Author
Emanuela Risi
Bio: Emanuela Risi is an academic researcher from Sapienza University of Rome. The author has contributed to research in topics: Breast cancer & Metastatic breast cancer. The author has an hindex of 12, co-authored 38 publications receiving 519 citations.
Papers
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TL;DR: Mechanisms of resistance to CDK4/6 inhibitors are presented, largely focussing on roles of Rb, cyclin E1, and the PIK3CA pathway, with discussion of associated biomarkers which have been investigated and applied in recent pre-clinical and clinical studies.
Abstract: The recent arrival of CDK4/6 inhibitor agents, with an approximate doubling of progression-free survival (PFS) associated with their use in hormone receptor-positive, HER2-negative advanced breast cancer (BC), has radically changed the approach to managing this disease However, resistance to CDK4/6 inhibitors is considered a near-inevitability in most patients Mechanisms of resistance to these agents are multifactorial, and research in this field is still evolving Biomarkers with the ability to identify early resistance, or to predict the likelihood of successful treatment using CDK4/6 inhibitors are yet to be identified, and represent an area of unmet clinical need Here we present selected mechanisms of resistance to CDK4/6 inhibitors, largely focussing on roles of Rb, cyclin E1, and the PIK3CA pathway, with discussion of associated biomarkers which have been investigated and applied in recent pre-clinical and clinical studies These biological drivers may furthermore influence clinical treatment strategies adopted beyond CDK4/6 resistance
109 citations
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TL;DR: Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer and may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET.
70 citations
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TL;DR: In a multicenter group of EBC patients, a model based on preoperative serum metabolomic profiles was developed that was prognostic for disease recurrence, independent of traditional clinicopathologic risk factors.
Abstract: Purpose: Detecting signals of micrometastatic disease in patients with early breast cancer (EBC) could improve risk stratification and allow better tailoring of adjuvant therapies. We previously showed that postoperative serum metabolomic profiles were predictive of relapse in a single-center cohort of estrogen receptor (ER)-negative EBC patients. Here, we investigated this further using preoperative serum samples from ER-positive, premenopausal women with EBC who were enrolled in an international phase III trial.Experimental Design: Proton nuclear magnetic resonance (NMR) spectroscopy of 590 EBC samples (319 with relapse or ≥6 years clinical follow-up) and 109 metastatic breast cancer (MBC) samples was performed. A Random Forest (RF) classification model was built using a training set of 85 EBC and all MBC samples. The model was then applied to a test set of 234 EBC samples, and a risk of recurrence score was generated on the basis of the likelihood of the sample being misclassified as metastatic.Results: In the training set, the RF model separated EBC from MBC with a discrimination accuracy of 84.9%. In the test set, the RF recurrence risk score correlated with relapse, with an AUC of 0.747 in ROC analysis. Accuracy was maximized at 71.3% (sensitivity, 70.8%; specificity, 71.4%). The model performed independently of age, tumor size, grade, HER2 status and nodal status, and also of Adjuvant! Online risk of relapse score.Conclusions: In a multicenter group of EBC patients, we developed a model based on preoperative serum metabolomic profiles that was prognostic for disease recurrence, independent of traditional clinicopathologic risk factors. Clin Cancer Res; 23(6); 1422-31. ©2017 AACR.
64 citations
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TL;DR: The findings suggest that PNET/EWS is a rare aggressive tumor affecting principally young people, with a poor prognosis for patients with M1 disease; chemotherapy is an effective strategy in M1 Disease and probably also in M0 disease.
55 citations
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TL;DR: The current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response are reviewed.
Abstract: Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting. In addition, molecular mechanisms of acquired resistance to palbociclib have been analyzed only in preclinical studies. Here we review the current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response.
49 citations
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TL;DR: This review presents the available drug-enzyme X-ray crystal structures for 27 of the approved drugs as well as the chemical structures and physicochemical properties of all of the FDA-approved small molecule protein kinase antagonists.
344 citations
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TL;DR: A crucial mechanism in controlling cell cycle progression is the precise timing of more than 32,000 phosphorylation and dephosphorylation reactions catalyzed by a network of protein kinases and phosphoprotein phosphatases as determined by mass spectrometry.
246 citations
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TL;DR: The less-appreciated effects of CDK4/6 inhibitors on cancer cells are described, and ways by which they might be exploited to enhance the benefits of these agents for cancer patients are suggested.
239 citations
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27 Sep 2015
TL;DR: An overview of breast cancer, conventional therapy, novel technologies in the management of Breast cancer, and rational approaches for targeting breast cancer is provided.
Abstract: Breast cancer is the most prevalent cancer among women worldwide. However, increased survival is due to the dramatic advances in the screening methods, early diagnosis, and breakthroughs in treatments. Over the course of the last decade, many acquisitions have taken place in this critical field of research in the pharmaceutical industry. Advances in molecular biology and pharmacology aided in better understanding of breast cancer, enabling the design of smarter therapeutics able to target cancer and respond to its microenvironment efficiently. Patents and research papers investigating diagnosis and treatment strategies for breast cancer using novel technologies have been surveyed for the past 15 years. Various nanocarriers have been introduced to improve the therapeutic efficacy of anticancer drugs, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of breast cancer, conventional therapy, novel technologies in the management of breast cancer, and rational approaches for targeting breast cancer.
Highlights:
1. Breast cancer is the most common cancer in women worldwide. However, survival rates vary widely, optimistically heading toward a positive trend. Increased survival is due to the drastic shift in the screening methods, early diagnosis, and breakthroughs in treatments.
2. Different strategies of breast cancer classification and staging have evolved over the years. Intrinsic (molecular) subtyping is essential in clinical trials and well understanding of the disease.
3. Many novel technologies are being developed to detect distant metastases and recurrent disease as well as to assess response to breast cancer management.
4. Intensive research efforts are actively ongoing to take novel breast cancer therapeutics to potential clinical application.
5. Most of the recent research papers and patents discuss one of the following strategies: the development of new drug entities that specifically target the breast tumor cells; tailor designing a novel carrier system that can multitask and multifunction as a drug carrier, targeting vehicle and even as a diagnostic tool, direct conjugation of a therapeutic drug moiety with a targeting moiety, diagnostic moiety or pharmacokinetics altering moiety; or the use of innovative nontraditional approaches such as genetic engineering, stem cells, or vaccinations.
220 citations
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TL;DR: From the analytical point of view, NMR has pros and cons but does provide a peculiar holistic perspective that may speak for its future adoption as a population‐wide health screening technique.
Abstract: Metabolomics deals with the whole ensemble of metabolites (the metabolome). As one of the -omic sciences, it relates to biology, physiology, pathology and medicine; but metabolites are chemical entities, small organic molecules or inorganic ions. Therefore, their proper identification and quantitation in complex biological matrices requires a solid chemical ground. With respect to for example, DNA, metabolites are much more prone to oxidation or enzymatic degradation: we can reconstruct large parts of a mammoth's genome from a small specimen, but we are unable to do the same with its metabolome, which was probably largely degraded a few hours after the animal's death. Thus, we need standard operating procedures, good chemical skills in sample preparation for storage and subsequent analysis, accurate analytical procedures, a broad knowledge of chemometrics and advanced statistical tools, and a good knowledge of at least one of the two metabolomic techniques, MS or NMR. All these skills are traditionally cultivated by chemists. Here we focus on metabolomics from the chemical standpoint and restrict ourselves to NMR. From the analytical point of view, NMR has pros and cons but does provide a peculiar holistic perspective that may speak for its future adoption as a population-wide health screening technique.
216 citations