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https://www.readbyqxmd.com/read/29792845/current-frontline-endocrine-treatment-options-for-women-with-hormone-receptor-positive-human-epidermal-growth-factor-receptor-2-her2-negative-advanced-stage-breast-cancer
#1
REVIEW
Hikmat N Abdel-Razeq
Despite the recent advances in breast cancer early detection and awareness, a significant portion of patients present with an advanced-stage disease and more patients will progress to stage IV despite adequate treatment of their initial early-stage disease. Hormone receptor (HR)-positive, Human Epidermal Growth Factor Receptor-2 (HER2)-negative subtype is the commonest among all breast cancer subtypes. The management of the advanced-stage disease of this subtype has evolved significantly over the past few years...
May 19, 2018: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/29789718/pdlim7-and-cdh18-regulate-the-turnover-of-mdm2-during-cdk4-6-inhibitor-therapy-induced-senescence
#2
Mary E Klein, Mark A Dickson, Cristina Antonescu, Li-Xuan Qin, Scott J Dooley, Afsar Barlas, Katia Manova, Gary K Schwartz, Aimee M Crago, Samuel Singer, Andrew Koff, William D Tap
CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells...
May 23, 2018: Oncogene
https://www.readbyqxmd.com/read/29789630/preclinical-evaluation-of-ribociclib-and-its-synergistic-effect-in-combination-with-alpelisib-in-non-keratinizing-nasopharyngeal-carcinoma
#3
Chi-Hang Wong, Brigette B Y Ma, Connie W C Hui, Kwok-Wai Lo, Edwin P Hui, Anthony T C Chan
Ribociclib is a specific cyclin dependent kinase (Cdk) 4/6 inhibitor that induces G1 arrest by blocking the formation of cyclin D1-Cdk4/6 complex and inhibiting retinoblastoma (RB) phosphorylation. Cyclin D1 is overexpressed in over 90% of nasopharyngeal carcinoma (NPC) and CCND1 gene activation plays a critical role in NPC pathogenesis. This study evaluated the preclinical activities of ribociclib in NPC cell lines and patient derived xenograft (PDX) models. Over 95% cell growth inhibition was observed at 96 hours after ribociclib treatment...
May 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29784737/nccn-guidelines-updates-breast-cancer
#4
Sharon H Giordano, Anthony D Elias, William J Gradishar
The emergence of CDK4/6 inhibitors has changed the treatment algorithm for advanced/metastatic estrogen receptor-positive breast cancer. In pivotal trials of palbociclib, ribociclib, and abemaciclib, doubling in progression-free survival has been seen. All 3 agents in this class are now included in the NCCN Guidelines for Breast Cancer, and clinicians should be incorporating these agents into their treatment algorithms. The other important issue in this breast cancer setting is extended duration of endocrine therapy...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29781317/combination-therapies-for-the-treatment-of-her2-positive-breast-cancer-current-and-future-prospects
#5
Mariana Brandão, Noam F Pondé, Francesca Poggio, Nuria Kotecki, Mauren Salis, Matteo Lambertini, Evandro de Azambuja
HER2-positive disease is an aggressive subtype of breast cancer that has been revolutionized by anti-HER2 directed therapies. Multiple drugs have been developed and are currently in clinical use, including trastuzumab, lapatinib, pertuzumab, T-DM1 and neratinib, alone or combined in "dual HER2-blockade" regimens. Areas covered: A comprehensive literature review was performed regarding the current state and the future of combination regimens containing anti-HER2 agents, focusing on their efficacy, toxicity and cost-effectiveness...
May 21, 2018: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/29772457/in-vitro-and-in-vivo-metabolic-investigation-of-the-palbociclib-by-uhplc-q-tof-ms-ms-and-in-silico-toxicity-studies-of-its-metabolites
#6
Balasaheb B Chavan, Shristy Tiwari, Shankar G, Rakesh D Nimbalkar, Prabha Garg, Srinivas R, M V N Kumar Talluri
Palbociclib (PAB) is a CDK4/6 inhibitor and U. S Food and Drug Administration (FDA) granted regular approval for the treatment of hormone receptor (HR) positive, metastatic breast cancer in combination with an aromatase inhibitor in postmenopausal women. Metabolite identification is a crucial aspect during drug discovery and development as the drug metabolites may be pharmacologically active or possess toxicological activity. As there are no reports on the metabolism studies of the PAB, the present study focused on investigation of the in vitro and in vivo metabolic fate of the drug...
May 14, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29768351/the-cdk4-6-inhibitor-in-hr-positive-advanced-breast-cancer-a-systematic-review-and-meta-analysis
#7
Wu Ding, Zhian Li, Caiyun Wang, GuoDong Ruan, LuPing Chen, Chuanjian Tu
BACKGROUND: Recently, several high-quality clinical randomized controlled trials (RCTs) have identified that cyclin-dependent kinases (CDKs) 4/6 inhibitors obtained a great safety and efficacy, which can be consequently applied as a combination therapy with letrozole or fulvestrant for women who had advanced breast cancer and progressed while receiving endocrine therapy. In this systemic review, we performed a meta-analysis to explore whether CDK4/6 inhibitors had a significantly benefit to treating hormone receptor-positive (HR-positive)/human epidermal growth factor receptor 2 negative (HER2-negative) advanced breast cancer...
May 2018: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29767250/diosmetin-suppresses-human-prostate-cancer-cell-proliferation-through-the-induction-of-apoptosis-and-cell-cycle-arrest
#8
Christine Oak, Ahmad O Khalifa, Ilaha Isali, Natarajan Bhaskaran, Ethan Walker, Sanjeev Shukla
Diosmetin, a plant flavonoid, has been shown to exert promising effects on prostate cancer cells as an anti‑proliferative and anticancer agent. In this study, using western blot analysis for protein expression and flow cytometry for cell cycle analysis, we determined that the treatment of the LNCaP and PC‑3 prostate cancer cells with diosmetin resulted in a marked decrease in cyclin D1, Cdk2 and Cdk4 expression levels (these proteins remain active in the G0‑G1 phases of the cell cycle). These changes were accompanied by a decrease in c-Myc and Bcl-2 expression, and by an increase in Bax, p27Kip1 and FOXO3a protein expression, which suggests the potential modulatory effects of diosmetin on protein transcription...
May 16, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29764587/-role-of-pd-0332991-on-the-proliferation-and-apoptosis-of-vascular-endothelial-cells
#9
Chenlong Zhao, Minghui Liu, Yongwen Li, Hongbing Zhang, Ying Li, Hao Gong, Yin Yuan, Weiting Li, Hongyu Liu, Jun Chen
BACKGROUND: Angiogenesis is an important process in the development of tumor. PD 0332991, a cell cycle inhibitor, can specifically inhibit CD4/6 phosphorylation and cell cycle progression. In xeongraft mice models, PD 0332991 treated mice had significantly decreased angiogenesis and vascular density compared with the control group, but the mechanism remains unknown. The purpose of this study is to investigate the role and molecular mechanism of PD 0332991 on vascular endothelial cells...
May 20, 2018: Zhongguo Fei Ai za Zhi, Chinese Journal of Lung Cancer
https://www.readbyqxmd.com/read/29744983/expression-of-p16-ink-4a-is-a-biomarker-of-chondrocyte-aging-but-does-not-cause-osteoarthritis
#10
Brian O Diekman, Garrett A Sessions, John A Collins, Anne K Knecht, Susan L Strum, Natalia K Mitin, Cathy S Carlson, Richard F Loeser, Norman E Sharpless
Cellular senescence drives a functional decline of numerous tissues with aging by limiting regenerative proliferation and/or by producing pro-inflammatory molecules known as the senescence-associated secretory phenotype (SASP). The senescence biomarker p16INK 4a is a potent inhibitor of the cell cycle but is not essential for SASP production. Thus, it is unclear whether p16INK 4a identifies senescence in hyporeplicative cells such as articular chondrocytes and whether p16INK 4a contributes to pathologic characteristics of cartilage aging...
May 9, 2018: Aging Cell
https://www.readbyqxmd.com/read/29743141/chemotherapy-patient-with-stevens-johnson-syndrome-presents-to-the-emergency-department-a-case-report
#11
Stephanie Widmer, Michele Grossman
BACKGROUND: Stevens-Johnson syndrome (SJS) is part of a continuum of severe mucocutaneous reactions, commonly thought to be triggered by certain medications. The syndrome itself is characterized by diffuse necrosis and detachment of the epidermis. CASE REPORT: This case report discusses a patient who presented to the Emergency Department with signs and symptoms of Stevens-Johnson syndrome four days after chemotherapy administration of ribociclib (Kisqali®). Ribociclib is a newly approved, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor indicated for the treatment of hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+/HER2-) metastatic breast cancer...
April 11, 2018: American Journal of Emergency Medicine
https://www.readbyqxmd.com/read/29739788/mapk-reliance-via-acquired-cdk4-6-inhibitor-resistance-in-cancer
#12
Renee de Leeuw, Christopher McNair, Matthew J Schiewer, Neermala P Neupane, Lucas J Brand, Michael A Augello, Zhen Li, Larry C Cheng, Akihiro Yoshida, Sean M Courtney, Starr Hazard, Gerald Hardiman, Maha Hussain, J Alan Diehl, Justin M Drake, William K Kelly, Karen E Knudsen
PURPOSE: Loss of cell cycle control is a hallmark of cancer, which can be targeted with agents, including Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1-S cell cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types, and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon...
May 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29733964/aspartate-beta-hydroxylase-promotes-cholangiocarcinoma-progression-by-modulating-rb1-phosphorylation
#13
Chiung-Kuei Huang, Yoshifumi Iwagami, Jing Zou, Sarah Casulli, Shaolei Lu, Katsuya Nagaoka, Chengcheng Ji, Kousuke Ogawa, Kevin Y Cao, Jin-Song Gao, Rolf I Carlson, Jack R Wands
Cholangiocarcinoma (CCA) is a highly lethal and aggressive disease. Recently, IDH1/2 mutations have been identified in approximately 20% of CCAs which suggests an involvement of 2-oxoglutarate (2-OG) -dependent dioxygenases in oncogenesis. We investigated if the 2-OG dependent dioxygenase, aspartate beta-hydroxylase (ASPH) was important in tumor development and growth. Immunoassays were used to clarify how ASPH modulates CCA progression by promoting phosphorylation of the retinoblastoma protein (RB1). A xenograft model was employed to determine the role of ASPH on CCA growth...
May 4, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29733812/hypoxia-induced-autophagy-activation-through-nf-%C3%AE%C2%BAb-pathway-regulates-cell-proliferation-and-migration-to-induce-pulmonary-vascular-remodeling
#14
Xiaogang Jing, Tianci Jiang, Lingling Dai, Xi Wang, Liuqun Jia, Huan Wang, Lin An, Meng Liu, Rui Zhang, Zhe Cheng
OBJECTIVES: This study aimed to investigate whether autophagy mediated cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia and to validate the underlying mechanism. METHODS: The rat model of chronic hypoxia-induced pulmonary vascular remodeling was established. Rat primary PASMCs were isolated and cultured in vitro in hypoxia or normoxia to explore the underlying mechanism. RESULTS: Hypoxia exposure for 21 days induced pulmonary vascular remodeling in rats, accompanied by enhanced proliferation and decreased apoptosis, as well as induced expression of autophagic marker LC3II in their lungs...
May 4, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29731991/targeted-next-generation-sequencing-of-well-differentiated-dedifferentiated-liposarcoma-reveals-novel-gene-amplifications-and-mutations
#15
Neeta Somaiah, Hannah C Beird, Andrea Barbo, Juhee Song, Kenna R Mills Shaw, Wei-Lien Wang, Karina Eterovic, Ken Chen, Alexander Lazar, Anthony P Conley, Vinod Ravi, Patrick Hwu, Andrew Futreal, George Simon, Funda Meric-Bernstam, David Hong
Well-differentiated/dedifferentiated liposarcoma is a common soft tissue sarcoma with approximately 1500 new cases per year. Surgery is the mainstay of treatment but recurrences are frequent and systemic options are limited. 'Tumor genotyping' is becoming more common in clinical practice as it offers the hope of personalized targeted therapy. We wanted to evaluate the results and the clinical utility of available next-generation sequencing panels in WD/DD liposarcoma. Patients who had their tumor sequenced by either FoundationOne ( n = 13) or the institutional T200/T200...
April 13, 2018: Oncotarget
https://www.readbyqxmd.com/read/29731395/cdk4-6-inhibitors-the-mechanism-of-action-may-not-be-as-simple-as-once-thought
#16
REVIEW
Mary E Klein, Marta Kovatcheva, Lara E Davis, William D Tap, Andrew Koff
CDK4/6 inhibitors are among a new generation of therapeutics. Building upon the striking success of the combination of CDK4/6 inhibitors and the hormone receptor antagonist letrozole in breast cancer, many other combinations have recently entered clinical trials in multiple diseases. To achieve maximal benefit with CDK4/6 inhibitors it will be critical to understand the cellular mechanisms by which they act. Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest, and discuss how this knowledge may inform new combinations, improve outcomes, and modify dosing schedules in the future...
April 10, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29729292/cyclin-e-overexpression-confers-resistance-to-the-cdk4-6-specific-inhibitor-palbociclib-in-gastric-cancer-cells
#17
Ahrum Min, Jung Eun Kim, Yu-Jin Kim, Jee Min Lim, Seongyeong Kim, Jin Won Kim, Kyung-Hun Lee, Tae-Yong Kim, Do-Youn Oh, Yung-Jue Bang, Seock-Ah Im
Palbociclib is a specific inhibitor of CDK4/6 and has been shown to provide a survival benefit in hormone receptor-positive advanced breast cancer. TCGA database reported that about half of gastric cancers exhibit abnormalities in cell-cycle-related molecules, suggesting that gastric cancer is a good candidate for palbociclib treatment; however, the antitumor effects and predictive markers of palbociclib in gastric cancer remain incompletely described. Herein, the effect and predictive markers of palbociclib on gastric cancer cells were investigated...
May 2, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29726995/the-balance-of-pi3k-and-erk-signaling-is-dysregulated-in-prolactinoma-and-modulated-by-dopamine
#18
Allyson K Roof, Siwanon Jirawatnotai, Tammy Trudeau, Crystal Kuzyk, Margaret E Wierman, Hiroaki Kiyokawa, Arthur Gutierrez-Hartmann
Prolactin-secreting adenomas, or prolactinomas, cause hypogonadism, osteoporosis, and infertility. Although dopamine agonists (DAs) are used clinically to treat prolactinoma, and reduce prolactin secretion via cAMP inhibition, the precise mechanism by which DAs inhibit lactotrope proliferation has not been defined. Here we report the novel finding that PI3K signals through AKT and mTOR to drive proliferation of pituitary somatolactotrope GH4T2 cells. We demonstrate that the DA cabergoline reduces activity of the mTOR effector s6K, and diminishes GH4T2 cell proliferation primarily via activation of the long isoform of the dopamine D2 receptor (D2R)...
May 2, 2018: Endocrinology
https://www.readbyqxmd.com/read/29725889/use-of-cyclin-dependent-kinase-cdk-4-6-inhibitors-for-hormone-receptor-positive-human-epidermal-growth-factor-receptor-2-negative-metastatic-breast-cancer-a-roundtable-discussion-by-the-breast-cancer-therapy-expert-group-bcteg
#19
REVIEW
Jame Abraham, Robert Coleman, Anthony Elias, Frankie Ann Holmes, Kevin Kalinsky, Muaiad Kittaneh, Elyse Lower, Reshma Mahtani, E Terry Mamounas, Mark Pegram, Charles Vogel
PURPOSE: To provide an overview of clinical data supporting the use of cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic breast cancer (mBC), from the perspective of the practicing oncologist community. METHODS: A recent roundtable discussion was convened by The Breast Cancer Therapy Expert Group (BCTEG) to review existing data on this topic and its impact on their current practice...
May 4, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29719410/oncogene-mutational-analysis-in-chinese-gastrointestinal-stromal-tumor-patients
#20
Qiong Chen, Rong Li, Zhi-Gao Zhang, Qiao-Ting Deng, Kun Li, Hao Wang, Xue-Xi Yang, Ying-Song Wu
Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors and exhibit a high frequency of oncogenic KIT or PDGFRA mutations. Tyrosine kinase inhibitors (TKIs) have been mainly used in the treatment of GISTs bearing KIT/PDGFRA mutations. However, other mutation profiles have been found to affect the sensitivity to and effectiveness of TKIs in the treatment of GISTs. Purpose: The aim of the present study was to describe the mutational status of multiple genes in GIST samples and to provide information for finding potential predictive markers of therapeutic targets in Chinese GIST patients...
2018: OncoTargets and Therapy
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