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Palbociclib

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https://www.readbyqxmd.com/read/29342248/clinical-considerations-of-the-role-of-palbociclib-in-the-management-of-advanced-breast-cancer-patients-with-and-without-visceral-metastases
#1
N C Turner, R S Finn, M Martin, S-A Im, A DeMichele, J Ettl, V Diéras, S Moulder, O Lipatov, M Colleoni, M Cristofanilli, D R Lu, A Mori, C Giorgetti, S Iyer, C Huang Bartlett, K A Gelmon
Background: This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods: Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N=521) and postmenopausal women untreated for ABC (PALOMA-2; N=666) were randomized 2:1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo...
January 11, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29338448/the-safety-of-palbociclib-for-the-treatment-of-advanced-breast-cancer
#2
Tom Degenhardt, Rachel Wuerstlein, Tanja Eggersmann, Nadia Harbeck
Despite improvements in the diagnosis and management of early stage breast cancer, about one third of the patients still progress to metastatic disease. Most of the patients with metastatic breast cancer have a hormone receptor positive and human epidermal growth factor receptor 2 negative subtype with a median survival of more than 3 years. For these patients, endocrine therapy with its favorable toxicity profile is the current standard of care. However, patients with metastatic breast cancer have an incurable disease...
January 17, 2018: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29337187/metabolomics-reveals-that-dietary-xenoestrogens-alter-cellular-metabolism-induced-by-palbociclib-letrozole-combination-cancer-therapy
#3
Benedikt Warth, Philipp Raffeiner, Ana Granados, Tao Huan, Mingliang Fang, Erica M Forsberg, H Paul Benton, Laura Goetz, Caroline H Johnson, Gary Siuzdak
Recently, the palbociclib/letrozole combination therapy was granted accelerated US FDA approval for the treatment of estrogen receptor (ER)-positive breast cancer. Since the underlying metabolic effects of these drugs are yet unknown, we investigated their synergism at the metabolome level in MCF-7 cells. As xenoestrogens interact with the ER, we additionally aimed at deciphering the impact of the phytoestrogen genistein and the estrogenic mycotoxin zearalenone. A global metabolomics approach was applied to unravel metabolite and pathway modifications...
January 10, 2018: Cell Chemical Biology
https://www.readbyqxmd.com/read/29335521/non-canonical-roles-of-pfkfb3-in-regulation-of-cell-cycle-through-binding-to-cdk4
#4
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
#5
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/29326029/neoadjuvant-treatment-with-trastuzumab-and-pertuzumab-plus-palbociclib-and-fulvestrant-in-her2-positive-er-positive-breast-cancer-na-pher2-an-exploratory-open-label-phase-2-study
#6
Luca Gianni, Giancarlo Bisagni, Marco Colleoni, Lucia Del Mastro, Claudio Zamagni, Mauro Mansutti, Milvia Zambetti, Antonio Frassoldati, Raffaella De Fato, Pinuccia Valagussa, Giuseppe Viale
BACKGROUND: In the neoadjuvant setting, blockade of HER2 plus use of an aromatase inhibitor in patients with HER2-positive and oestrogen receptor (ER)-positive breast cancer leads to a pathological complete response in 21% of patients. Convergence of HER2 and ER signals on RB1 suggests that a combined pharmacological intervention directed to these targets could be synergistic. To test this approach, we combined palbociclib to block RB1, fulvestrant to block ER, and trastuzumab with pertuzumab to block HER2 in patients with HER2-positive, ER-positive breast cancer...
January 8, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29311118/therapeutic-challenge-with-a-cdk-4-6-inhibitor-induces-an-rb-dependent-smac-mediated-apoptotic-response-in-non-small-cell-lung-cancer
#7
Chellappagounder Thangavel, Ettickan Boopathi, Yi Liu, Christopher McNair, Alex Haber, Maryna Perepelyuk, Anshul Bhardwaj, Sankar Addya, Adam Ertel, Sunday Shoyele, Ruth Birbe, Joseph M Salvino, Adam P Dicker, Karen E Knudsen, Robert B Den
The retinoblastoma tumor suppressor (RB), a key regulator of cell cycle progression and proliferation, is functionally suppressed in up to 50% of non-small cell lung cancer (NSCLC).  RB function is exquisitely controlled by a series of proteins including the CyclinD-CDK4/6 complex. In the current study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.   Experimental Design and Results: We employed multiple isogenic RB proficient and deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo  We demonstrate that while short term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth...
January 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29307217/subacute-cutaneous-lupus-erythematosus-induced-by-palbociclib
#8
Joanie Pinard, Mital Patel, Scott R Granter, Ruth Ann Vleugels, Joseph F Merola
No abstract text is available yet for this article.
January 1, 2018: Journal of Cutaneous Medicine and Surgery
https://www.readbyqxmd.com/read/29306306/use-of-oral-antineoplastic-in-special-situations-in-a-third-level-hospital-real-life-results
#9
Carmen Garcia-Muñoz, Pedro Pablo Rodriguez-Quesada, José Miguel Ferrari-Piquero
OBJECTIVE: To analyse the effectiveness and safety of oral antineoplastic drugs  (ANEOs) that are authorized in special situations in a third-level hospital and to  compare the results obtained with the clinical evidence used for this  authorization. METHOD: Descriptive observational and retrospective study. We included all  adult patients who started treatment with ANEO in special situations during the  year 2016. We collected demographic, treatment-related and clinical variables  (overall survival (OS), progression-free survival (PFS))...
January 1, 2018: Farmacia Hospitalaria
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
#10
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/29291023/combined-venetoclax-and-alvocidib-in-acute-myeloid-leukemia
#11
James Bogenberger, Clifford Whatcott, Nanna Hansen, Devora Delman, Chang-Xin Shi, Wontak Kim, Hillary Haws, Katherine Soh, Ye Sol Lee, Peter Peterson, Adam Siddiqui-Jain, Steven Weitman, Keith Stewart, David Bearss, Ruben Mesa, Steven Warner, Raoul Tibes
More effective treatment options for elderly acute myeloid leukemia (AML) patients are needed as only 25-50% of patients respond to standard-of-care therapies, response duration is typically short, and disease progression is inevitable even with some novel therapies and ongoing clinical trials. Anti-apoptotic BCL-2 family inhibitors, such as venetoclax, are promising therapies for AML. Nonetheless, resistance is emerging. We demonstrate that venetoclax combined with cyclin-dependent kinase (CDK) inhibitor alvocidib is potently synergistic in venetoclax-sensitive and -resistant AML models in vitro, ex vivo and in vivo...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29283884/a-hypothesis-driven-approach-identifies-cdk4-and-cdk6-inhibitors-as-candidate-drugs-for-treatments-of-adrenocortical-carcinomas
#12
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/29261702/combination-of-palbociclib-with-enzalutamide-shows-in-vitro-activity-in-rb-proficient-and-androgen-receptor-positive-triple-negative-breast-cancer-cells
#13
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/29247857/a-highly-potent-cdk4-6-inhibitor-was-rationally-designed-to-overcome-blood-brain-barrier-in-gliobastoma-therapy
#14
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/29247442/efficacy-of-palbociclib-plus-fulvestrant-after-everolimus-in-hormone-receptor-positive-metastatic-breast-cancer
#15
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/29247039/h3b-6527-is-a-potent-and-selective-inhibitor-of-fgfr4-in-fgf19-driven-hepatocellular-carcinoma
#16
Jaya Julie Joshi, Heather Coffey, Erik Corcoran, Jennifer Tsai, Chia-Ling Huang, Kana Ichikawa, Sudeep Prajapati, Ming-Hong Hao, Suzanna Bailey, Jeremy Wu, Victoria Rimkunas, Craig Karr, Vanitha Subramanian, Pavan Kumar, Crystal MacKenzie, Raelene Hurley, Takashi Satoh, Kun Yu, Eunice Park, Nathalie Rioux, Amy Kim, Weidong G Lai, Lihua Yu, Ping Zhu, Silvia Buonamici, Nicholas Larsen, Peter Fekkes, John Wang, Markus Warmuth, Dominic J Reynolds, Peter G Smith, Anand Selvaraj
Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response...
December 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/29243224/palbociclib-synergizes-with-braf-and-mek-inhibitors-in-treatment-na%C3%A3-ve-melanoma-but-not-after-the-development-of-braf-inhibitor-resistance
#17
Claire A Martin, Carleen Cullinane, Laura Kirby, Shatha Abuhammad, Emily J Lelliott, Kelly Waldeck, Richard J Young, Natalie Brajanovski, Donald P Cameron, Rachael Walker, Elaine Sanij, Gretchen Poortinga, Ross D Hannan, Richard B Pearson, Rodney J Hicks, Grant A McArthur, Karen E Sheppard
Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination were assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors...
December 15, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29240261/mitochondrial-dysfunction-rad51-and-ku80-proteolysis-promote-apoptotic-effects-of-dinaciclib-in-bcl-xl-silenced-cells
#18
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
#19
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
#20
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
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