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https://www.readbyqxmd.com/read/29674428/optimising-endocrine-therapy-in-postmenopausal-women-with-advanced-breast-cancer
#1
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
#2
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
#3
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
#4
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
https://www.readbyqxmd.com/read/29644000/cdk4-6-inhibition-as-maintenance-and-combination-therapy-for-high-grade-serous-ovarian-cancer
#5
Mangala Iyengar, Patrick O'Hayer, Alex Cole, Tara Sebastian, Kun Yang, Lan Coffman, Ronald J Buckanovich
High grade serous ovarian cancer (HGSOC) is a disease with a high relapse rate and poor overall survival despite good initial responses to platinum-based therapy. Cell cycle inhibition with targeted CDK4/6 inhibitors is a new therapeutic approach showing promise as a maintenance therapy in cancer. As multiple genes in the CDK4/6 pathway are commonly mutated or dysregulated in ovarian cancer, we evaluated the efficacy of the CDK4/6 inhibitor Ribociclib alone, in combination with chemotherapy, and as maintenance therapy in several models of HGSOC...
March 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/29623577/use-of-dual-mtor-inhibitor-mln0128-against-everolimus-resistant-breast-cancer
#6
Karineh Petrossian, Duc Nguyen, Chiao Lo, Noriko Kanaya, George Somlo, Yvonne Xiaoyong Cui, Chiun-Sheng Huang, Shiuan Chen
PURPOSE: HR+/HER2- aromatase inhibitor-resistant metastatic breast cancer can be treated with everolimus and a second AI until the cancer recurs. Targeting these everolimus-resistant patients with the latest standard of care, CDK4/6 inhibitors, has not been clearly addressed. Understanding the signaling transduction pathways, which everolimus resistance activates, will elucidate the mechanisms and offer treatment strategies of everolimus resistance. METHODS: To mimic the clinical setting, letrozole-resistant cells were used to generate an everolimus-resistant model (RAD-R)...
April 5, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29617654/identification-of-cdc25-as-a-common-therapeutic-target-for-triple-negative-breast-cancer
#7
Jeff C Liu, Letizia Granieri, Mariusz Shrestha, Dong-Yu Wang, Ioulia Vorobieva, Elizabeth A Rubie, Rob Jones, YoungJun Ju, Giovanna Pellecchia, Zhe Jiang, Carlo A Palmerini, Yaacov Ben-David, Sean E Egan, James R Woodgett, Gary D Bader, Alessandro Datti, Eldad Zacksenhaus
CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition...
April 3, 2018: Cell Reports
https://www.readbyqxmd.com/read/29605511/tetrandrine-inhibits-deregulated-cell-cycle-in-pancreatic-cancer-cells-differential-regulation-of-p21-cip1-waf1-p27-kip1-and-cyclin-d1
#8
Karnika Singh, Qin Dong, Prakash S TimiriShanmugam, Sweaty Koul, Hari K Koul
Current therapies in Pancreatic Cancer (PaCa) are ineffective due to deregulated cell cycle driven by landscape mutations. In this study, we show for the first time that tetrandrine (TET) inhibits proliferation of the PaCa cells and inhibits PaCa tumor growth. TET inhibits cell cycle transition at G1/S boundary. TET increased levels of p21Cip1/Waf1 and p27Kip1 , had no effect on the levels of CDK4/6 proteins and decreased the levels of cyclin D1 and pRb proteins. TET resulted in changes in mRNA levels of cyclin D1 and p21Cip1/Waf1 but had no effect on the mRNA of p27Kip1 ...
March 29, 2018: Cancer Letters
https://www.readbyqxmd.com/read/29587820/the-anti-tumor-efficacy-of-cdk4-6-inhibition-is-enhanced-by-the-combination-with-pi3k-akt-mtor-inhibitors-through-impairment-of-glucose-metabolism-in-tnbc-cells
#9
Daniele Cretella, Andrea Ravelli, Claudia Fumarola, Silvia La Monica, Graziana Digiacomo, Andrea Cavazzoni, Roberta Alfieri, Alessandra Biondi, Daniele Generali, Mara Bonelli, Pier Giorgio Petronini
No abstract text is available yet for this article.
March 27, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29582246/current-treatment-patterns-among-postmenopausal-women-with-hr-her2-metastatic-breast-cancer-in-us-community-oncology-practices-an-observational-study
#10
Deborah Goldschmidt, Anand A Dalal, Hela Romdhani, Sneha Kelkar, Annie Guerin, Genevieve Gauthier, Eric Q Wu, Polly Niravath, Tania Small
INTRODUCTION: Recent approval of novel agents has changed the treatment landscape for post menopausal women with hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) metastatic breast cancer (mBC). The objective of this study was to describe contemporary treatment patterns among postmenopausal women with HR+/HER2- mBC in the real-world setting. METHODS: Data were collected from 64 community oncologists in the US between February and June 2017 using an online medical records extraction tool...
March 26, 2018: Advances in Therapy
https://www.readbyqxmd.com/read/29581135/er-breast-cancers-resistant-to-prolonged-neoadjuvant-letrozole-exhibit-an-e2f4-transcriptional-program-sensitive-to-cdk4-6-inhibitors
#11
Angel Guerrero-Zotano, Thomas Stricker, Luigi Formisano, Katherine E Hutchinson, Daniel G Stover, Kyung-Min Lee, Luis J Schwarz, Jennifer M Giltnane, Monica V Estrada, Valerie M Jansen, Alberto Servetto, Joaquín Gavilá, José Alejandro Pérez-Fidalgo, Ana Lluch, Antonio Llombart-Cussac, Mohamed Amine Bayar, Stefan Michiels, Fabrice Andre, Monica Arnedos, Vicente Guillem, Amparo Ruiz-Simon, Carlos L Arteaga
PURPOSE: This study aimed to identify biomarkers of resistance to endocrine therapy in ER+ breast cancers (BC) treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA-sequencing in 68 ER+ BC from patients treated with preoperative letrozole (median 7 months). Results:Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC>1, FDR<0...
March 26, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29576629/update-breast-cancer-2018-part-1-primary-breast-cancer-and-biomarkers
#12
Florin-Andrei Taran, Andreas Schneeweiss, Michael P Lux, Wolfgang Janni, Andreas D Hartkopf, Naiba Nabieva, Friedrich Overkamp, Hans-Christian Kolberg, Peyman Hadji, Hans Tesch, Achim Wöckel, Johannes Ettl, Diana Lüftner, Markus Wallwiener, Volkmar Müller, Matthias W Beckmann, Erik Belleville, Diethelm Wallwiener, Sara Y Brucker, Peter A Fasching, Tanja N Fehm, Florian Schütz
This summary provides an overview of how new therapies or new aspects of established therapies relate to the latest findings. Neoadjuvant therapy, local therapy, new aspects of systemic therapy, and prognostic and predictive factors are presented. In the neoadjuvant setting, the association between pathological complete response (pCR) and prognosis is still of interest as is the identification of new molecular predictors for new therapies such as CDK4/6 inhibitors. As regards surgical treatment, the target is still to reduce the aggressiveness of surgery...
March 2018: Geburtshilfe und Frauenheilkunde
https://www.readbyqxmd.com/read/29564743/a-gene-expression-signature-of-retinoblastoma-loss-of-function-predicts-resistance-to-neoadjuvant-chemotherapy-in-er-positive-her2-positive-breast-cancer-patients
#13
Emanuela Risi, Andrea Grilli, Ilenia Migliaccio, Chiara Biagioni, Amelia McCartney, Cristina Guarducci, Martina Bonechi, Matteo Benelli, Stefania Vitale, Laura Biganzoli, Silvio Bicciato, Angelo Di Leo, Luca Malorni
PURPOSE: HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients...
March 22, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29564714/preclinical-and-clinical-development-of-palbociclib-and-future-perspectives
#14
REVIEW
E Martínez de Dueñas, J Gavila-Gregori, S Olmos-Antón, A Santaballa-Bertrán, A Lluch-Hernández, E J Espinal-Domínguez, M Rivero-Silva, A Llombart-Cussac
Cyclin-dependent kinases (CDKs) play a key role in cell cycle regulation, which makes them a clear therapeutic target to interfere with cell division and proliferation in cancer patients. Palbociclib, a specific inhibitor of CDK4/6 with outstanding clinical efficacy data and limited toxicity, has been recently approved for the treatment of hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, either in combination with an aromatase inhibitor or in combination with fulvestrant in women who have received prior endocrine therapy...
March 21, 2018: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/29541385/targeting-the-cyclin-dependent-kinase-and-retinoblastoma-axis-overcomes-standard-of-care-resistance-in-braf-v600e-mutant-melanoma
#15
Antoneicka L Harris, Samantha E Lee, Louis K Dawson, Laura A Marlow, Brandy H Edenfield, William F Durham, Thomas J Flotte, Michael Thompson, Daniel L Small, Aidan J Synnott, Svetomir N Markovic, John A Copland
Patient-derived tumor xenograft (PDTX) mouse models were used to discover new therapies for naïve and drug resistant BRAF V600E -mutant melanoma. Tumor histology, oncogenic protein expression, and antitumor activity were comparable between patient and PDTX-matched models thereby validating PDTXs as predictive preclinical models of therapeutic response in patients. PDTX models responsive and non-responsive to BRAF/MEK standard of care (SOC) therapy were used to identify efficacious combination therapies. One such combination includes a CDK4/6 inhibitor that blocks cell cycle progression...
February 16, 2018: Oncotarget
https://www.readbyqxmd.com/read/29539425/the-cdk4-6-inhibitor-abemaciclib-induces-a-t-cell-inflamed-tumor-microenvironment-and-enhances-the-efficacy-of-pd-l1-checkpoint-blockade
#16
David A Schaer, Richard P Beckmann, Jack A Dempsey, Lysiane Huber, Amelie Forest, Nelusha Amaladas, Yanxia Li, Ying Cindy Wang, Erik R Rasmussen, Darin Chin, Andrew Capen, Carmine Carpenito, Kirk A Staschke, Linda A Chung, Lacey M Litchfield, Farhana F Merzoug, Xueqian Gong, Philip W Iversen, Sean Buchanan, Alfonso de Dios, Ruslan D Novosiadly, Michael Kalos
Abemaciclib, an inhibitor of cyclin dependent kinases 4 and 6 (CDK4/6), has recently been approved for the treatment of hormone receptor-positive breast cancer. In this study, we use murine syngeneic tumor models and in vitro assays to investigate the impact of abemaciclib on T cells, the tumor immune microenvironment and the ability to combine with anti-PD-L1 blockade. Abemaciclib monotherapy resulted in tumor growth delay that was associated with an increased T cell inflammatory signature in tumors. Combination with anti-PD-L1 therapy led to complete tumor regressions and immunological memory, accompanied by enhanced antigen presentation, a T cell inflamed phenotype, and enhanced cell cycle control...
March 13, 2018: Cell Reports
https://www.readbyqxmd.com/read/29528755/emerging-therapeutic-targets-for-the-treatment-of-malignant-rhabdoid-tumors
#17
Karolina Nemes, Michael C Frühwald
Malignant Rhabdoid Tumor (MRT) is a rare and highly aggressive malignancy primarily affecting infants and young children. The most common anatomic locations are the central nervous system (AT/RT), the kidneys (RTK) and other soft tissues (eMRT). The genetic origin of this disease is linked to mutations in SMARCB1, a gene encoding a core subunit of the SWI/SNF chromatin-remodeling complex. Areas covered: Conventional multimodal treatment may offer a significant survival benefit to certain patients. It remains to be determined, however, which patients will prove resistant to chemotherapy and need novel therapeutic approaches...
March 12, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29527939/different-inhibitors-for-the-same-target-in-metastatic-luminal-breast-cancer-is-there-any-difference
#18
Elie El Rassy, Ziad Bakouny, Tarek Assi, Joseph Kattan
AIM: To determine which of the CDK4/6 inhibitors is the optimal treatment in metastatic luminal breast cancer. MATERIALS & METHODS: A network meta-analysis using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The associations of aromatase inhibitor with ribociclib, palbociclib and abemaciclib were similar in efficacy. Palbociclib-based regimen was associated with significantly lower treatment discontinuation rates compared with the other approved drugs in this indication...
March 12, 2018: Future Oncology
https://www.readbyqxmd.com/read/29522364/abemaciclib-for-the-treatment-of-breast-cancer
#19
Takeshi Kotake, Masakazu Toi
There have been numerous clinical trials of CDK4/6 inhibitors performed on various carcinomas including breast cancer. One such inhibitor tested and which has ongoing clinical trials for breast cancer is abemaciclib. Abemaciclib is a molecular-targeted agent that targets basic cell cycle regulatory mechanisms. Areas covered: This review discusses the available clinical data and ongoing clinical trials of abemaciclib in breast cancer. Expert opinion: Abemaciclib has demonstrated a clear anti-tumour effect and manageable toxicity against HR-positive, HER2-negative breast cancer in many clinical trials and is expected to be an important standard therapy...
March 9, 2018: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/29518312/discovery-of-n1-4-7-cyclopentyl-6-dimethylcarbamoyl-7h-pyrrolo-2-3-d-pyrimidin-2-yl-amino-phenyl-n8-hydroxyoctanediamide-as-a-novel-inhibitor-targeting-cyclin-dependent-kinase-4-9-cdk4-9-and-histone-deacetlyase1-hdac1-against-malignant-cancer
#20
Yongtao Li, Xiaohe Luo, Qingxiang Guo, Yongwei Nie, Tianqi Wang, Chao Zhang, Zhi Huang, Xin Wang, Yanhua Liu, Yanan Chen, Jian-Yu Zheng, Shengyong Yang, Yan Fan, Rong Xiang
A series of novel, highly potent, selective inhibitors targeting both CDK4/9 and HDAC1 have been designed and synthesized. N1-(4-((7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d] pyrimidin-2-yl) amino) phenyl)-N8-hydroxyoctanediamide (6e) was discovered. The lead compound 6e with excellent CDK4/9 and HDAC1 inhibitory activity of IC50 = 8.8 nM, 12 nM and 2.2 nM respectively, can effectively induce apoptosis of cancer cell lines. The kinase profiling of compound 6e showed excellent selectivity and specificity...
March 8, 2018: Journal of Medicinal Chemistry
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