer Science
https://www.readbyqxmd.com/read/29058175/ribociclib-with-letrozole-vs-letrozole-alone-in-elderly-patients-with-hormone-receptor-positive-her2-negative-breast-cancer-in-the-randomized-monaleesa-2-trial
#19
Gabe S Sonke, Lowell L Hart, Mario Campone, Frans Erdkamp, Wolfgang Janni, Sunil Verma, Cristian Villanueva, Erik Jakobsen, Emilio Alba, Erik Wist, Anne M Favret, Thomas Bachelot, Roberto Hegg, Paul Wheatley-Price, Farida Souami, Santosh Sutradhar, Michelle Miller, Caroline Germa, Howard A Burris
PURPOSE: Determine the efficacy and safety of first-line ribociclib plus letrozole in elderly patients with HR+, HER2- advanced breast cancer. METHODS: 668 postmenopausal women with HR+, HER2- advanced breast cancer and no prior systemic therapy for advanced disease were enrolled in the Phase II MONALEESA-2 trial (NCT01958021); 295 patients were aged ≥ 65 years. Patients were randomized to ribociclib (600 mg/day; 3-weeks-on/1-week-off) plus letrozole (2.5 mg/day) or placebo plus letrozole until disease progression, unacceptable toxicity, death, or treatment discontinuation...
October 22, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29039822/ribociclib-kisqali-for-advanced-or-metastatic-breast-cancer
#20
(no author information available yet)
No abstract text is available yet for this article.
October 23, 2017: Medical Letter on Drugs and Therapeutics
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