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CDK4/6 AND cancer

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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/29784737/nccn-guidelines-updates-breast-cancer
#2
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
#3
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
#4
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
#5
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/29763779/clinical-implications-of-the-non-luminal-intrinsic-subtypes-in-hormone-receptor-positive-breast-cancer
#6
REVIEW
Juan Miguel Cejalvo, Tomás Pascual, Aranzazu Fernández-Martínez, Fara Brasó-Maristany, Roger R Gomis, Charles M Perou, Montserrat Muñoz, Aleix Prat
Gene expression profiling has had a considerable impact on our understanding ofbreastcancer biology. Duringthelast decade, 4 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched [HER2-E] and Basal-like) have been identified and intensively studied. In this article, we review and discuss the clinical implications of the 2 non-luminal subtypes (i.e. HER2-E and Basal-like) identified within hormone receptor (HR)-positive disease. After reviewing 32 studies for a total of 13,091 samples, ∼8% and ∼ 15% of early and metastatic HR+/HER2-negative breast cancer, respectively, were found to be non-luminal...
May 7, 2018: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29743141/chemotherapy-patient-with-stevens-johnson-syndrome-presents-to-the-emergency-department-a-case-report
#7
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
#8
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/29735403/proteins-of-the-retinoblastoma-pathway-fen1-and-mgmt-are-novel-potential-prognostic-biomarkers-in-pancreatic-adenocarcinoma
#9
Joel Isohookana, Kirsi-Maria Haapasaari, Ylermi Soini, Joni Leppänen, Peeter Karihtala
BACKGROUND: We studied the expression of some major proteins involved in cell-cycle regulation and DNA repair, the roles of which are not well known in pancreatic ductal adenocarcinoma (PDAC), but which have a significant impact on carcinogenesis of many other cancers. METHODS: We immunohistochemically assessed expression levels of the cell-cycle regulators Rb1, p16 and cyclin-dependent kinase 4 (CDK4), and the DNA repair enzymes O6-methylguanine-DNA-alkyltransferase (MGMT) and flap endonuclease-1 (FEN1) separately in malignant tissue and benign tissue from resection margins in 102 cases of PDAC...
May 1, 2018: Pathology, Research and Practice
https://www.readbyqxmd.com/read/29731395/cdk4-6-inhibitors-the-mechanism-of-action-may-not-be-as-simple-as-once-thought
#10
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
#11
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/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
#12
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/29716938/dual-mapk-cdk-targeting-in-melanoma-new-approaches-new-challenges
#13
Ryan J Sullivan
<b/> Dual MAPK and CDK4/6 targeting is an emerging strategy in melanoma, but toxicity and acquired resistance are limitations. In this issue, two groups (Teh and colleagues and Romano and colleagues) show that therapeutic resistance mechanisms converge on the PI3K pathway, and inhibition of this pathway's mediators can overcome this resistance. Cancer Discov; 8(5); 532-3. ©2018 AACR See related article by Romano et al., p. 556 See related article by Teh et al., p. 568 .
May 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29716919/abemaciclib-a-selective-cdk4-6-inhibitor-enhances-the-radiosensitivity-of-non-small-cell-lung-cancer-in-vitro-and-in-vivo
#14
Sarwat Naz, Anastasia L Sowers, Rajani Choudhuri, Maria F Wissler, Janet Gamson, Askale Mathias, John A Cook, James B Mitchell
PURPOSE: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of CDK4/6 inhibitor, Abemaciclib in Non-Small Cell Lung Cancer cells (NSCLC) in vitro and in vivo Experimental Design: IR enhancement by Abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR-induced DNA damage repair was evaluated by γ-H2AX analysis. Global metabolic alterations by Abemaciclib and IR combination was evaluated by LC/MS mass spectrometry and YSI-Bioanalyzer...
May 1, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29700711/cyclin-dependent-kinase-4-6-inhibitors-in-hormone-receptor-positive-early-breast-cancer-preliminary-results-and-ongoing-studies
#15
REVIEW
Dorota Kwapisz
The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER-positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed...
April 26, 2018: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29680736/computational-approach-for-generating-robust-models-for-discovering-novel-molecules-as-cyclin-dependent-kinase-4-inhibitors
#16
V Divya, V L Pushpa, S Sarithamol, K B Manoj
Cyclin Dependent Kinase 4 is a striking target for the proposal of anti-cancer drugs since its overexpression is associated with various types of cancers. In the present study, 2D and 3D atom based QSAR study were accomplished with 6 component PLS factor for 230 pyrido[2,3-d]pyramidine correspondents along with flexible ligand docking in the extra precision mode with the application of core constraints followed by the binding energy determinations. Kernel based partial least square analysis fitting with fingerprints initially created worthy models, among which the one with molprint2D fingerprints generated a noble model with a score value of 0...
April 14, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29674428/optimising-endocrine-therapy-in-postmenopausal-women-with-advanced-breast-cancer
#17
Thomas Ho Lai Yau, Kl Cheung
Hormone receptor-positive breast cancer is commonly treated with endocrine therapy; however, overtime cancer cells can develop endocrine resistance. This review aims to document combination therapy and sequential therapy in the use of endocrine agents and targeted agents. By conducting two systematic searches using 4 databases: Cochrane Library, MEDLINE, EMBASE, and Web of Science. A total of 26 studies that covered combination therapy were obtained and included for the review. 14 were phase III documenting combinations of mechanistic target of rapamycin (mTOR), phosphoinositide-3-kinase (PI3K), vascular endothelial growth factor receptor (VEGFR), human epidermal growth factor receptor 2 (HER2), and cyclin dependent kinase 4/6 (CDK4/6) inhibitors...
April 19, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29670855/current-therapies-for-human-epidermal-growth-factor-receptor-2-positive-metastatic-breast-cancer-patients
#18
REVIEW
Alexey A Larionov
The median survival of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) has more than doubled, since the discovery of HER2-targeted treatments: it rose from less than 2 years in 2001 (prior introduction of trastuzumab) to more than 4 years in 2017. The initial generation of HER2-targeted therapies included trastuzumab with taxanes in the first line, followed by the addition of lapatinib and by a switch to another cytotoxic agent after progression. Results of CLEOPATRA, EMILIA, and TH3RESA trials have changed this clinical practice...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29670090/inhibition-of-cyclin-dependent-kinase-4-as-a-potential-therapeutic-strategy-for-treatment-of-synovial-sarcoma
#19
Xiaoyang Li, Nicole A Seebacher, Cassandra Garbutt, Hangzhan Ma, Peng Gao, Tao Xiao, Francis J Hornicek, Zhenfeng Duan
Synovial sarcoma is a highly aggressive but rare form of soft tissue malignancy that primarily affects the extremities of the arms or legs, for which current chemotherapeutic agents have not been proven to be very effective. The cyclin-dependent kinase 4/6-retinoblastoma protein (CDK4/6-Rb) pathway of cell cycle control is known to be aberrant in a large proportion of cancers. Recently, CDK4 inhibitors have successfully been used pre-clinically for the treatment of many human cancers, and in 2015, following the success of clinical trials, the FDA approved the first selective CDK4/6 inhibitor, palbociclib, for the treatment of endocrine therapy resistant breast cancers...
April 18, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29669860/thermal-proteome-profiling-of-breast-cancer-cells-reveals-proteasomal-activation-by-cdk4-6-inhibitor-palbociclib
#20
Teemu P Miettinen, Julien Peltier, Anetta Härtlova, Marek Gierliński, Valerie M Jansen, Matthias Trost, Mikael Björklund
Palbociclib is a CDK4/6 inhibitor approved for metastatic estrogen receptor-positive breast cancer. In addition to G1 cell cycle arrest, palbociclib treatment results in cell senescence, a phenotype that is not readily explained by CDK4/6 inhibition. In order to identify a molecular mechanism responsible for palbociclib-induced senescence, we performed thermal proteome profiling of MCF7 breast cancer cells. In addition to affecting known CDK4/6 targets, palbociclib induces a thermal stabilization of the 20S proteasome, despite not directly binding to it...
April 18, 2018: EMBO Journal
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