Is There a Role for Dual PI3K/Mtor Inhibitors for Patients Affected With
Total Page:16
File Type:pdf, Size:1020Kb
Load more
Recommended publications
-
The Drug Sensitivity and Resistance Testing (DSRT) Approach
A phenotypic screening and machine learning platform eciently identifies triple negative breast cancer-selective and readily druggable targets Prson Gautam 1 Alok Jaiswal 1 Tero Aittokallio 1, 2 Hassan Al Ali 3 Krister Wennerberg 1,4 Identifying eective oncogenic targets is challenged by the complexity of genetic alterations in 1Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Finland cancer and their poorly understood relation to cell function and survival. There is a need for meth- Current kinome coverage of kinase inhibitors in TNBC exhibit diverse kinase dependencies MFM-223 is selectively addicted to FGFR2 2Department of Mathematics and Statistics, University of Turku, Finland 3The Miami Project to Cure Paralysis, Peggy and Harold Katz Family Drug Discovery Center, A A Sylvester Comprehensive Cancer Center, and Department of Neurological Surgery and Medicine ods that rapidly and accurately identify “pharmacologically eective” targets without the require- clinical evaluation TN Kinases MFM-223 CAL-120 MDA-MB-231 TNBC TNBC TNBC TNBC TNBC TNBC HER2+ 100 University of Miami Miller School of Medicine, Miami, FL 33136, USA. non- HER2+ FGFR1 0.97 0.00 0.00 MFM-223 BL1 BL2 M MSL IM LAR ER+, PR+ 50 ment for priori knowledge of complex signaling networks. We developed an approach that uses ma- cancerous FGFR2 56.46 0.00 0.00 CAL-120 25 4 MDA-MB-231 Biotech Research & Innovation Centre (BRIC) and Novo Nordisk Foundation Center HCC1937 CAL-85-1 CAL-120 MDA-MB-231 DU4475 CAL-148 MCF-10A SK-BR-3 BT-474 FGFR3 25.10 0.00 0.00 0 chine learning to relate results from unbiased phenotypic screening of kinase inhibitors to their bio- for Stem Cell Biology (DanStem), University of Copenhagen, Denmark HCC1599 HDQ-P1 BT-549 MDA-MB-436 MFM-223 FGFR4 0.00 0.00 0.00 MAXIS*Bk Clinical status MDA-MB-468 CAL-51 Hs578T MDA-MB-453 score chemical activity data. -
New Contributions in Undergraduate Research
PSU McNair Scholars Online Journal Volume 11 Issue 1 Without Borders: Original Contributions Article 6 in Undergraduate Research 2017 Wings Outstretched: New Contributions in Undergraduate Research Follow this and additional works at: https://pdxscholar.library.pdx.edu/mcnair Let us know how access to this document benefits ou.y Recommended Citation (2017) "Wings Outstretched: New Contributions in Undergraduate Research," PSU McNair Scholars Online Journal: Vol. 11: Iss. 1, Article 6. https://doi.org/10.15760/mcnair.2017.01 This open access Full Issue is distributed under the terms of the Creative Commons Attribution-NonCommercial- ShareAlike 4.0 International License (CC BY-NC-SA 4.0). All documents in PDXScholar should meet accessibility standards. If we can make this document more accessible to you, contact our team. Portland State University McNair Research Journal 2017 Without Borders: Original Contributions in Undergraduate Research 2017 Ronald E. McNair Scholars Journal Portland State University 1 About the Program The Portland State University (PSU) Ronald E. McNair Scholars Program at Portland State University works with motivated and talented undergraduates who want to pursue PhDs. It introduces juniors and seniors who are first-generation and low income, and/or members of under-represented groups to academic research and to effective strategies for getting into and graduating from PhD programs. The McNair Scholars Program has academic-year activities and a full-time summer research internship. Scholars take academic and skills-building seminars and workshops during the year, and each scholar works closely with a faculty mentor on original research in the summer. Scholars present their research findings at the McNair Summer Symposium and at other conferences, and are encouraged to publish their papers in the McNair Journal and other scholarly publications. -
Biological Heterogeneity of Chondrosarcoma: from (Epi) Genetics Through Stemness and Deregulated Signaling to Immunophenotype
cancers Review Biological Heterogeneity of Chondrosarcoma: From (Epi) Genetics through Stemness and Deregulated Signaling to Immunophenotype Agnieszka Zaj ˛ac 1 , Sylwia K. Król 2 , Piotr Rutkowski 1 and Anna M. Czarnecka 1,3,* 1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] (A.Z.); [email protected] (P.R.) 2 Department of Molecular and Translational Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, 02-781 Warsaw, Poland; [email protected] 3 Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-176 Warsaw, Poland * Correspondence: [email protected] Simple Summary: Chondrosarcoma (ChS) is the second most frequently diagnosed malignant bone tumor of cartilaginous origin and is generally resistant to standard treatment options. In this paper, we aim to review the current state of the knowledge regarding ChS. We discuss the genetic, epigenetic, and molecular abnormalities underlying its substantial biological and clinical heterogeneity. This review summarizes the critical genetic and molecular drivers of ChS development and progression, contributing to its radio- and chemotherapy resistance. We describe genomic aberrations and point mutations, as well as epigenetic modifications and deregulated signal transduction pathways. We Citation: Zaj ˛ac,A.; Król, S.K.; provide an insight into the stem-like characteristics and immunophenotype of ChS. The paper also Rutkowski, P.; Czarnecka, A.M. outlines potential diagnostic and prognostic biomarkers of ChS and recently identified novel targets Biological Heterogeneity of for future pharmacological interventions in patients. Chondrosarcoma: From (Epi) Genetics through Stemness and Abstract: Deregulated Signaling to Chondrosarcoma (ChS) is a primary malignant bone tumor. -
Mutational Landscape Differences Between Young-Onset and Older-Onset Breast Cancer Patients Nicole E
Mealey et al. BMC Cancer (2020) 20:212 https://doi.org/10.1186/s12885-020-6684-z RESEARCH ARTICLE Open Access Mutational landscape differences between young-onset and older-onset breast cancer patients Nicole E. Mealey1 , Dylan E. O’Sullivan2 , Joy Pader3 , Yibing Ruan3 , Edwin Wang4 , May Lynn Quan1,5,6 and Darren R. Brenner1,3,5* Abstract Background: The incidence of breast cancer among young women (aged ≤40 years) has increased in North America and Europe. Fewer than 10% of cases among young women are attributable to inherited BRCA1 or BRCA2 mutations, suggesting an important role for somatic mutations. This study investigated genomic differences between young- and older-onset breast tumours. Methods: In this study we characterized the mutational landscape of 89 young-onset breast tumours (≤40 years) and examined differences with 949 older-onset tumours (> 40 years) using data from The Cancer Genome Atlas. We examined mutated genes, mutational load, and types of mutations. We used complementary R packages “deconstructSigs” and “SomaticSignatures” to extract mutational signatures. A recursively partitioned mixture model was used to identify whether combinations of mutational signatures were related to age of onset. Results: Older patients had a higher proportion of mutations in PIK3CA, CDH1, and MAP3K1 genes, while young- onset patients had a higher proportion of mutations in GATA3 and CTNNB1. Mutational load was lower for young- onset tumours, and a higher proportion of these mutations were C > A mutations, but a lower proportion were C > T mutations compared to older-onset tumours. The most common mutational signatures identified in both age groups were signatures 1 and 3 from the COSMIC database. -
Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia
Published OnlineFirst September 20, 2013; DOI: 10.1158/2159-8290.CD-13-0350 RESEARCH ARTICLE Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia Tea Pemovska 1 , Mika Kontro 2 , Bhagwan Yadav 1 , Henrik Edgren 1 , Samuli Eldfors1 , Agnieszka Szwajda 1 , Henrikki Almusa 1 , Maxim M. Bespalov 1 , Pekka Ellonen 1 , Erkki Elonen 2 , Bjørn T. Gjertsen5 , 6 , Riikka Karjalainen 1 , Evgeny Kulesskiy 1 , Sonja Lagström 1 , Anna Lehto 1 , Maija Lepistö1 , Tuija Lundán 3 , Muntasir Mamun Majumder 1 , Jesus M. Lopez Marti 1 , Pirkko Mattila 1 , Astrid Murumägi 1 , Satu Mustjoki 2 , Aino Palva 1 , Alun Parsons 1 , Tero Pirttinen 4 , Maria E. Rämet 4 , Minna Suvela 1 , Laura Turunen 1 , Imre Västrik 1 , Maija Wolf 1 , Jonathan Knowles 1 , Tero Aittokallio 1 , Caroline A. Heckman 1 , Kimmo Porkka 2 , Olli Kallioniemi 1 , and Krister Wennerberg 1 ABSTRACT We present an individualized systems medicine (ISM) approach to optimize cancer drug therapies one patient at a time. ISM is based on (i) molecular profi ling and ex vivo drug sensitivity and resistance testing (DSRT) of patients’ cancer cells to 187 oncology drugs, (ii) clinical implementation of therapies predicted to be effective, and (iii) studying consecutive samples from the treated patients to understand the basis of resistance. Here, application of ISM to 28 samples from patients with acute myeloid leukemia (AML) uncovered fi ve major taxonomic drug-response sub- types based on DSRT profi les, some with distinct genomic features (e.g., MLL gene fusions in subgroup IV and FLT3 -ITD mutations in subgroup V). Therapy based on DSRT resulted in several clinical responses. -
( 12 ) United States Patent
US010624968B2 (12 ) United States Patent (10 ) Patent No.: US 10,624,968 B2 Bennett et al. (45 ) Date of Patent : Apr. 21 , 2020 ( 54 ) COMPOUNDS FOR TREATING CANCER WO 2005113554 12/2005 WO 2006078161 7/2006 WO 2006078846 7/2006 (71 ) Applicant: Bicycle Therapeutics Limited , WO 2006122806 11/2006 Cambridge (GB ) WO 2007016176 2/2007 WO 2007044729 4/2007 ( 72 ) Inventors : Gavin Bennett , Cambridge (GB ) ; WO 2007053452 5/2007 Daniel Paul Teufel , Cambridge (GB ) WO 2007070514 6/2007 WO 2007084786 7/2007 WO 2007129161 11/2007 ( 73 ) Assignee : BICYCLERD LIMITED , Cambridge WO 2008039218 4/2008 (GB ) WO 2008109943 9/2008 WO 2008118802 10/2008 ( * ) Notice : Subject to any disclaimer, the term of this WO 2009098450 8/2009 patent is extended or adjusted under 35 WO 2009114512 9/2009 WO 2010089115 8/2010 U.S.C. 154 ( b ) by 0 days . WO 2011090760 7/2011 WO 2013050615 4/2013 (21 ) Appl. No.: 15 /862,964 WO 2016067035 5/2016 WO 2017191460 11/2017 ( 22 ) Filed : Jan. 5 , 2018 WO 2018127699 7/2018 (65 ) Prior Publication Data OTHER PUBLICATIONS US 2018/0200378 A1 Jul. 19 , 2018 Paul Polakis . Antibody Drug Conjugates for Cancer Therapy. Pharmacol Rev. Jan 1 , 2016 ;68 ( 1 ) :3-19 . ( Year: 2016 ) . * Related U.S. Application Data Heinis et al. Phage- encoded combinatorial chemical libraries based (60 ) Provisional application No. 62/ 443,508, filed on Jan. on bicyclic peptides . Nat Chem Biol, 2009 ; 5 ( 7 ) : 502-07. ( Year: 2009) . * 6 , 2017 Eder et al. A phage display derived stabilised bicyclic peptide (51 ) Int. Ci. targeting MMP- 14 shows high imaging contrast in small animal A61K 47/64 ( 2017.01 ) PET imaging. -
Genetic and Bioinformatic Analyses of the Expression and Function of PI3K
Zhou et al. BMC Medical Genomics 2012, 5:34 http://www.biomedcentral.com/1755-8794/5/34 RESEARCH ARTICLE Open Access Genetic and bioinformatic analyses of the expression and function of PI3K regulatory subunit PIK3R3 in an Asian patient gastric cancer library Jin Zhou1, Geng Bo Chen3, Yew Chung Tang4, Rohit Anthony Sinha1, Yonghui Wu8, Chui Sun Yap1, Guihua Wang5, Junbo Hu5, Xianmin Xia5, Patrick Tan2,8,9,10, Liang Kee Goh3,6,7 and Paul Michael Yen1* Abstract Background: While there is strong evidence for phosphatidylinositol 3-kinase (PI3K) involvement in cancer development, there is limited information about the role of PI3K regulatory subunits. PIK3R3, the gene that encodes the PI3K regulatory subunit p55γ, is over-expressed in glioblastoma and ovarian cancers, but its expression in gastric cancer (GC) is not known. We thus used genetic and bioinformatic approaches to examine PIK3R3 expression and function in GC, the second leading cause of cancer mortality world-wide and highly prevalent among Asians. Methods: Primary GC and matched non-neoplastic mucosa tissue specimens from a unique Asian patient gastric cancer library were comprehensively profiled with platforms that measured genome-wide mRNA expression, DNA copy number variation, and DNA methylation status. Function of PIK3R3 was predicted by IPA pathway analysis of co-regulated genes with PIK3R3, and further investigated by siRNA knockdown studies. Cell proliferation was estimated by crystal violet dye elution and BrdU incorporation assay. Cell cycle distribution was analysed by FACS. Results: PIK3R3 was significantly up-regulated in GC specimens (n = 126, p < 0.05), and 9.5 to 15% tumors showed more than 2 fold increase compare to the paired mucosa tissues. -
A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase. -
Differential Prioritization of Therapies to Subtypes of Triple Negative Breast Cancer Using a Systems Medicine Method
www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 54), pp: 92926-92942 Research Paper Differential prioritization of therapies to subtypes of triple negative breast cancer using a systems medicine method Henri Wathieu1, Naiem T. Issa1,*, Aileen I. Fernandez1,*, Manisha Mohandoss2, Deanna M. Tiek1, Jennifer L. Franke1, Stephen W. Byers1,2, Rebecca B. Riggins1 and Sivanesan Dakshanamurthy1,2 1Georgetown-Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, 20057 USA 2Department of Biochemistry and Molecular Biology, Georgetown University, Washington, DC, 20057 USA *These authors have contributed equally to this work Correspondence to: Sivanesan Dakshanamurthy, email: [email protected] Keywords: triple negative breast cancer, systems biology, gene expression analysis, molecular subtyping, drug development Received: April 02, 2017 Accepted: September 08, 2017 Published: October 09, 2017 Copyright: Wathieu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Triple negative breast cancer (TNBC) is a group of cancers whose heterogeneity and shortage of effective drug therapies has prompted efforts to divide these cancers into molecular subtypes. Our computational platform, entitled GenEx-TNBC, applies concepts in systems biology and polypharmacology to prioritize thousands of approved and experimental drugs for therapeutic potential against each molecular subtype of TNBC. Using patient-based and cell line-based gene expression data, we constructed networks to describe the biological perturbation associated with each TNBC subtype at multiple levels of biological action. -
A Phase Ib Study of Alpelisib Or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer
Author Manuscript Published OnlineFirst on July 27, 2020; DOI: 10.1158/1078-0432.CCR-20-1008 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A Phase Ib study of alpelisib or buparlisib combined with tamoxifen plus goserelin in premenopausal women with HR-positive HER2-negative advanced breast cancer Yen-Shen Lu,1 Keun Seok Lee,2 Tsu-Yi Chao,3 Ling-Ming Tseng,4 Imjai Chitapanarux,5 Shin-Cheh Chen,6 Chien-Ting Liu,7 Joohyuk Sohn,8 Jee Hyun Kim,9 Yuan-Ching Chang,10 Youngsen Yang,11 Kanjana Shotelersuk,12 Kyung Hae Jung,13 Roberta Valenti,14 Cassandra Slader,14 Melissa Gao,14 Yeon Hee Park15 1Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. 2Center for Breast Cancer, National Cancer Center, Goyang, Republic of Korea. 3Division of Hematology/Oncology, Shuang Ho Hospital and Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan. 4Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University in Taipei. 5Division of Radiation Oncology, Department of Radiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 6Breast Surgery Division, Chang Gung Memorial Hospital, Linkou, Taoyouan City, Taiwan. 7Division of Hematology and Oncology, Chang Gung Memorial Hospital-Kaohsiung, Kaohsiung City, Taiwan. 8Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea. 9Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, South Korea. 10Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan. 11Taichung Veterans General Hospital, Taichung, Taiwan. 12Division of Therapeutic Radiology and Oncology, Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. -
Original Article a Preclinical Report of a Cobimetinib-Inspired Novel
Am J Cancer Res 2021;11(6):2590-2617 www.ajcr.us /ISSN:2156-6976/ajcr0131974 Original Article A preclinical report of a cobimetinib-inspired novel anticancer small-molecule scaffold of isoflavones, NSC777213, for targeting PI3K/AKT/mTOR/MEK in multiple cancers Bashir Lawal1,2*, Wen-Cheng Lo3,4,5*, Ntlotlang Mokgautsi1,2, Maryam Rachmawati Sumitra1,2, Harshita Khedkar1,2, Alexander TH Wu6,7,8,9, Hsu-Shan Huang1,2,10,11 1PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; 2Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; 3Department of Surgery, Division of Neurosurgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; 4Department of Neurosurgery, Taipei Medical University Hospital, Taipei 11031, Taiwan; 5Taipei Neuroscience Institute, Taipei Medical University, Taipei 11031, Taiwan; 6TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan; 7The PhD Program of Translational Medicine, College of Science and Technology, Taipei Medical University, Taipei 11031, Taiwan; 8Clinical Research Center, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan; 9Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 11490, Taiwan; 10School of Pharmacy, National Defense Medical Center, Taipei 11490, -
Deciphering the Long Non-Coding Rnas and Micrornas Coregulation Networks in Ovarian Cancer Development: an Overview
cells Review Deciphering the Long Non-Coding RNAs and MicroRNAs Coregulation Networks in Ovarian Cancer Development: An Overview César López-Camarillo 1,2,* , Erika Ruíz-García 2,3 , Yarely M. Salinas-Vera 4 , Macrina B. Silva-Cázares 5 , Olga N. Hernández-de la Cruz 1, Laurence A. Marchat 6 and Dolores Gallardo-Rincón 2,3 1 Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, 03100 CDMX, Mexico; [email protected] 2 Grupo de Investigación en Cáncer de Ovario y Endometrio, Instituto Nacional de Cancerología, 14080 CDMX, Mexico; [email protected] (E.R.-G.); [email protected] (D.G.-R.) 3 Laboratorio de Medicina Traslacional y Departamento de Tumores Gastrointestinales, Instituto Nacional de Cancerología, 14080 CDMX, Mexico 4 Departamento de Bioquímica, CINVESTAV-IPN, 07360 CDMX, Mexico; [email protected] 5 Coordinación Académica Región Altiplano, Universidad Autónoma de San Luis Potosí, 78700 San Luis Potosí, Mexico; [email protected] 6 Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, 07340 CDMX, Mexico; [email protected] * Correspondence: [email protected] Abstract: Non-coding RNAs are emergent elements from the genome, which do not encode for proteins but have relevant cellular functions impacting almost all the physiological processes oc- Citation: López-Camarillo, C.; curring in eukaryotic cells. In particular, microRNAs and long non-coding RNAs (lncRNAs) are a Ruíz-García, E.; Salinas-Vera, Y.M.; new class of small RNAs transcribed from the genome, which modulate the expression of specific Silva-Cázares, M.B.; Hernández-de la Cruz, O.N.; Marchat, L.A.; genes at transcriptional and posttranscriptional levels, thus adding a new regulatory layer in the flux Gallardo-Rincón, D.