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Precision Medicine In Cancer

Giuseppe Raschellà, Gerry Melino, Alessandra Gambacurta
Tumors constitute a large class of diseases that affect different organs and cell lineages. The molecular characterization of cancers of a given type has revealed an extraordinary heterogeneity in terms of genetic alterations and DNA mutations; heterogeneity that is further highlighted by single-cell DNA sequencing of individual patients. To address these issues, drugs that specifically target genes or altered pathways in cancer cells are continuously developed. Indeed, the genetic fingerprint of individual tumors can direct the modern therapeutic approaches to selectively hit the tumor cells while sparing the healthy ones...
October 19, 2018: Genes and Immunity
Konstantina Panoutsopoulou, Margaritis Avgeris, Andreas Scorilas
The elucidation of tumor molecular hallmarks and the identification of novel molecular markers are of first translational priority in breast and ovarian cancer research, aiming to support personalized disease treatment and monitoring decisions. Recent high-throughput studies have revealed that ~80% of the genome is transcribed into RNAs without protein-coding potential, namely non-coding RNAs (ncRNAs), challenging the concept of "junk DNA". Undoubtedly, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) represent the best-studied family classes, emerging as the most powerful gene-expression regulators at epigenetic, transcriptional and post-transcriptional levels...
October 19, 2018: Expert Review of Molecular Diagnostics
Yanmei Liu, Shujun Gao, Jie Zhu, Ya Zheng, Haiyan Zhang, Hong Sun
Dihydroartemisinin (DHA), the primary of artemisinin extracted from the traditional Chinese medicine Artemisia annua, has been used in malaria treatment for a long time. Recently, many studies have indicated that, in addition to antimalarial effects, DHA also exhibits anticancer activity in certain types of neoplasms, including ovarian cancer. However, the precise anti-ovarian cancer mechanism of DHA is still unclear. Abnormal activation of the hedgehog (Hh) pathway is closely related to tumorigenesis and progression of ovarian cancer...
October 18, 2018: Cancer Medicine
Masayuki Nagahashi, Yoshifumi Shimada, Hiroshi Ichikawa, Hitoshi Kameyama, Kazuaki Takabe, Shujiro Okuda, Toshifumi Wakai
Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS-based gene panel tests has generated practical diagnostic tools that enabled individualized cancer-patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double-strand break repair pathway...
October 18, 2018: Cancer Science
B P Hobbs, M J Kane, D S Hong, R Landin
Within the evidentiary hierarchy of experimental inquiry, randomized trials are the gold standard. Oncology patients enter clinical studies with diverse lifestyles, treatment pathways, host tissue environments, and competing co-morbidities. Randomization attempts to balance prognostic characteristics among study arms, thereby enabling statistical inference of "average benefit" and attribution to the studied therapies. In contrast, interpretations of uncontrolled trials require additional scrutiny to attempt to place the findings in the context of external evidence...
October 18, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Tadayuki Kou, Masashi Kanai, Mayumi Kamada, Masahiko Nakatsui, Shigemi Matsumoto, Yasushi Okuno, Manabu Muto
Recent innovations in next-generation sequencing (NGS) technologies have enabled comprehensive genomic profiling of human cancers in the clinical setting. The ability to profile has launched a worldwide trend known as precision medicine, and the fusion of genomic profiling and pharmacogenomics is paving the way for precision medicine for cancer. The profiling is coupled with information about chemical therapies available to patients with specific genotypes. As a result, the chemogenomic space in play is not only the standard chemical and genome space but also the mutational genome and chemical space...
2018: Methods in Molecular Biology
Yoichiro Kato, Hitoshi Zembutsu, Ryo Takata, Tomohiko Matsuura, Renpei Kato, Mitsugu Kanehira, Kazuhiro Iwasaki, Noriyuki Yamada, Toyomasa Katagiri, Tamotsu Sugai, Tomoaki Fujioka, Yusuke Nakamura, Wataru Obara
The present study established systems to predict the chemo-sensitivity of muscle invasive bladder cancer (MIBC) for neoadjuvant chemotherapy (NAC) with methotrexate, vinblastine, doxorubicin plus cisplatin (M-VAC) and carboplatin plus gemcitabine (CaG) by analyzing microarray data. The primary aim of the study was to investigate whether the clinical response would increase by combining these prediction systems. Treatment of each MIBC case was allocated into M-VAC NAC, CaG NAC, surgery, or radiation therapy groups by their prediction score (PS), which was calculated using the designed chemo-sensitivity prediction system...
November 2018: Oncology Letters
Guilherme Suarez-Kurtz
Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAF<1%) in addition to polymorphisms (MAF>1%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics...
October 11, 2018: Clinics
Emily G Greengard
Neuroblastoma is the most common extra-cranial solid tumor encountered in childhood and accounts for 15% of pediatric cancer-related deaths. Although there has been significant improvement in the outcomes for patients with high-risk disease, the therapy needed to achieve a cure is quite toxic and for those that do experience a disease recurrence, the prognosis is very dismal. Given this, there is a tremendous need for novel therapies for children with high-risk neuroblastoma and the molecular discoveries over recent years provide hope for developing new, less toxic, and potentially more efficacious treatments...
October 15, 2018: Children
Kaitlin E Sundling, Alarice C Lowe
Circulating tumor cells (CTCs) have long been assumed to be the substrate of cancer metastasis. However, only in recent years have we begun to leverage the potential of CTCs found in minimally invasive peripheral blood specimens to improve care for cancer patients. Currently, CTC enumeration is an accepted prognostic indicator for breast, prostate, and colorectal cancer; however, CTC enumeration remains largely a research tool. More recently, the focus has shifted to CTC characterization and isolation which holds great promise for predictive testing...
October 15, 2018: Advances in Anatomic Pathology
Shaimaa Bakr, Olivier Gevaert, Sebastian Echegaray, Kelsey Ayers, Mu Zhou, Majid Shafiq, Hong Zheng, Jalen Anthony Benson, Weiruo Zhang, Ann N C Leung, Michael Kadoch, Chuong D Hoang, Joseph Shrager, Andrew Quon, Daniel L Rubin, Sylvia K Plevritis, Sandy Napel
Medical image biomarkers of cancer promise improvements in patient care through advances in precision medicine. Compared to genomic biomarkers, image biomarkers provide the advantages of being non-invasive, and characterizing a heterogeneous tumor in its entirety, as opposed to limited tissue available via biopsy. We developed a unique radiogenomic dataset from a Non-Small Cell Lung Cancer (NSCLC) cohort of 211 subjects. The dataset comprises Computed Tomography (CT), Positron Emission Tomography (PET)/CT images, semantic annotations of the tumors as observed on the medical images using a controlled vocabulary, and segmentation maps of tumors in the CT scans...
October 16, 2018: Scientific Data
Michele Carbone, Ivano Amelio, El Bachir Affar, James Brugarolas, Lisa A Cannon-Albright, Lewis C Cantley, Webster K Cavenee, Zhijian Chen, Carlo M Croce, Alan D' Andrea, David Gandara, Carlotta Giorgi, Wei Jia, Qing Lan, Tak Wah Mak, James L Manley, Katsuhiko Mikoshiba, Jose N Onuchic, Harvey I Pass, Paolo Pinton, Carol Prives, Nathaniel Rothman, Said M Sebti, James Turkson, Xifeng Wu, Haining Yang, Herbert Yu, Gerry Melino
The relative contribution of intrinsic genetic factors and extrinsic environmental ones to cancer aetiology and natural history is a lengthy and debated issue. Gene-environment interactions (G x E) arise when the combined presence of both a germline genetic variant and a known environmental factor modulates the risk of disease more than either one alone. A panel of experts discussed our current understanding of cancer aetiology, known examples of G × E interactions in cancer, and the expanded concept of G × E interactions to include somatic cancer mutations and iatrogenic environmental factors such as anti-cancer treatment...
October 15, 2018: Cell Death and Differentiation
Hui Liu, Yan Zhao, Lin Zhang, Xing Chen
Patients of the same cancer may differ in their responses to a specific medical therapy. Identification of predictive molecular features for drug sensitivity holds the key in the era of precision medicine. Human cell lines have harbored most of the same genetic changes found in patients' tumors and thus are widely used in the research of drug response. In this work, we formulated drug-response prediction as a recommender system problem and then adopted a neighbor-based collaborative filtering with global effect removal (NCFGER) method to estimate anti-cancer drug responses of cell lines by integrating cell-line similarity networks and drug similarity networks based on the fact that similar cell lines and similar drugs exhibit similar responses...
September 22, 2018: Molecular Therapy. Nucleic Acids
Juan Ignacio Pascual Piédrola, Mateo Hevia Suárez, Francisco Javier Ancizu Markert, Angel García Cortés, Pablo Doménech López, Santiago Chiva San Román, José María Velis Campillo, Fernando Díez-Caballero Alonso, José Enrique Robles García, David Rosell Costa, Felipe Villacampa Aubá, Fernando Ramón de Fata Chillón, Bernardino Miñana López
Prostate cancer is a health problem in many Countries worldwide. Understanding the essential function of androgens in the prostate physiology led to the development of hormonal blockade as a therapeutic option in advanced disease, with limited response with time and development of resistance. In this stage, where castration resistant prostate cancer (CRPC) is defined, it is associated with poor prognosis because survival varies between 18 and 24 months. Even with castration levels, tumors are dependent on the functional androgen receptor (AR)...
September 2018: Archivos Españoles de Urología
Chin-Sheng Hung, Sheng-Chao Wang, Yi-Ting Yen, Tzong-Huei Lee, Wu-Che Wen, Ruo-Kai Lin
Lung and breast cancer are the leading causes of mortality in women worldwide. The discovery of molecular alterations that underlie these two cancers and corresponding drugs has contributed to precision medicine. We found that CCND2 is a common target in lung and breast cancer. Hypermethylation of the CCND2 gene was reported previously; however, no comprehensive study has investigated the clinical significance of CCND2 alterations and its applications and drug discovery. Genome-wide methylation and quantitative methylation-specific real-time polymerase chain reaction (PCR) showed CCND2 promoter hypermethylation in Taiwanese breast cancer patients...
October 10, 2018: International Journal of Molecular Sciences
Weimin Yin, Xiaolu Yu, Xuejia Kang, Yuge Zhao, Pengfei Zhao, Hongyue Jin, Xuhong Fu, Yakun Wan, Chengyuan Peng, Yongzhuo Huang
Precision medicine has made a significant breakthrough in the past decade. The most representative success is the molecular targeting therapy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) with oncogenic drivers, approved by the US Food and Drug Administration (FDA) as first-line therapeutics for substituting chemotherapy. However, the rapidly developed TKI resistance invariably leads to unsustainable treatment. For example, gefitinib is the first choice for advanced NSCLC with EGFR mutation, but most patients would soon develop secondary EGFRT790M mutation and acquire gefitinib resistance...
October 11, 2018: Small
Linda M Polfus, Laura M Raffield, Marsha M Wheeler, Russell P Tracy, Leslie A Lange, Guillaume Lettre, Amanda Miller, Adolfo Correa, Russell P Bowler, Joshua C Bis, Shabnam Salimi, Nancy Swords Jenny, Nathan Pankratz, Biqi Wang, Michael H Preuss, Lisheng Zhou, Arden Moscati, Girish N Nadkarni, Ruth J F Loos, Xue Zhong, Bingshan Li, Jill M Johnsen, Deborah A Nickerson, Alex P Reiner, Paul L Auer, Nhlbi Trans-Omics For Precision Medicine Consortium
E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies (GWAS) in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine (TOPMed) whole-genome sequencing (WGS) data in 2,249 African Americans (AAs) from the Jackson Heart Study (JHS), we examined genome-wide associations with soluble E-selectin levels. In addition to replicating known signals at ABO, we identified a novel association of a common loss-of-function, missense variant in FUT6 (rs17855739,p...
October 10, 2018: Human Molecular Genetics
Mengyuan Yang, Xuefeng Fang, Jun Li, Dong Xu, Qian Xiao, Shaojun Yu, Hanguang Hu, Shanshan Weng, Kefeng Ding, Ying Yuan
BACKGROUND: Substantial progress has been made in metastatic colorectal cancer (mCRC) treatment, but there is still a fraction of patients cannot find any effective therapeutic strategy after guideline-recommended standard chemotherapy and molecular targeted therapy. CASE PRESENTATION: Here we present a KRAS/NRAS/BRAF wild-type mCRC patient who has been previously treated with FOLFIRI (fluorouracil, leucovorin, and irinotecan), XELOX (capecitabine and oxaliplatin), cetuximab and bevacizumab, and then received the next generation sequencing (NGS) and whose metastatic subcutaneous nodule was resected to generate patient-derived xenograft (PDX) models...
October 11, 2018: Cancer Biology & Therapy
Xiaofeng Dai, Yi Mei, Jianqi Nie, Zhonghu Bai
Adoptive T cell immunotherapy, involving the reprogramming of immune cells to target specific cancer or virus-infected cells, has been recognized as a promising novel approach for the treatment of complex diseases. The impressive global momentum of this therapeutic approach has highlighted the urgent need for establishing it as an effective and standardized onco-therapeutic approach in a large manufacturing scale. However, given its heterogeneity and uncertainty in nature, adoptive T cell immunotherapy is associated with a high failure rate that restricts its manufacturing to a limited number of institutions worldwide...
October 11, 2018: Biotechnology Journal
Partha Basu, Asima Mukhopadhyay, Ikuo Konishi
Recent advances in molecular biology of cancer have led to the development of targeted agents, mainly of monoclonal antibodies and small-molecule compounds. Unlike traditional drugs that inhibit DNA synthesis and mitosis, these agents target the signaling pathways of cancer cells, stroma, and vasculature in tumor tissues. For gynecologic cancers, drugs targeting angiogenesis such as anti-VEGF antibody have been used in the treatment of advanced or recurrent ovarian and cervical cancers, and the drugs targeting homologous recombination deficiency such as PARP inhibitors have been approved for maintenance after chemotherapy in platinum-sensitive ovarian cancer...
October 2018: International Journal of Gynaecology and Obstetrics
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