Methods of treating urothelial carcinoma

Abstract

Methods and compositions for treating a urothelial and/or a micropapillary carcinoma, such as a micropapillary urothelial carcinoma are disclosed.

1 .- 30 . (canceled) 
     
     
         31 . A method of treating a subject having a urothelial carcinoma, comprising administering to the subject an effective amount of an agent that targets and/or inhibits HER2, thereby treating the urothelial carcinoma. 
     
     
         32 . The method of  claim 31 , wherein the urothelial carcinoma is a micropapillary urothelial carcinoma (MPUC). 
     
     
         33 . The method of  claim 31 , further comprising identifying the subject, or a cancer or tumor sample from the subject, as having one or both of:
 (a) the presence or absence of an alteration in HER2; or   (b) the presence or absence of a micropapillary histology.   
     
     
         34 . A method of treating a subject having a carcinoma, comprising:
 acquiring knowledge of:   (a) the presence of an alteration in HER2; and   (b) the presence of a micropapillary histology in the subject, or a cancer or tumor sample from the subject; and   administering to the subject an effective amount of an agent that targets and/or inhibits HER2, wherein the carcinoma is chosen from a cancer of the urinary tract, bladder, or urothelial cells,   thereby treating the carcinoma.   
     
     
         35 . The method of  claim 34 , wherein the carcinoma does not have, or is identified as not having, a gene amplification or overexpression of HER2 or a HER2 gene product. 
     
     
         36 . The method of  claim 34 , wherein the carcinoma comprises, or is identified as having, an alteration in HER2 that results in an increased activity of a HER2 gene product, compared to a wild type activity of HER2. 
     
     
         37 . The method of  claim 34 , wherein the alteration in HER2 is chosen from:
 (i) a substitution, a deletion or an insertion;   (ii) an alteration in the extracellular domain of HER2;   (iii) an alteration in domain II of HER2;   (iv) a missense mutation;   (v) a substitution at position 310 of HER2;   (vi) a substitution of a serine residue at position 310 of HER2 to phenylalanine or tyrosine;   (vii) a substitution at position 157 of HER2; or   (viii) a substitution of an arginine residue at position 157 of HER2 to tryptophan.   
     
     
         38 . The method of  claim 34 , wherein the subject does not have, or is identified as not having, an elevated level of a HER2 gene product; or is negative for, or is identified as being negative for, a HER2 gene product. 
     
     
         39 . The method of  claim 34 , wherein the subject is undergoing or has undergone treatment with a non-HER2 therapeutic agent or therapeutic modality. 
     
     
         40 . The method of  claim 39 , wherein the non-HER2 therapeutic agent or therapeutic modality comprises one or more of: methotrexate, vinblastine, doxorubicin, or cisplatin. 
     
     
         41 . The method of  claim 34 , wherein the agent inhibits a HER2 gene or gene product. 
     
     
         42 . The method of  claim 34 , wherein the agent is chosen from one or more of: a kinase inhibitor; a multi-specific kinase inhibitor; a HER2 inhibitor; an EGFR inhibitor; a pan ERBB inhibitor; a small molecule inhibitor that is selective for HER2; an antibody molecule; a monoclonal or a bispecific antibody against HER2; an antibody to HER2 conjugated to a cytotoxic agent; or a HER2 cellular immunotherapy. 
     
     
         43 . The method of  claim 34 , wherein the agent is chosen from one or more of: AV-203, AMG 888, U3-1287, APC8024, DN24-02, Neuvenge, Lapuleucel-T, MM-111, MM-121, SAR256212, MM-141, LJM716, REGN1400, MEHD7945A, RG7597, RG7116, Trastuzumab, trastuzumab emtansine (T-DM1), pertuzumab, afatinib, TAK-285, Neratinib, Dacomitinib, BMS-690514, BMS-599626, Pelitinib, CP-724714, Lapatinib, TAK-165, ARRY-380, AZD8931, or Neratinib. 
     
     
         44 . The method of  claim 34 , wherein the agent is chosen from an antisense molecule, a ribozyme, a double stranded RNA, or a triple helix molecule that hybridizes to and/or inhibits a HER2 nucleic acid. 
     
     
         45 . A method of determining the presence of a HER2 alteration in a urothelial and/or a micropapillary carcinoma, comprising (i), (ii) or both (i)-(ii):
 (i) acquiring knowledge that a nucleic acid molecule comprising the HER2 alteration is present in a tumor sample from a subject; and/or   (ii) acquiring knowledge of a micropapillary histology in a tumor sample from a subject; and   responsive to a determination of the presence of the HER2 alteration and/or micropapillary histology, the method further comprises one or more of:   (1) stratifying a patient population;   (2) identifying or selecting the subject as likely or unlikely to respond to a HER2 inhibitor treatment;   (3) selecting a treatment option comprising an agent that targets and/or inhibits HER2;   (4) administering an agent that targets and/or inhibits HER2; or   (5) evaluating the likelihood of increased or decreased patient survival.   
     
     
         46 . A method for screening for an agent that inhibits the expression or activity of HER2 having an alteration, comprising:
 optionally, determining if the alteration is present;   contacting a polypeptide or protein comprising the alteration or a host cell expressing the alteration with a candidate agent; and   detecting a change in a parameter associated with the alteration,   wherein said parameter is selected from one or more of:   (i) direct binding of the candidate agent to the polypeptide or protein comprising the alteration;   (ii) a change in kinase activity;   (iii) a change in an activity of a cell containing the alteration;   (iv) a change in tumor present in an animal subject; or   (v) a change in the level of the polypeptide or protein comprising the alteration or a nucleic acid molecule comprising the alteration.   
     
     
         47 . A kit comprising an agent that targets and/or inhibits HER2, or a composition comprising an agent that targets and/or inhibits HER2, with instructions for use in treating a urothelial and/or a micropapillary urothelial carcinoma, and/or instructions for determining the presence of a HER2 alteration and/or a MPUC histology, wherein the HER2 alteration is chosen from:
 (i) a substitution, a deletion or an insertion;   (ii) an alteration in the extracellular domain of HER2;   (iii) an alteration in domain II of HER2;   (iv) a missense mutation;   (v) a substitution at position 310 of HER2;   (vi) a substitution of a serine residue at position 310 of HER2 to phenylalanine or tyrosine;   (vii) a substitution at position 157 of HER2; or   (viii) a substitution of an arginine residue at position 157 of HER2 to tryptophan.   
     
     
         48 . A purified or an isolated preparation of a nucleic acid derived from a urothelial and/or a micropapillary urothelial carcinoma, containing an interrogation position useful for determining if a HER2 alteration is present, disposed in a sequencing device, or a sample holder for use in such a device, wherein the HER2 alteration is chosen from:
 (i) a substitution, a deletion or an insertion;   (ii) an alteration in the extracellular domain of HER2;   (iii) an alteration in domain II of HER2;   (iv) a missense mutation;   (v) a substitution at position 310 of HER2;   (vi) a substitution of a serine residue at position 310 of HER2 to phenylalanine or tyrosine;   (vii) a substitution at position 157 of HER2; or   (viii) a substitution of an arginine residue at position 157 of HER2 to tryptophan.   
     
     
         49 . A reaction mixture, comprising:
 a detection reagent, or a purified or isolated preparation thereof; and   a target nucleic acid derived from a urothelial and/or a micropapillary urothelial carcinoma cell, which comprises a sequence having an interrogation position for a HER2 alteration, wherein the HER2 alteration is chosen from:   (i) a substitution, a deletion or an insertion;   (ii) an alteration in the extracellular domain of HER2;   (iii) an alteration in domain II of HER2;   (iv) a missense mutation;   (v) a substitution at position 310 of HER2;   (vi) a substitution of a serine residue at position 310 of HER2 to phenylalanine or tyrosine;   (vii) a substitution at position 157 of HER2; or   (viii) a substitution of an arginine residue at position 157 of HER2 to tryptophan.   
     
     
         50 . A method of making a reaction mixture of  claim 49 , comprising:
 combining a detection reagent, or a purified or isolated preparation thereof, with a target nucleic acid derived from a urothelial and/or a micropapillary urothelial carcinoma, which comprises a sequence having an interrogation position for a HER2 alteration, wherein the HER2 alteration is chosen from:   (i) a substitution, a deletion or an insertion;   (ii) an alteration in the extracellular domain of HER2;   (iii) an alteration in domain II of HER2;   (iv) a missense mutation;   (v) a substitution at position 310 of HER2;   (vi) a substitution of a serine residue at position 310 of HER2 to phenylalanine or tyrosine;   (vii) a substitution at position 157 of HER2; or   (viii) a substitution of an arginine residue at position 157 of HER2 to tryptophan.