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https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#1
REVIEW
Ciara C O'Sullivan, Nicole N Davarpanah, Jame Abraham, Susan E Bates
Approximately 50% of patients with advanced human epidermal growth factor 2 (HER2)-positive breast cancer and triple-negative breast cancer (TNBC) ultimately develop breast cancer brain metastases (BCBM), which are associated with significant morbidity and mortality. The advent of HER2-directed therapy resulted in greatly improved survival outcomes, but unfortunately at the price of an increased cumulative incidence of BCBM. We review challenges in the management of BCBM, and potential treatment strategies, including novel agents such as poly-adenosine diphosphate (ADP) ribose polymerase (PARP) inhibitors (olaparib, veliparib), cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib, abemaciclib), and taxane derivatives (eg, ANG1005 and TPI-287)...
April 2017: Seminars in Oncology
https://www.readbyqxmd.com/read/28918692/the-cyclin-dependent-kinase-4-6-inhibitor-abemaciclib-exerts-dose-dependent-cytostatic-and-cytocidal-effects-and-induces-autophagy-in-multiple-myeloma-cells
#2
Noriyoshi Iriyama, Hirotsugu Hino, Shota Moriya, Masaki Hiramoto, Yoshihiro Hatta, Masami Takei, Keisuke Miyazawa
The D-type cyclin (CCND)-cyclin-dependent kinase 4/6 (CDK4/6) complex has been implicated in multiple myeloma development. We investigated the biological activity of CDK4/6 inhibitor abemaciclib on cell growth and survival in three myeloma cell lines, KMS-12-PE, RPMI 8226, and IM-9. Abemaciclib inhibited myeloma cell growth in a dose-dependent manner in all cell lines, with significant differences seen at a concentration of 320 nM. Treatment with 1 μM abemaciclib increased the fraction of cells in the G0/G1 phase and decreased the fraction in the S-G2/M phases...
September 18, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28758424/ribociclib-for-the-treatment-of-advanced-hormone-receptor-positive-her2-negative-breast-cancer
#3
Sara López-Tarruella, Yolanda Jerez, Iván Márquez-Rodas, Isabel Echavarria, Miguel Martin
CDK4/6 inhibitors are a promising new class of drugs for hormone-receptor-positive breast cancer and have been shown to overcome and delay hormone resistance in advanced breast cancer. Ribociclib, a selective oral inhibitor of CDK4/6, was approved by the US FDA for first-line treatment of hormone-receptor-positive/HER2-negative metastatic breast cancer. This review summarizes the clinical evidence available for ribociclib, from preclinical data to the pivotal studies, with a special focus on toxicity and its management...
July 31, 2017: Future Oncology
https://www.readbyqxmd.com/read/28741274/cyclin-dependent-kinase-4-6-inhibitors-in-breast-cancer-palbociclib-ribociclib-and-abemaciclib
#4
REVIEW
Dorota Kwapisz
PURPOSE: The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression and its dysregulation is an important contributor to endocrine therapy resistance. CDK4/6 inhibitors trigger cell cycle arrest in Rb protein (pRb)-competent cells. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising results of efficacy and manageable safety profiles. The main objective of this review is to discuss preclinical and clinical data to date, and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in breast cancer...
July 24, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28706010/clinical-management-of-potential-toxicities-and-drug-interactions-related-to-cyclin-dependent-kinase-4-6-inhibitors-in-breast-cancer-practical-considerations-and-recommendations
#5
REVIEW
Laura M Spring, Mark L Zangardi, Beverly Moy, Aditya Bardia
Aberrations of the cell cycle are pervasive in cancer, and selective cell cycle inhibition of cancer cells is a target of choice for a number of novel cancer therapeutics. Cyclin-dependent kinases (CDKs) are key regulatory enzymes that control cell cycle transitions and the commitment to cell division. Palbociclib and ribociclib are both orally active, highly selective reversible inhibitors of CDK4 and CDK6 that are approved by the U.S. Food and Drug Administration (FDA) for hormone receptor-positive metastatic breast cancer in combination with specific endocrine therapies...
September 2017: Oncologist
https://www.readbyqxmd.com/read/28657360/a-current-and-comprehensive-review-of-cyclin-dependent-kinase-inhibitors-for-the-treatment-of-metastatic-breast-cancer
#6
Burak Bilgin, Mehmet A N Sendur, Didem Şener Dede, Muhammed Bülent Akıncı, Bülent Yalçın
BACKGROUND: Resistance to endocrine treatment generally occurs over time, especially in the metastatic stage. In this paper, we aimed to review the mechanisms of cyclin-dependent kinase (CDK) 4/6 inhibition and clinical usage of new agents in the light of recent literature updates. SCOPE: A literature search was carried out using PubMed, Medline and ASCO and ESMO annual-meeting abstracts by using the following search keywords; "palbociclib", "abemaciclib", "ribociclib", "cyclin-dependent kinase inhibitors" and "CDK 4/6" in metastatic breast cancer (MBC)...
July 25, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28620137/biological-specificity-of-cdk4-6-inhibitors-dose-response-relationship-in-vivo-signaling-and-composite-response-signature
#7
Erik S Knudsen, Jack Hutcheson, Paris Vail, Agnieszka K Witkiewicz
Recently developed potent and selective CDK4/6 inhibitors fall into two classes based on structure and toxicity profiles in clinical studies. One class, exemplified by palbociclib and ribociclib, exhibits neutropenia as a dose-limiting toxicity and requires discontinuous dosing. In contrast, the structurally distinct CDK4/6 inhibitor abemaciclib is dosed continuously, and has diarrhea and fatigue as dose-limiting toxicities. In preclinical models, palbociclib has been extensively studied and induces cell cycle inhibition in an RB-dependent manner...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28580882/monarch-2-abemaciclib-in-combination-with-fulvestrant-in-women-with-hr-her2-advanced-breast-cancer-who-had-progressed-while-receiving-endocrine-therapy
#8
RANDOMIZED CONTROLLED TRIAL
George W Sledge, Masakazu Toi, Patrick Neven, Joohyuk Sohn, Kenichi Inoue, Xavier Pivot, Olga Burdaeva, Meena Okera, Norikazu Masuda, Peter A Kaufman, Han Koh, Eva-Maria Grischke, Martin Frenzel, Yong Lin, Susana Barriga, Ian C Smith, Nawel Bourayou, Antonio Llombart-Cussac
Purpose MONARCH 2 ( ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC). Patients and Methods MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease...
September 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28580868/cell-cycle-therapeutics-come-of-age
#9
REVIEW
Matthew Ingham, Gary K Schwartz
The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy...
September 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28540640/a-population-pharmacokinetic-and-pharmacodynamic-analysis-of-abemaciclib-in-a-phase-i-clinical-trial-in-cancer-patients
#10
Sonya C Tate, Amanda K Sykes, Palaniappan Kulanthaivel, Edward M Chan, P Kellie Turner, Damien M Cronier
BACKGROUND AND OBJECTIVES: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated clinical activity in a number of different cancer types. The objectives of this study were to characterize the pharmacokinetics of abemaciclib in cancer patients using population pharmacokinetic (popPK) modeling, and to evaluate target engagement at clinically relevant dose levels. METHODS: A phase I study was conducted in cancer patients which incorporated intensive pharmacokinetic sampling after single and multiple oral doses of abemaciclib...
May 24, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28537883/preclinical-characterization-of-abemaciclib-in-hormone-receptor-positive-breast-cancer
#11
Raquel Torres-Guzmán, Bruna Calsina, Ana Hermoso, Carmen Baquero, Beatriz Alvarez, Joaquín Amat, Ann M McNulty, Xueqian Gong, Karsten Boehnke, Jian Du, Alfonso de Dios, Richard P Beckmann, Sean Buchanan, María José Lallena
Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for CDK4 and CDK6 that has shown antitumor activity as a single agent in hormone receptor positive (HR+) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using in vitro and in vivo breast cancer models. Treatment of estrogen receptor positive (ER+) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28533223/monarch-1-a-phase-ii-study-of-abemaciclib-a-cdk4-and-cdk6-inhibitor-as-a-single-agent-in-patients-with-refractory-hr-her2-metastatic-breast-cancer
#12
Maura N Dickler, Sara M Tolaney, Hope S Rugo, Javier Cortés, Véronique Diéras, Debra Patt, Hans Wildiers, Clifford A Hudis, Joyce O'Shaughnessy, Esther Zamora, Denise A Yardley, Martin Frenzel, Andrew Koustenis, José Baselga
Purpose: The phase II MONARCH 1 study was designed to evaluate the single-agent activity and adverse event (AE) profile of abemaciclib, a selective inhibitor of CDK4 and CDK6, in women with refractory hormone receptor-positive (HR(+)), HER2(-) metastatic breast cancer (MBC).Experimental Design: MONARCH 1 was a phase II single-arm open-label study. Women with HR(+)/HER2(-) MBC who had progressed on or after prior endocrine therapy and had 1 or 2 chemotherapy regimens in the metastatic setting were eligible. Abemaciclib 200 mg was administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicity...
September 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28453226/palbociclib-induces-activation-of-ampk-and-inhibits-hepatocellular-carcinoma-in-a-cdk4-6-independent-manner
#13
Feng-Shu Hsieh, Yao-Li Chen, Man-Hsin Hung, Pei-Yi Chu, Ming-Hsien Tsai, Li-Ju Chen, Yung-Jen Hsiao, Chih-Ting Shih, Mao-Ju Chang, Tzu-I Chao, Chung-Wai Shiau, Kuen-Feng Chen
Palbociclib, a CDK4/6 inhibitor, has recently been approved for hormone receptor-positive breast cancer patients. The effects of palbociclib as a treatment for other malignancies, including hepatocellular carcinoma (HCC), are of great clinical interest and are under active investigation. Here, we report the effects and a novel mechanism of action of palbociclib in HCC. We found that palbociclib induced both autophagy and apoptosis in HCC cells through a mechanism involving 5' AMP-activated protein kinase (AMPK) activation and protein phosphatase 5 (PP5) inhibition...
August 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28438180/recent-advances-of-highly-selective-cdk4-6-inhibitors-in-breast-cancer
#14
REVIEW
Hanxiao Xu, Shengnan Yu, Qian Liu, Xun Yuan, Sridhar Mani, Richard G Pestell, Kongming Wu
Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219)...
April 24, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28359238/hr-her2-advanced-breast-cancer-and-cdk4-6-inhibitors-mode-of-action-clinical-activity-and-safety-profiles
#15
Sarah L Sammons, Donna L Topping, Kimberly L Blackwell
Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapies have shown great promise in improving clinical outcomes for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Addition of a CDK4/6 inhibitor to endocrine therapy increases efficacy and delays disease progression. Successful use of CDK4/6 inhibitor-based therapies in the clinic requires insight into the unique side-effect profiles of this class of agents and effective patient monitoring...
March 30, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28351928/ribociclib-lee011-mechanism-of-action-and-clinical-impact-of-this-selective-cyclin-dependent-kinase-4-6-inhibitor-in-various-solid-tumors
#16
REVIEW
Debu Tripathy, Aditya Bardia, William R Sellers
The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here, we describe the mechanism of action of ribociclib and review preclinical and clinical data from phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors...
March 28, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28197838/the-growing-role-of-cdk4-6-inhibitors-in-treating-hormone-receptor-positive-advanced-breast-cancer
#17
REVIEW
Ami N Shah, Massimo Cristofanilli
Single-agent endocrine therapy has been the standard therapeutic choice for the management of hormone receptor (HR)-positive, Her2-negative advanced breast cancer (ABC) for decades. However, the rapidly accumulating data regarding the biological role and safety of CDK4/6 inhibitors and the first-in-class approval of palbociclib have made these novel agents an essential component of treatment for HR-positive ABC. In the frontline setting, palbociclib in combination with endocrine therapy showed an improvement in progression-free survival (PFS) by 10 months to nearly 25 months when compared with endocrine therapy alone and a clinical benefit rate (CBR = stable disease >24 weeks + partial response + complete response) of 85%...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28126188/-cell-cycle-inhibitors-in-endocrine-receptor-positive-breast-cancer
#18
Marie-Paule Sablin, Francesco Ricci, Delphine Loirat, Aude Jobard, Clémence Basse, Emanuela Romano, Christophe Le Tourneau, Véronique Dieras
Dysregulation of cellular cycle is a key component of carcinogenesis and its targeting represents an interesting approach. Recently, the development of selective inhibitors of the cycle targeting the cyclin-dependent kinases (CDK) 4 and 6 revived interest in this therapeutic class after the failure of pan-inhibitors. Palbociclib, ribociclib, and abemaciclib are the 3 drugs with the most advanced development. They demonstrated preclinical activity in luminal breast cancer models and are under clinical evaluation...
February 2017: Bulletin du Cancer
https://www.readbyqxmd.com/read/27986713/abemaciclib-shows-promise-for-early-breast-cancer
#19
(no author information available yet)
Treatment with the CDK4/6 inhibitor abemaciclib, alone or in combination with endocrine therapy, significantly lowered expression of the protein Ki67-a key marker of cell proliferation-in women with hormone receptor-positive, HER2-negative breast cancer. The findings from the phase II neoMONARCH trial suggest that CDK4/6 inhibition may be effective for neoadjuvant treatment of early breast cancer.
December 16, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27864221/cyclin-d-mediates-tolerance-of-genome-doubling-in-cancers-with-functional-p53
#20
A Crockford, L P Zalmas, E Grönroos, S M Dewhurst, N McGranahan, M E Cuomo, V Encheva, A P Snijders, J Begum, S Purewal, J Cerveira, H Patel, M J Renshaw, C Swanton
BACKGROUND: Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidisation, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53 We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events. METHODS: We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently-derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor...
November 17, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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