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CDk4/6 and Breast

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https://www.readbyqxmd.com/read/29352052/estrogen-receptor-positive-breast-cancer-exploiting-signaling-pathways-implicated-in-endocrine-resistance
#1
REVIEW
Adam M Brufsky, Maura N Dickler
Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) pathogenesis and hold promising implications for the future of therapy. The estrogen receptor-α is a predominant endocrine regulatory protein in the breast and in estrogen-induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal...
January 19, 2018: Oncologist
https://www.readbyqxmd.com/read/29349755/adjuvant-endocrine-therapy
#2
Rena Shah, Ruth M O'Regan
The use of hormonal therapy in breast cancer has improved the overall outcome for patients with early-stage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hormone therapy. Ongoing studies are evaluating the role of additional targeted therapies, such as CDK4/6 inhibitors, to further improve outcome for patients with early-stage hormone receptor-positive breast cancer...
2018: Cancer Treatment and Research
https://www.readbyqxmd.com/read/29335521/non-canonical-roles-of-pfkfb3-in-regulation-of-cell-cycle-through-binding-to-cdk4
#3
Wenzhi Jia, Xiaoping Zhao, Li Zhao, Hui Yan, Jiajin Li, Hao Yang, Gang Huang, Jianjun Liu
There is growing interest in studying the molecular mechanisms of crosstalk between cancer metabolism and the cell cycle. 6-phosphate fructose-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) is a well-known glycolytic activator that plays an important role in tumorigenesis. We investigated whether PFKFB3 was directly involved in oncogenic signaling networks. Mass Spectrometry showed that PFKFB3 interacts with cyclin-dependent kinase (CDK) 4, which controls the transition from G1 phase to S phase of the cell cycle...
January 16, 2018: Oncogene
https://www.readbyqxmd.com/read/29330290/dual-inhibition-of-cdk4-and-cdk2-via-targeting-p27-tyrosine-phosphorylation-induces-a-potent-and-durable-response-in-breast-cancer-cells
#4
Priyank Patel, Vladislav Tsiperson, Susan R S Gottesman, Jonathan Somma, Stacy W Blain
Cyclin-dependent kinase 4/6 (CDK4/6) specific inhibitors, such as Palbociclib, have shown clinical efficacy, but primary or secondary resistance has emerged as a problem. To develop more effective therapeutic approaches, investigation is needed into the mechanisms of resistance or adaption. Here, it is demonstrated that CDK2 compensates for loss of CDK4 activity to rescue Palbociclib-arrested breast cancer cells, suggesting that inhibition of both kinases is required to achieve durable response. In addition, a novel strategy is described to inhibit tyrosine phosphorylation of p27Kip1 (CDKN1B) and simultaneously inhibit both CDK2 and CDK4...
January 12, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29282688/cell-cycle-regulation-in-treatment-of-breast-cancer
#5
Zijie Cai, Qiang Liu
Cell cycle progression and cell proliferation are under precise and orchestrated control in normal cells. However, uncontrolled cell proliferation caused by aberrant cell cycle progression is a crucial characteristic of cancer. Understanding cell cycle progression and its regulation sheds light on cancer treatment. Agents targeting cell cycle regulators (such as CDKs) have been considered as promising candidates in cancer treatment. Although the first-generation pan-CDK inhibitors failed in clinical trials because of their adverse events and low efficacy, new selective CDK 4/6 inhibitors showed potent efficacy with tolerable safety in preclinical and clinical studies...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29261702/combination-of-palbociclib-with-enzalutamide-shows-in-vitro-activity-in-rb-proficient-and-androgen-receptor-positive-triple-negative-breast-cancer-cells
#6
Chun-Yu Liu, Ka-Yi Lau, Chia-Chi Hsu, Ji-Lin Chen, Chia-Han Lee, Tzu-Ting Huang, Yi-Ting Chen, Chun-Teng Huang, Po-Han Lin, Ling-Ming Tseng
OBJECTIVES: Triple negative breast cancer (TNBC) lacks specific drug targets and remains challenging. Palbociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is approved for metastatic estrogen receptor (ER)-positive and human epithermal growth factor 2 (HER2)-negative breast cancer. The nature of cell cycle inhibition by palbociclib suggests its potential in TNBC cells. Retinoblastoma (RB, a known substrate of CDK4/6) pathway deregulation is a frequent occurrence in TNBC and studies have revealed that pharmacological CDK4/6 inhibition induces a cooperative cytostatic effect with doxorubicin in RB-proficient TNBC models...
2017: PloS One
https://www.readbyqxmd.com/read/29250202/asco-2017-highlights-in-breast-cancer
#7
REVIEW
Rupert Bartsch, Elisabeth Bergen
At the 2017 ASCO Annual Meeting, several pertinent studies in the field of breast cancer were presented and some are deemed as being potentially practice changing. BrighTNess was the first phase III study to investigate the addition of carboplatin to standard neoadjuvant chemotherapy in triple-negative breast cancer; while toxicity was increased in the experimental group, a significantly higher pathologic complete remission (pCR) rate was observed as well suggesting that adding carboplatin to neoadjuvant anthracycline, cyclophosphamide and taxane-containing regimens is efficacious in otherwise healthy patients...
2017: Memo
https://www.readbyqxmd.com/read/29247442/efficacy-of-palbociclib-plus-fulvestrant-after-everolimus-in-hormone-receptor-positive-metastatic-breast-cancer
#8
Pauline du Rusquec, Clément Palpacuer, Loic Campion, Anne Patsouris, Paule Augereau, Carole Gourmelon, Marie Robert, Laurence Dumas, Folliard Caroline, Mario Campone, Jean-Sébastien Frenel
BACKGROUND: Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. METHODS: From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed...
December 15, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29236940/polyclonal-rb1-mutations-and-acquired-resistance-to-cdk-4-6-inhibitors-in-patients-with-metastatic-breast-cancer
#9
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
#10
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/29234249/mechanisms-of-resistance-to-cdk4-6-inhibitors-in-breast-cancer-and-potential-biomarkers-of-response
#11
REVIEW
Cristina Guarducci, Martina Bonechi, Giulia Boccalini, Matteo Benelli, Emanuela Risi, Angelo Di Leo, Luca Malorni, Ilenia Migliaccio
Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting...
October 2017: Breast Care
https://www.readbyqxmd.com/read/29234248/incorporating-cdk4-6-inhibitors-in-the-treatment-of-advanced-luminal-breast-cancer
#12
REVIEW
Isabel Echavarria, Yolanda Jerez, Miguel Martin, Sara López-Tarruella
After optimizing endocrine monotherapy modalities in the setting of advanced luminal breast cancer (BC), dual endocrine/targeted therapy combinations have been tested with positive results, and are transforming this BC subtype treatment landscape. Cell cycle deregulation is a hallmark of cancer that has become a key druggable target in hormone receptor (HR)-positive BC due to its role in endocrine resistance mechanisms. Cyclin dependent kinase (CDK)4/6 inhibitors have experienced a fast development in combination with endocrine therapy and have already been commercialized in some countries...
October 2017: Breast Care
https://www.readbyqxmd.com/read/29232554/genomic-aberrations-that-activate-d-type-cyclins-are-associated-with-enhanced-sensitivity-to-the-cdk4-and-cdk6-inhibitor-abemaciclib
#13
Xueqian Gong, Lacey M Litchfield, Yue Webster, Li-Chun Chio, Swee Seong Wong, Trent R Stewart, Michele Dowless, Jack Dempsey, Yi Zeng, Raquel Torres, Karsten Boehnke, Cecilia Mur, Carlos Marugán, Carmen Baquero, Chunping Yu, Steven M Bray, Isabella H Wulur, Chen Bi, Shaoyou Chu, Hui-Rong Qian, Philip W Iversen, Farhana F Merzoug, Xiang S Ye, Christoph Reinhard, Alfonso De Dios, Jian Du, Charles W Caldwell, María José Lallena, Richard P Beckmann, Sean G Buchanan
Most cancers preserve functional retinoblastoma (Rb) and may, therefore, respond to inhibition of D-cyclin-dependent Rb kinases, CDK4 and CDK6. To date, CDK4/6 inhibitors have shown promising clinical activity in breast cancer and lymphomas, but it is not clear which additional Rb-positive cancers might benefit from these agents. No systematic survey to compare relative sensitivities across tumor types and define molecular determinants of response has been described. We report a subset of cancers highly sensitive to CDK4/6 inhibition and characterized by various genomic aberrations known to elevate D-cyclin levels and describe a recurrent CCND1 3'UTR mutation associated with increased expression in endometrial cancer...
December 11, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29229752/ribociclib-extends-survival-in-hr-breast-cancer
#14
(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/29218622/inhibiting-cdk-in-cancer-therapy-current-evidence-and-future-directions
#15
REVIEW
Smruthi Vijayaraghavan, Stacy Moulder, Khandan Keyomarsi, Rachel M Layman
Cell cycle dysregulation is a hallmark of all cancers, resulting in uncontrolled proliferation. Cyclin dependent kinases (CDKs), a family of proteins that are involved in the regulation of the cell cycle, are frequently overexpressed or mutated in cancer. Hence, CDK-inhibiting drugs have been developed and evaluated as cancer therapeutics. Clinical trials have shown CDK4/6 inhibitors (CDK4/6i) to be relatively safe and effective, and these are now standard of care treatment for advanced hormone receptor positive breast cancer...
December 7, 2017: Targeted Oncology
https://www.readbyqxmd.com/read/29188531/mir-519d-3p-suppresses-breast-cancer-cell-growth-and-motility-via-targeting-lim-domain-kinase-1
#16
Dengfeng Li, Hongming Song, Tianqi Wu, Dan Xie, Jiashu Hu, Junyong Zhao, Qiang Shen, Lin Fang
Breast cancer is the most common female cancer in women, and its estrogen receptor (ER)-negative subtype (ENBC) and triple-negative subtype (TNBC) have unfavorable prognosis in comparison with ER-positive subtype. MiRNAs are small noncoding RNAs that bind to the 3'-UTR region of targeting mRNAs to regulate gene expression. Mir-519d-3p was found to be associated with breast cancer for its potential role in proliferation and metastasis. To explore its potential role and mechanism of miR-519d-3p in breast carcinogenesis, we determined whether miR-519d-3p regulates breast cancer cell proliferation and motility by performing wound-healing assays and migration-invasion assays...
November 29, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/29177689/expression-of-cyclin-d1-protein-in-residual-tumor-after-neoadjuvant-chemotherapy-for-breast-cancer
#17
S L Villegas, S Darb-Esfahani, G von Minckwitz, J Huober, K Weber, F Marmé, J Furlanetto, C Schem, B M Pfitzner, B Lederer, K Engels, S Kümmel, V Müller, K Mehta, C Denkert, S Loibl
PURPOSE: Hormone receptor (HR)-positive breast cancer (BC) shows a poor response to neoadjuvant chemotherapy (NACT). New treatment targets like the Cyclin D1-CDK4/CDK6 complex are promising adjuvant/post-neoadjuvant therapeutic strategies. Evaluating Cyclin D1 overexpression in residual tumor could recognize those patients that benefit most from such post-neoadjuvant treatment. In this study, we determined Cyclin D1 expression in residual BC after NACT. Secondary aims were to correlate Cyclin D1 expression levels with clinicopathological parameters and to assess its prognostic value after NACT...
November 25, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29164917/efficacy-and-safety-of-palbociclib-in-heavily-pretreated-patients-with-hr-her2-%C3%A2-metastatic-breast-cancer
#18
Marija Ban, Branka Petrić Miše, Ana Majić, Ivanka Dražić, Eduard Vrdoljak
AIM: CDK4/6 inhibitors in the first and second treatment line in patients with HR+/HER2- metastatic breast cancer (mBC) in combination with hormonal therapy improve progression free survival. Role of CDK4/6 inhibitors in further treatment lines remains unclear. METHODS: Retrospective analysis of 24 HR+/HER2- heavily pretreated mBC patients is presented. RESULTS: A total of 58.3% patients achieved stable disease. No objective response was observed...
November 22, 2017: Future Oncology
https://www.readbyqxmd.com/read/29162134/serum-thymidine-kinase-1-activity-as-a-pharmacodynamic-marker-of-cyclin-dependent-kinase-4-6-inhibition-in-patients-with-early-stage-breast-cancer-receiving-neoadjuvant-palbociclib
#19
Nusayba Bagegni, Shana Thomas, Ning Liu, Jingqin Luo, Jeremy Hoog, Donald W Northfelt, Matthew P Goetz, Andres Forero, Mattias Bergqvist, Jakob Karen, Magnus Neumüller, Edward M Suh, Zhanfang Guo, Kiran Vij, Souzan Sanati, Matthew Ellis, Cynthia X Ma
BACKGROUND: Thymidine kinase 1 (TK1) is a cell cycle-regulated enzyme with peak expression in the S phase during DNA synthesis, and it is an attractive biomarker of cell proliferation. Serum TK1 activity has demonstrated prognostic value in patients with early-stage breast cancer. Because cyclin-dependent kinase 4/6 (CDK4/6) inhibitors prevent G1/S transition, we hypothesized that serum TK1 could be a biomarker for CDK4/6 inhibitors. We examined the drug-induced change in serum TK1 as well as its correlation with change in tumor Ki-67 levels in patients enrolled in the NeoPalAna trial (ClinicalTrials...
November 21, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29147869/hematological-adverse-effects-in-breast-cancer-patients-treated-with-cyclin-dependent-kinase-4-and-6-inhibitors-a-systematic-review-and-meta-analysis
#20
REVIEW
Loay Kassem, Kyrillus S Shohdy, Shaimaa Lasheen, Omar Abdel-Rahman, Thomas Bachelot
BACKGROUND: The introduction of specific cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors significantly improved progression-free survival in hormone receptor-positive metastatic breast cancer. CDK 4/6 inhibitors induce cell cycle arrest via liberating the tumor suppressor retinoblastoma protein from CDK4/6 inhibitory effect. Preliminary studies suggested an increase in the hematological toxicities which might affect the quality of life in such palliative setting. METHODS: We searched PubMed, ASCO, ESMO and San Antonio meeting databases for randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors with safety data provided on the incidence of hematological adverse effects...
November 16, 2017: Breast Cancer: the Journal of the Japanese Breast Cancer Society
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