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CDk4/6 and Breast

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https://www.readbyqxmd.com/read/29143969/the-molecular-basis-of-cytotoxicity-of-%C3%AE-spinasterol-from-ganoderma-resinaceum-induction-of-apoptosis-and-overexpression-of-p53-in-breast-and-ovarian-cancer-cell-lines
#1
Nada K Sedky, Zaynab El Gammal, Amir E Wahba, Eman Mosad, Zahraa Y Waly, Amira Ali El-Fallal, Reem K Arafa, Nagwa El-Badri
OBJECTIVES: Despite advances in therapy of breast and ovarian cancers, they still remain among the most imperative causes of cancer death in women. The first can be considered one of the most widespread diseases among females, while the latter is more lethal and needs prompt treatment. Thus, the research field can still benefit from discovery of new compounds that can be of potential use in management of these grave illnesses. We hereby aimed to assess the antitumor activity of the phytosterol α-spinasterol isolated from Ganoderma resinaceum mushroom on human breast cancer cell lines (MCF-7, MDA-MB-231), as well as, on human ovarian cancer cell line (SKOV-3)...
November 16, 2017: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29137354/erps294-is-a-biomarker-of-ligand-or-mutational-er%C3%AE-activation-and-a-breast-cancer-target-for-cdk2-inhibition
#2
Gary K Scott, David Chu, Ravneet Kaur, Julia Malato, Daniel E Rothschild, Katya Frazier, Serenella Eppenberger-Castori, Byron Hann, Ben Ho Park, Christopher C Benz
ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29108713/risk-of-adverse-events-with-the-addition-of-targeted-agents-to-endocrine-therapy-in-patients-with-hormone-receptor-positive-metastatic-breast-cancer-a-systematic-review-and-meta-analysis
#3
REVIEW
Samuel Martel, Marco Bruzzone, Marcello Ceppi, Christian Maurer, Noam Falbel Ponde, Arlindo R Ferreira, Giulia Viglietti, Lucia Del Mastro, Catherine Prady, Evandro de Azambuja, Matteo Lambertini
BACKGROUND: Combining targeted agents and endocrine therapy (ET) improves outcomes in hormone receptor-positive metastatic breast cancer patients but increases the risk of adverse events (AEs). This meta-analysis aims to estimate the comparative risk of AEs with ET in addition to targeted agents in this setting. METHODS: A systematic literature search of MEDLINE, EMBASE, Cochrane Library and conference proceedings up to July 17th 2017 was conducted to identify randomized controlled trials investigating ET with or without CDK4/6, mTOR, PI3K inhibitors and anti-HER2 agents...
October 28, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29103175/efficacy-and-safety-in-older-patient-subsets-in-studies-of-endocrine-monotherapy-versus-combination-therapy-in-patients-with-hr-her2-%C3%A2-advanced-breast-cancer-a-review
#4
REVIEW
Rachel A Freedman, Sara M Tolaney
PURPOSE: Prospective information regarding the tolerability and efficacy of endocrine therapy (ET) alone and in combination with targeted agents in older patients in the metastatic setting is limited. This review summarizes available trial data in this population. METHODS: We searched PubMed for Phase 2 or 3 trials with age-stratified patient cohorts (≥ 65 vs. < 65 years in most studies) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer treated with ET ± targeted agents...
November 4, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29100169/the-next-era-of-treatment-for-hormone-receptor-positive-her2-negative-advanced-breast-cancer-triplet-combination-based-endocrine-therapies
#5
REVIEW
Javier Cortés, Seock-Ah Im, Esther Holgado, Jose M Perez-Garcia, Peter Schmid, Mariana Chavez-MacGregor
Until recently, the standard of care for hormone receptor-positive (HR+) breast cancer was single-agent endocrine therapy, which aims to prevent estrogen receptor signaling. This therapeutic strategy has extended survival without the toxicity associated with chemotherapy, but primary endocrine therapy resistance is common, and secondary resistance develops over time. Adjunct downstream inhibition of the cyclin-dependent kinase (CDK)4/6 pathway, intended to delay and prevent endocrine therapy resistance, has further extended progression-free survival in patients receiving endocrine therapy; however, resistance still eventually develops in these patients...
October 12, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/29090083/gastrointestinal-adverse-effects-of-cyclin-dependent-kinase-4-and-6-inhibitors-in-breast-cancer-patients-a-systematic-review-and-meta-analysis
#6
REVIEW
Kyrillus S Shohdy, Shaimaa Lasheen, Loay Kassem, Omar Abdel-Rahman
BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors show promising results in metastatic breast cancer. However, an increased incidence of adverse events is remarkable. Among others, gastrointestinal (GI) involvement is of momentous impact on patients and their quality of life. METHODS: Our search included PubMed, ASCO, ESMO and SABCS databases. Randomized phase II/III trials in metastatic breast cancer receiving CDK4/6 inhibitors were identified and considered relevant based on providing a sufficient safety profile on the incidence of adverse GI effects...
November 2017: Therapeutic Advances in Drug Safety
https://www.readbyqxmd.com/read/29059158/raf-inhibitor-ly3009120-sensitizes-ras-or-braf-mutant-cancer-to-cdk4-6-inhibition-by-abemaciclib-via-superior-inhibition-of-phospho-rb-and-suppression-of-cyclin-d1
#7
S-H Chen, X Gong, Y Zhang, R D Van Horn, T Yin, L Huber, T F Burke, J Manro, P W Iversen, W Wu, S V Bhagwat, R P Beckmann, R V Tiu, S G Buchanan, S-B Peng
KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29027483/cdk4-6-blockade-in-breast-cancer-current-experience-and-future-perspectives
#8
Dimitrios Zardavas, Noam Pondé, Konstantinos Tryfonidis
Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer...
October 23, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28978559/fda-oks-abemaciclib-for-er-her2-breast-cancer
#9
(no author information available yet)
The FDA has approved abemaciclib for women with advanced or metastatic ER-positive, HER2-negative breast cancer whose disease has progressed on endocrine therapy. This is the third CDK4/6 inhibitor to get the agency's go-ahead in 2.5 years.
October 4, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28978004/detection-of-esr1-mutations-in-circulating-cell-free-dna-from-patients-with-metastatic-breast-cancer-treated-with-palbociclib-and-letrozole
#10
Rekha Gyanchandani, Karthik J Kota, Amruth R Jonnalagadda, Tanya Minteer, Beth A Knapick, Steffi Oesterreich, Adam M Brufsky, Adrian V Lee, Shannon L Puhalla
ESR1 mutations are frequently acquired in hormone-resistant metastatic breast cancer (MBC). CDK4/6 inhibition along with endocrine therapy is a promising strategy in hormone receptor-positive MBC. However, the incidence and impact of ESR1 mutations on clinical outcome in patients treated with CDK4/6 inhibitors have not been defined. In this study, we evaluated the frequency of ESR1 mutations in cfDNA from 16 patients with MBC undergoing palbociclib and letrozole therapy. Four common ESR1 mutations (D538G, Y537C, Y537N, and Y537S) were analyzed in serial blood draws using ddPCR...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28961554/cdk4-6-inhibition-in-early-and-metastatic-breast-cancer-a-review
#11
REVIEW
A F de Groot, C J Kuijpers, J R Kroep
Breast cancer (BC) is responsible for 14% of cancer-related deaths in women [1]. Cyclin-dependent kinase (CDK) 4/6 inhibitors are a new class of selective drugs, offering an effective and tolerable treatment. CDK4/6 inhibitors induce cell cycle arrest in the G1 phase, and may thereby prevent tumour progression. Three CDK4/6 inhibitors have been tested in clinical BC trials: palbociclib, ribociclib, and abemaciclib. The Food and Drug Administration (FDA) and European Commission (EMA) have approved palbociclib for the treatment of patients HR+ HER2- locally advanced or metastatic BC (aBC) in combination with an aromatase inhibitor as initial therapy in postmenopausal women or in combination with fulvestrant in women who have received prior endocrine therapy...
November 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28947566/cytoplasmic-cyclin-e-mediates-resistance-to-aromatase-inhibitors-in-breast-cancer
#12
Iman Doostan, Cansu Karakas, Mehrnooh Kohansal, Kwang Hui Low, Matthew J Ellis, John A Olson, Vera Suman, Kelly Hunt, Stacy Moulder-Thompson, Khandan Keyomarsi
PURPOSE: Preoperative aromatase inhibitor (AI) therapy has demonstrated efficacy in hormone receptor (HR)-positive postmenopausal breast cancer. However, many patients have disease that is either intrinsically resistant to AIs or that responds initially but develops resistance after prolonged exposure. We have shown that patients with breast tumors expressing the deregulated forms of cyclin E (low molecular weight forms [LMW-E]) have poor overall survival. Herein, we hypothesize that LMW-E expression can identify HR-positive tumors that are unresponsive to neoadjuvant AI therapy due to the inability of AIs to induce a cytostatic effect...
September 25, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28947417/combined-cdk4-6-and-pi3k%C3%AE-inhibition-is-synergistic-and-immunogenic-in-triple-negative-breast-cancer
#13
Zhi Ling Teo, Stephanie Versaci, Sathana Dushyanthen, Franco Caramia, Peter Savas, Chris Mintoff, Magnus Zethoven, Balaji Virassamy, Stephen J Luen, Grant A McArthur, Wayne A Phillips, Phillip K Darcy, Sherene Loi
New treatments for triple-negative breast cancer (TNBC) are urgently needed. Despite there being little evidence of clinical activity as single-agent therapies, we show that dual blockade of PI3Kα and CDK4/6 is synergistically effective against multiple RB1-wildtype TNBC models. Combined PI3Kα and CDK4/6 inhibition significantly increased apoptosis, cell cycle arrest, and tumor immunogenicity and generated immunogenic cell death in human TNBC cell lines. Combination treatment also significantly improved disease control in human xenograft models compared with either monotherapy...
September 25, 2017: Cancer Research
https://www.readbyqxmd.com/read/28947133/palbociclib-induced-autophagy-and-senescence-in-gastric-cancer-cells
#14
Claudio A Valenzuela, Leandro Vargas, Valentina Martinez, Sindy Bravo, Nelson E Brown
Targeting cyclin D-CDK4/6 kinase complexes has recently been shown to increase the survival of breast cancer patients with estrogen receptor positive breast tumors. Based on these outcomes, CDK4/6 inhibitors are currently being tested, alone o in combination with other drugs, in the treatment of other malignancies characterized by hyper-activation of cyclin D-CDK4/6 complexes. Nonetheless, a better understanding of the cellular processes that are implemented in response to CDK4/6 inhibition is necessary to expand the therapeutic window and confront the development of drug resistance...
November 15, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28939653/first-line-abemaciclib-effective-in-er-breast-cancer
#15
(no author information available yet)
Interim data from the MONARCH3 study indicate that abemaciclib is an effective first-line therapy for advanced ER-positive, HER2-negative breast cancer. Adding the investigational CDK4/6 inhibitor to letrozole significantly improved patients' progression-free survival, compared with those given a placebo alongside endocrine therapy.
September 22, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28923217/current-challenges-in-the-management-of-breast-cancer-brain-metastases
#16
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/28875723/ribociclib-for-post-menopausal-women-with-hr-her2-advanced-or-metastatic-breast-cancer
#17
REVIEW
Mark L Zangardi, Laura M Spring, Gayle C Blouin, Aditya Bardia
The introduction of CDK4/6 inhibitors, such as ribociclib, has changed the treatment landscape for post-menopausal women with HR+/HER2- advanced or metastatic breast cancer. As first-line treatment of HR+/HER2- MBC, the addition of a CDK4/6 inhibitor to an aromatase inhibitor improves progression-free survival compared to an aromatase inhibitor alone. Areas covered: In this drug profile, we review the current market for HR+/HER2- MBC, as well as the characteristics, mechanism, pharmacology, pharmacodynamics, pharmacokinetics, metabolism, clinical efficacy, toxicities, monitoring, and dosing modification of the CDK4/6 inhibitor ribociclib...
November 2017: Expert Review of Clinical Pharmacology
https://www.readbyqxmd.com/read/28856074/utilizing-tumor-and-plasma-liquid-biopsy-in-treatment-decision-making-for-an-estrogen-receptor-positive-advanced-breast-cancer-patient
#18
Bing Xu, Amy Krie, Pradip De, Casey Williams, Rachel Elsey, Jessica Klein, Brian Leyland-Jones
Breast cancer affects 12% of females in the United States and is the leading cause of cancer death in the female population. Personalized therapy is being used in clinical practice to treat breast cancer based on tumor molecular profiling, which can be obtained from tissue biopsy or plasma liquid biopsy as circulating tumor deoxyribonucleic acid (ctDNA). The available ctDNA tests provide a non-invasive way to monitor the cancer genome in a real-time manner. In this case report, a 38-year-old female with recurrent estrogen receptor (ER) positive breast cancer is treated with letrozole, everolimus, and palbociclib...
June 29, 2017: Curēus
https://www.readbyqxmd.com/read/28819400/rapid-breast-cancer-disease-progression-following-cyclin-dependent-kinase-4-and-6-inhibitor-discontinuation
#19
Sami I Bashour, Iman Doostan, Khandan Keyomarsi, Vicente Valero, Naoto T Ueno, Powel H Brown, Jennifer K Litton, Kimberly B Koenig, Meghan Karuturi, Sausan Abouharb, Debasish Tripathy, Stacy L Moulder-Thompson, Nuhad K Ibrahim
Background: CDK 4 and 6 inhibitors (CDK4/6i), which arrest unregulated cancer cell proliferation, show clinical efficacy in breast cancer. Unexpectedly, a patient treated on a CDK4/6i-based trial, as first-line therapy in metastatic breast cancer, developed rapid disease progression following discontinuation of study drug while receiving standard second-line therapy off trial. We thus sought to expand this observation within a population of patients treated similarly at The University of Texas MD Anderson Cancer Center...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28813415/cdk4-6-inhibition-triggers-anti-tumour-immunity
#20
Shom Goel, Molly J DeCristo, April C Watt, Haley BrinJones, Jaclyn Sceneay, Ben B Li, Naveed Khan, Jessalyn M Ubellacker, Shaozhen Xie, Otto Metzger-Filho, Jeremy Hoog, Matthew J Ellis, Cynthia X Ma, Susanne Ramm, Ian E Krop, Eric P Winer, Thomas M Roberts, Hye-Jung Kim, Sandra S McAllister, Jean J Zhao
Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity...
August 24, 2017: Nature
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