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https://www.readbyqxmd.com/read/29910109/update-on-cardio-oncology-novel-cancer-therapeutics-and-associated-cardiotoxicities
#1
REVIEW
Avirup Guha, Merna Armanious, Michael G Fradley
There have been significant advances in the field of oncology leading to improved survival as a result of novel targeted and immunotherapies. Despite these improved outcomes, there is increased recognition of cardiotoxicities associated with these therapies that can lead to significant morbidity and mortality. As such, the field of cardio-oncology has seen significant growth over the last several years. In this review, we discuss recent advances in the field of cardio-oncology and provide a detailed discussion of the cardiovascular complications associated with novel cancer therapeutics including tyrosine kinase inhibitors, proteasome inhibitors, histone deacetylase inhibitors, CDK4/6 inhibitors and immunotherapies...
June 8, 2018: Trends in Cardiovascular Medicine
https://www.readbyqxmd.com/read/29904623/cdk4-6-and-pdgfra-signaling-as-therapeutic-targets-in-diffuse-intrinsic-pontine-glioma
#2
REVIEW
Christine Hoeman, Chen Shen, Oren J Becher
Diffuse intrinsic pontine gliomas (DIPGs) are incurable childhood brain tumors, whereby the standard of care is focal radiation, a treatment that provides temporary relief for most patients. Surprisingly, decades of clinical trials have failed to identify additional therapies that can prolong survival in this disease. In this conference manuscript, we discuss how genetic engineered mouse modeling techniques with the use of a retroviral gene delivery system can help dissect the complex pathophysiology of this disease...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29899762/the-role-of-abemaciclib-in-treatment-of-advanced-breast-cancer
#3
REVIEW
Amelia McCartney, Erica Moretti, Giuseppina Sanna, Marta Pestrin, Emanuela Risi, Luca Malorni, Laura Biganzoli, Angelo Di Leo
Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2- ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone...
2018: Therapeutic Advances in Medical Oncology
https://www.readbyqxmd.com/read/29893769/modulation-of-rb-phosphorylation-and-antiproliferative-response-to-palbociclib-the-preoperative-palbociclib-pop-randomized-clinical-trial
#4
M Arnedos, M A Bayar, B Cheaib, V Scott, I Bouakka, A Valent, J Adam, V Leroux-Kozal, V Marty, A Rapinat, C Mazouni, B Sarfati, I Bieche, C Balleyguier, D Gentien, S Delaloge, M Lacroix-Triki, S Michiels, F Andre
Background: The CDK4/6 inhibitor Palbociclib is a new standard treatment in hormone-receptor positive breast cancer patients. No predictive biomarkers have been identified and no pharmacodynamics has properly been described so far. Patients and methods: Patients with early breast cancer were randomized 3:1 to oral palbociclib 125mg daily for 14 days until the day before the surgery vs. no treatment. Primary objective was antiproliferative response defined as a natural logarithm of Ki67 expression at day 15 below 1...
June 11, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/29891002/overcoming-endocrine-resistance-in-metastatic-hormone-receptor-positive-breast-cancer
#5
REVIEW
Anishka D'Souza, Darcy Spicer, Janice Lu
Endocrine therapy has historically formed the basis of treatment of metastatic hormone receptor-positive breast cancer. The development of endocrine resistance has led to the development of newer endocrine drug combinations. Use of the CDK4/6 inhibitors has significantly improved progression-free survival in this group of patients. There are multiple studies of the use of P13K inhibitors and mTOR inhibitors for use as subsequent lines of therapy, particularly for endocrine resistance. The optimal sequencing of therapy should be based on medical comorbidities, prior adjuvant therapies, quality of life, side-effect profile, and disease-free interval...
June 11, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29886395/parp1-promoter-links-cell-cycle-progression-with-adaptation-to-oxidative-environment
#6
REVIEW
Julita Pietrzak, Corinne M Spickett, Tomasz Płoszaj, László Virág, Agnieszka Robaszkiewicz
Although electrophiles are considered as detrimental to cells, accumulating recent evidence indicates that proliferating non-cancerous and particularly cancerous cells utilize these agents for pro-survival and cell cycle promoting signaling. Hence, the redox shift to mild oxidant release must be balanced by multiple defense mechanisms. Our latest findings demonstrate that cell cycle progression, which dictates oxidant level in stress-free conditions, determines PARP1 transcription. Growth modulating factors regulate CDK4/6-RBs-E2Fs axis...
June 2, 2018: Redox Biology
https://www.readbyqxmd.com/read/29880982/4th-international-consensus-conference-on-advanced-breast-cancer-abc4-lisbon-november-4-2017-abc4-consensus-assessment-by-a-panel-of-german-experts
#7
Michael Untch, Rachel Würstlein, Norbert Marschner, Diana Lüftner, Doris Augustin, Susanne Briest, Johannes Ettl, Renate Haidinger, Lothar Müller, Volkmar Müller, Eugen Ruckhäberle, Nadia Harbeck, Christoph Thomssen
The fourth international advanced breast cancer consensus conference (ABC4) on the diagnosis and treatment of advanced breast cancer (ABC) headed by Professor Fatima Cardoso was once again held in Lisbon on November 2 - 4, 2017. To simplify matters, the abbreviation ABC will be used hereinafter in the text. In clinical practice, the abbreviation corresponds to metastatic breast cancer or locally far-advanced disease. This year the focus was on new developments in the treatment of ABC. Topics discussed included the importance of CDK4/6 inhibition in hormone receptor (HR)-positive ABC, the use of dual antibody blockade to treat HER2-positive ABC, PARP inhibition in triple-negative ABC and the potential therapeutic outcomes...
May 2018: Geburtshilfe und Frauenheilkunde
https://www.readbyqxmd.com/read/29875320/wild-type-kras-expands-and-exhausts-hematopoietic-stem-cells
#8
Joshua P Sasine, Heather A Himburg, Christina M Termini, Martina Roos, Evelyn Tran, Liman Zhao, Jenny Kan, Michelle Li, Yurun Zhang, Stéphanie C de Barros, Dinesh S Rao, Christopher M Counter, John P Chute
Oncogenic Kras expression specifically in hematopoietic stem cells (HSCs) induces a rapidly fatal myeloproliferative neoplasm in mice, suggesting that Kras signaling plays a dominant role in normal hematopoiesis. However, such a conclusion is based on expression of an oncogenic version of Kras. Hence, we sought to determine the effect of simply increasing the amount of endogenous wild-type Kras on HSC fate. To this end, we utilized a codon-optimized version of the murine Kras gene (Krasex3op) that we developed, in which silent mutations in exon 3 render the encoded mRNA more efficiently translated, leading to increased protein expression without disruption to the normal gene architecture...
June 7, 2018: JCI Insight
https://www.readbyqxmd.com/read/29868122/screen-for-microrna-and-drug-interactions-in-breast-cancer-cell-lines-points-to-mir-126-as-a-modulator-of-cdk4-6-and-pik3ca-inhibitors
#9
Federica Baldassari, Carlotta Zerbinati, Marco Galasso, Fabio Corrà, Linda Minotti, Chiara Agnoletto, Maurizio Previati, Carlo M Croce, Stefano Volinia
Background: Breast cancer (BC) represents the most common cancer in women worldwide. Due to its heterogeneous nature, breast cancer management might benefit from differential treatments toward personalized medicine. Additionally, drug resistance is a common phenomenon. We systematically investigated the effect of 14 different drugs administered on BC cell lines in combination with microRNAs (miRNA, miR). Methods: Thirty-eight miRNAs, all associated with BC by clinical and molecular parameters including progression, prognosis and subtypes, were tested for their effects on the viability of 12 different BC cell lines...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29862232/breakthroughs-in-the-treatment-of-advanced-squamous-cell-nsclc-not-the-neglected-sibling-anymore
#10
REVIEW
Georgios Tsironis, Dimitrios C Ziogas, Anastasios Kyriazoglou, Marita Lykka, Konstantinos Koutsoukos, Aristotelis Bamias, Meletios-Athanasios Dimopoulos
During the last years, translational research has contributed in many advances in the treatment of non-small cell lung cancer (NSCLC) discovering genetic alternations or recognizing the immuno-escape and neo-angiogenesis of lung cancer. Although the majority of these advances took place in the non-squamous histological subtype, therapeutic options for patients diagnosed with advanced squamous cell lung cancer (SqCLC) have been also enriched significantly with the addition of nab-paclitaxel in the conventional chemotherapy; the introduction of necitumumab, afatinib and erlotinib in the inhibition of epidermal growth factor receptor (EGFR) axis and of ramucirumab in the inhibition of VEGF-induced angiogenesis and last with the approvals of nivolumab, pembrolizumab atezolizumab and durvalumab soon in the promising field of immunotherapies...
April 2018: Annals of Translational Medicine
https://www.readbyqxmd.com/read/29847850/cdk4-6-inhibitors-game-changers-in-the-management-of-hormone-receptor%C3%A2-positive-advanced-breast-cancer
#11
REVIEW
Mirat Shah, Maria Raquel Nunes, Vered Stearns
The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors palbociclib, ribociclib, and abemaciclib are rapidly transforming the care of patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) advanced breast cancer. Current clinical questions include how to choose among these agents and how to sequence them with other therapies. Areas of active inquiry include identifying predictive biomarkers for CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitors after disease progression, creating novel treatment combinations, and expanding use beyond HR+/HER2- advanced breast cancer...
May 15, 2018: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/29844131/tmprss2-erg-controls-luminal-epithelial-lineage-and-antiandrogen-sensitivity-in-pten-and-tp53-mutated-prostate-cancer
#12
Alexandra M Blee, Yundong He, Yinhui Yang, Zhenqing Ye, Yuqian Yan, Yunqian Pan, Tao Ma, Joseph A Dugdale, Emily Kuehn, Manish Kohli, Rafael E Jimenez, Yu Chen, Wanhai Xu, Liguo Wang, Haojie Huang
PURPOSE: Deletions or mutations in PTEN and TP53 tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor ERG is observed in approximately 50% of all prostate cancers, many of which also harbor PTEN and TP53 alterations. However, the role of ERG in lineage plasticity of PTEN / TP53 -altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance...
May 29, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29844123/combined-c-met-trk-inhibition-overcomes-resistance-to-cdk4-6-inhibitors-in-glioblastoma
#13
Inan Olmez, Ying Zhang, Laryssa Manigat, Mouadh Benamar, Breanna Brenneman, Ichiro Nakano, Jakub Godlewski, Agnieszka Bronisz, Jeongwu Lee, Tarek Abbas, Roger Abounader, Benjamin Purow
Glioblastoma (GBM) is the most common primary brain malignancy and carries an extremely poor prognosis. Recent molecular studies revealed the CDK4/6-Rb-E2F axis and receptor tyrosine kinase (RTK) signaling to be deregulated in most GBM, creating an opportunity to develop more effective therapies by targeting both pathways. Using a phospho-RTK protein array, we found that both c-Met and TrkA-B pathways were significantly activated upon CDK4/6 inhibition in GBM cells. We therefore investigated the efficacy of combined CDK4/6 and c-Met/TrkA-B inhibition against GBM...
May 29, 2018: Cancer Research
https://www.readbyqxmd.com/read/29807045/androgen-blockade-based-clinical-trials-landscape-in-triple-negative-breast-cancer
#14
REVIEW
Yaqin Shi, Fang Yang, Doudou Huang, Xiaoxiang Guan
Androgen receptor (AR) targeted treatment has shown promising preliminary results in triple negative breast cancer (TNBC). Identification of AR-associated signaling pathways is of great significance for in-depth understanding of their roles in pathogenesis of TNBC. To meet this objective, preclinical and clinical studies were conducted to clarify the biological interactions of AR signaling and combination strategies based on AR-targeted therapy. Biologically, AR signaling in TNBC which not only interacts with a network of key pathways, involving PI3K/AKT/mTOR, cell cycle, and DNA damage repair pathways, but mediates pivotal processes of tumor initiation and immunogenic modulation, may present an opportunity to overcome the insensitivity of single AR-targeted therapy...
May 25, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29804650/cdk4-6-inhibitors-in-combination-with-hormone-therapy-for-hr-her2-advanced-breast-cancer-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials
#15
Yunfu Deng, Guangzhi Ma, Wen Li, Ting Wang, Yaqin Zhao, Qiang Wu
BACKGROUND: This meta-analysis of randomized controlled trials aimed to comprehensively assess the efficacy and toxicity of cyclin-dependent kinase (CDK) 4/6 inhibitors in advanced breast cancer (ABC) with hormone-receptor positive (HR+ ) and human epidermal growth factor receptor 2 negative (HER2- ) disease. METHODS: We performed a systematical search using Cochrane Library, PubMed, Embase, and Web of Science up to March 2018. Only phase 2 and 3 randomized clinical trials assessing the efficacy and toxicity of the combination regimen of CDK4/6 inhibitors plus hormone therapy compared with hormone therapy alone were eligible for this meta-analysis...
May 4, 2018: Clinical Breast Cancer
https://www.readbyqxmd.com/read/29793947/comprehensive-profiling-of-dna-repair-defects-in-breast-cancer-identifies-a-novel-class-of-endocrine-therapy-resistance-drivers
#16
Meenakshi Anurag, Nindo Punturi, Jeremy Hoog, Matthew N Bainbridge, Matthew J Ellis, Svasti Haricharan
PURPOSE: This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER+ disease. EXPERIMENTAL DESIGN: Expression and mutational status of DDR genes in ER+ breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery data set), with outcomes in METABRIC, TCGA and Loi data sets (validation data sets), and in patient derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER+ breast cancer cell lines...
May 23, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29792845/current-frontline-endocrine-treatment-options-for-women-with-hormone-receptor-positive-human-epidermal-growth-factor-receptor-2-her2-negative-advanced-stage-breast-cancer
#17
REVIEW
Hikmat N Abdel-Razeq
Despite the recent advances in breast cancer early detection and awareness, a significant portion of patients present with an advanced-stage disease and more patients will progress to stage IV despite adequate treatment of their initial early-stage disease. Hormone receptor (HR)-positive, Human Epidermal Growth Factor Receptor-2 (HER2)-negative subtype is the commonest among all breast cancer subtypes. The management of the advanced-stage disease of this subtype has evolved significantly over the past few years...
May 19, 2018: Hematology/oncology and Stem Cell Therapy
https://www.readbyqxmd.com/read/29789718/pdlim7-and-cdh18-regulate-the-turnover-of-mdm2-during-cdk4-6-inhibitor-therapy-induced-senescence
#18
Mary E Klein, Mark A Dickson, Cristina Antonescu, Li-Xuan Qin, Scott J Dooley, Afsar Barlas, Katia Manova, Gary K Schwartz, Aimee M Crago, Samuel Singer, Andrew Koff, William D Tap
CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated and dedifferentiated liposarcoma their clinical promise is associated with their ability to downregulate the MDM2 protein. The downregulation of MDM2 following treatment with CDK4/6 inhibitors also induces many cultured tumor cell lines derived from different types of malignancies to progress from quiescence into senescence. Here we used cultured human cell lines and defined a role for PDLIM7 and CDH18, regulating MDM2 protein in CDK4/6 inhibitor-treated cells...
May 23, 2018: Oncogene
https://www.readbyqxmd.com/read/29789630/preclinical-evaluation-of-ribociclib-and-its-synergistic-effect-in-combination-with-alpelisib-in-non-keratinizing-nasopharyngeal-carcinoma
#19
Chi-Hang Wong, Brigette B Y Ma, Connie W C Hui, Kwok-Wai Lo, Edwin P Hui, Anthony T C Chan
Ribociclib is a specific cyclin dependent kinase (Cdk) 4/6 inhibitor that induces G1 arrest by blocking the formation of cyclin D1-Cdk4/6 complex and inhibiting retinoblastoma (RB) phosphorylation. Cyclin D1 is overexpressed in over 90% of nasopharyngeal carcinoma (NPC) and CCND1 gene activation plays a critical role in NPC pathogenesis. This study evaluated the preclinical activities of ribociclib in NPC cell lines and patient derived xenograft (PDX) models. Over 95% cell growth inhibition was observed at 96 hours after ribociclib treatment...
May 22, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29784737/nccn-guidelines-updates-breast-cancer
#20
Sharon H Giordano, Anthony D Elias, William J Gradishar
The emergence of CDK4/6 inhibitors has changed the treatment algorithm for advanced/metastatic estrogen receptor-positive breast cancer. In pivotal trials of palbociclib, ribociclib, and abemaciclib, doubling in progression-free survival has been seen. All 3 agents in this class are now included in the NCCN Guidelines for Breast Cancer, and clinicians should be incorporating these agents into their treatment algorithms. The other important issue in this breast cancer setting is extended duration of endocrine therapy...
May 2018: Journal of the National Comprehensive Cancer Network: JNCCN
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