US010202605B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,202 , 605 B2 Kang et al. (45 ) Date of Patent: * Feb . 12, 2019 (54 ) METHODS OF IDENTIFYING AND (56 ) References Cited TREATING POOR - PROGNOSIS CANCERS U . S . PATENT DOCUMENTS ( 71) Applicant : The Trustees of Princeton University , 3 ,687 , 808 A 8 / 1972 Merigan , Jr. et al . .. .. 435 /91 . 3 Princeton , NJ (US ) 4 , 323 ,546 A 4 / 1982 Crockford et al. .. .. .. .. 424 / 1 . 49 4 ,683 , 195 A 7 / 1987 M MullisUITIS et al. 435 / 6 . 11 ( 72 ) Inventors : Yibin Kang , Princeton , NJ (US ) ; 4 ,683 , 202 A 7 / 1987 Mullis .. .. 435 / 91. 2 Guohong Hu , Piscataway, NJ (US ) 4 , 965, 188 A 10 / 1990 Mullis et al. .. .. .. 435 / 6 . 12 4 ,981 , 785 A 1 / 1991 Nayak .. .. .. 435 / 7 . 94 5 , 030 , 559 A 7 / 1991 Nicolson et al . .. .. .. .. 435 / 7 . 23 ( 73 ) Assignee : The Trustees of Princeton University , 5 ,034 , 506 A 7 / 1991 Summerton et al . .. 528 / 391 Princeton , NJ (US ) 5 , 223 , 409 A 6 / 1993 Ladner et al . .. .. .. .. 506 / 1 5 ,358 ,691 A 10 / 1994 Clark et al. .. .. .. .. 422 /64 ( * ) Notice : Subject to any disclaimer, the term of this 5 ,489 ,677 A 2 / 1996 Sanghvi et al. .. .. .. 536 / 22 . 1 patent is extended or adjusted under 35 5 , 538 , 848 A 7 / 1996 Livak et al . .. .. .. .. 435 / 6 . 16 5 ,539 , 082 A 7 / 1996 Nielsen et al . .. .. .. .. 530 / 300 U . S . C . 154 ( b ) by 0 days . 5 , 565, 332 A 10 / 1996 Hoogenboom et al . .. 435 /69 . 1 This patent is subject to a terminal dis 5 ,585 , 089 A 12 / 1996 Queen et al . .. .. .. .. .. 424 / 133 . 1 5 , 599 ,677 A 2 / 1997 Dowell et al. 435 / 7 . 4 . claimer . 5 ,602 , 240 A 2 / 1997 De Mesmaeker et al. 536 / 22 . 1 5 ,639 ,606 A 6 / 1997 Willey . 435 / 6 . 12 (21 ) Appl. No. : 15 /901 , 174 5 ,643 , 765 A 7 / 1997 Willey .. 435 /91 . 2 5 ,672 ,480 A 9 / 1997 Dowell et al. 435 / 7 . 4 ( 22 ) Filed : Feb. 21, 2018 5 , 705 , 188 A 1 / 1998 Junichi et al. 424 / 450 5 ,714 ,331 A 2 / 1998 Buchardt .. .. .. .. .. .. 435 / 6 . 14 5 ,719 ,262 A 2 / 1998 Buchardt . .. .. 530 / 300 (65 ) Prior Publication Data 5 ,736 , 137 A 4 / 1998 Anderson et al. .. .. .. 424 / 133 . 1 US 2018 /0230472 A1 Aug. 16 , 2018 5 , 824 , 544 A 10 / 1998 Armentano et al. .. .. 435 / 320 . 1 5 , 830 ,730 A 11/ 1998 German et al. .. .. .. .. 435 /455 Related U . S . Application Data (Continued ) (63 ) Continuation of application No . 15 /004 ,706 , filed on FOREIGN PATENT DOCUMENTS Jan . 22 , 2016 , now Pat. No. 9 , 932 , 587 , which is a continuation of application No . 14 /619 , 977 , filed on WOwo WO 1997 / 30731 8 / 1997 Feb . 11 , 2015 , now abandoned , which is a WO 1999 /02685 1 / 1999 continuation of application No. 12 /215 ,998 , filed on (Continued ) Jun . 30 , 2008 , now abandoned . OTHER PUBLICATIONS (60 ) Provisional application No . 60 / 937 ,789 , filed on Jun . Santiago et al, PNAS , 2008 , vol . 105 , pp . 5809 -5814 . * 28 , 2007 . Takahagi et al , Molecular Reproduction and Development, 2005 , vol. 71, pp . 331 - 338 . * (51 ) Int . Cl. Amano , et al. “ Dosage - Dependent over - Expression of Genes in the C07H 21/ 02 ( 2006 . 01 ) Trisomic Region of TSLCJE Mouse Model for Down Syndrome. ” Hum Mol Genet , 13 ( 13 ) : 1333 - 1340 ( 2004 ) . CO7H 21/ 04 ( 2006 .01 ) Anderson and Young , “ Quantitative Filter Hybridization . ” In Nucleic A61K 31/ 70 ( 2006 .01 ) Acid Hybridisation : A Practical Approach (Hames , et a 1 , Eds . ) , pp . C12N 15 / 113 ( 2010 .01 ) 73 - 111, IRL Press , Oxford Washington , DC ( 1985 ) . A61K 31 /00 ( 2006 .01 ) Ballestrero , et al . “ Tumor Necrosis Factor - Related Apoptosis A61K 31 /7105 ( 2006 .01 ) Inducing Ligand Cooperates with Anticancer Drugs to Overcome C120 1 / 6886 ( 2018 .01 ) Chemoresistance in Antiapoptotic Bcl - 2 Family Members Express A61K 31 / 337 ( 2006 .01 ) ing Jurkat Cells. " Clin Cancer Res, 10 ( 4 ) : 1463 - 1470 ( 2004 ) . A61K 31 / 704 ( 2006 . 01 ) (Continued ) A61K 45 /06 ( 2006 . 01 ) Primary Examiner — Sean McGarry A61K 31/ 713 ( 2006 .01 ) ( 74 ) Attorney , Agent, or Firm — Medlen & Carroll, LLP C12N 5 / 00 ( 2006 . 01 ) (52 ) U . S . CI. (57 ) ABSTRACT CPC . .. .. .. C12N 15 / 1135 ( 2013 .01 ) ; A61K 31/ 00 The present invention relates generally to methods for ( 2013 .01 ) ; A61K 31/ 337 ( 2013 . 01 ) ; A61K identifying cancer patients with a poor prognosis , and to 31 / 704 ( 2013 .01 ) ; A6IK 31/ 713 ( 2013 .01 ) ; therapeutic modalities for improving prognosis by combat A61K 31 /7105 ( 2013 .01 ) ; A61K 45 / 06 ing metastasis and abrogating chemoresistance in cancer (2013 . 01 ) ; C120 1 /6886 ( 2013 .01 ) ; C12N cells . Embodiments of the present invention provide an 2310 / 11 (2013 .01 ) ; CI2N 2310 / 14 ( 2013 .01 ) ; objective means of prognostication regarding the long - term C12N 2320 /30 ( 2013 .01 ) ; C12N 2320 / 31 outcome of an incident of cancer, breast cancer in particular . (2013 . 01 ) ; C12Q 2600 / 118 ( 2013 .01 ) ; C12Q Therapeutic modalities include immunotherapy and anti 2600/ 156 (2013 .01 ) sense therapy . Prognosis is determined by measuring the ( 58 ) Field of Classification Search number of copies of the metadherin gene in the patient' s None cells . See application file for complete search history . 15 Claims, 15 Drawing Sheets US 10 ,202 ,605 B2 Page 2 (56 ) References Cited Brown and Ruoslahti , “ Metadherin , a Cell Surface Protein in Breast Tumors That Mediates Lung Metastasis . ” Cancer Cell , 5 ( 4 ) : 365 U . S . PATENT DOCUMENTS 374 (2004 ) . Brummelkamp, et al . “ A System for Stable Expression of Short 5 , 872 , 154 A 2 / 1999 Wilson et al . .. .. .. .. 424 / 154 . 1 5 , 876 , 978 A 3 / 1999 Willey et al. .. .. .. 435 /91 . 2 Interfering RNAs in Mammalian Cells . ” Science , 296 (5567 ) : 550 5 , 885 ,530 A 3 / 1999 Babson et al. .. .. .. .. 422 /65 553 ( 2002 ) . 5 , 885 , 808 A 3 / 1999 Spooner 435 / 456 Caplen et a 1, “ Specific Inhibition of Gene Expression by Small 5 , 981, 225 A 11/ 1999 Kochanek et al . .. .. 435 /69 . 1 Double - Stranded RNAs in Invertebrate and Vertebrate Systems. " 5 , 994 , 106 A 11/ 1999 Kovesdi et al . .. .. .. .. .. 435 /91 . 4 Proc Natl Acad Sci U S A , 98 ( 17 ) :9742 -9747 ( 2001) . 5 , 994 , 128 A 11/ 1999 Fallaux et al. .. .. .. 435 /325 Carell, et al . “ A Novel Procedure for the Synthesis of Libraries 5 , 994 , 132 A 11/ 1999 Chamberlain et al. .. .. 435 / 369 Containing Small Organic Molecules .” Angewandte Chemie Inter 6 , 001, 557 A 12 / 1999 Wilson et al. .. .. .. .. 435 / 5 6 ,019 , 978 A 2 / 2000 Ertl et al. .. .. .. .. .. .. .. 424 / 199 . 1 national Edition in English , 33 (20 ) :2059 - 2061 ( 1994 ) . 6 ,033 , 908 A 3 / 2000 Bout et al. 435 / 325 Carell , et al. “ A Solution -Phase Screening Procedure for the Isola 6 , 054 , 297 A 4 / 2000 Carter et al. .. 435 /69 . 6 tion of Active Compounds from a Library ofMolecules . ” Angewandte 6 , 159 , 685 A 12 / 2000 Pinkel et al . .. .. .. .. .. 435 / 6 . 14 Chemie International Edition in English , 33 ( 20 ) :2061 -2064 ( 1994 ) . 6 , 159 , 750 A 12 / 2000 Edmonds . .. 436 / 537 Carrasco , et al . “ High -Resolution Genomic Profiles Define Distinct 6 , 180 , 349 B1 1 / 2001 Ginzinger et al. .. 435 /6 . 11 Clinico - Pathogenetic Subgroups of Multiple Myeloma Patients ." 6 , 180 , 370 B1 1 / 2001 Queen et al. .. .. .. .. 435 /69 . 6 6 , 198 , 107 B1 3 / 2001 Seville .. .. 250 /458 . 1 Cancer Cell , 9 ( 4 ) :313 - 325 (2006 ) . 6 , 312 ,694 B1 11 / 2001 Thorpe et al. .. 424 / 178 . 1 Carthew , “ Gene Silencing by Double - Stranded RNA. ” Curr Opin 6 ,506 , 559 B1 1 /2003 Fire et al. .. .. 435 /6 . 16 Cell Biol, 13 ( 2 ) : 244 - 248 ( 2001) . 7 , 273 , 855 B2 9 / 2007 Jupe . .. .. 514 / 44 R Chambers , et al . “ Dissemination and Growth of Cancer Cells in 2003/ 0022854 A1 1 / 2003 Dow et al . .. .. .. .. .. .. 514 / 44 A Metastatic Sites . ” Nat Rev Cancer , 2 ( 8 ) :563 - 572 (2002 ) . 2004 /0138171 A1 7 / 2004 Suzuki et al . .. .. 514 /53 Chen , et al . “ Gene Expression Patterns in Human Liver Cancers . ” 2004 / 0171552 A1 9 / 2004 Peled et al . .. .. .. 514 / 1 . 4 Mol Biol Cell , 13 (6 ) : 1929 - 1939 (2002 ) . 2005 /0208057 A1 9 / 2005 Ruoslahti et al . .. .. .. .. 424 / 155 . 1 Chin , et al . “ Genomic and Transcriptional Aberrations Linked to 2007 / 0087345 AL 4 /2007 Olson -Munoz et al. .. .. 435 / 6 . 11 Breast Cancer Pathophysiologies . ” Cancer Cell , 10 (6 ) :529 -541 2008 / 0090233 A1 4 / 2008 Garcia et al . .. .. .. 435 /6 .14 ( 2006 ) . Cho , et al. “ An Unnatural Biopolymer. ” Science , 261( 5126 ) : 1303 FOREIGN PATENT DOCUMENTS 1305 ( 1993 ) . Clark , et a 1 , "Genomic Analysis of Metastasis Reveals an Essential WO WO1999 /60010 11 / 1999 Role for Rhoc . ” Nature , 406 (6795 ) :532 -535 (2000 ) . WO WO 2000 /09675 2 / 2000 Crawley and Furge , “ Identification of Frequent Cytogenetic Aber WO WO 2000 / 12738 3 / 2000 rations in Hepatocellular Carcinoma Using Gene -Expression Microar WO WO 2001 / 98537 12 / 2001 ray Data. ” Genome Biol , 3 ( 12 ) : 1 - 8 (2002 ) . WO WO 2003 /070966 8 / 2003 Cull et al ., " Screening for receptor ligands using large libraries of WO WO 2003 / 072599 9 / 2003 peptides linked to the C terminus of the lac repressor. ” Proc . Natl . WO WO 2003 /075853 9 /2003 WO WO 2003 /084993 10 / 2003 Acad . Sci. USA 89 : 1865 - 1869 ( 1992 ) . WO WO 2004 / 071460 8 / 2004 Cwirla , et al . “ Peptides on Phage: A Vast Library of Peptides for WO WO 2004 /071499 8 / 2004 Identifying Ligands. ” Proc Natl Acad Sci USA , 87 ( 16 ) :6378 -6382 WO WO 2004 /098512 11/ 2004 ( 1990 ) . WO WO 2004 /098516 11/ 2004 Devlin , et al . “ Random Peptide Libraries: A Source of Specific WO WO 2005 /020899 3 / 2005 Protein Binding Molecules .” Science , 249 ( 4967 ) :404 -406 ( 1990 ) .