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 for selecting a treatment for a subject having a micropapillary carcinoma of the urinary tract, bladder, or urothelial cells, comprising:
 (a) detecting in a sample from the subject a HER2 alteration, wherein the HER2 alteration is:
 (i) an alteration in a HER2 gene that results in an increased activity of a HER2 gene product, compared to a wild type activity of a HER2 gene product; and/or 
 (ii) an alteration in a HER2 gene or gene product, wherein the alteration is: 
 a substitution, a deletion or an insertion in a HER2 gene, 
 an alteration in the extracellular domain of a HER2 polypeptide, 
 an alteration in domain II of a HER2 polypeptide, 
 a missense mutation in a HER2 gene, 
 a substitution at position 310 of a HER2 polypeptide, 
 a substitution of a serine residue at position 310 of a HER2 polypeptide to a phenylalanine or tyrosine residue, 
 a substitution at position 157 of a HER2 polypeptide, or
 a substitution of an arginine residue at position 157 of a HER2 polypeptide to a tryptophan residue; 
 
   (b) selecting a treatment for the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells in the subject based, at least in part, on the detecting, wherein the selected treatment comprises one or more agents that inhibit a HER2 gene or gene product; and   (c) generating a report indicating the selected treatment.   
     
     
         32 . The method of  claim 31 , wherein the report further comprises an indication of the presence in the sample of the HER2 alteration and/or an identification of nucleotide values of the HER2 alteration. 
     
     
         33 . The method of  claim 31 , wherein the report further comprises an indication of micropapillary histology of the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells. 
     
     
         34 . The method of  claim 32 , wherein the report further comprises an identifier for the subject. 
     
     
         35 . The method of  claim 31 , wherein the report further comprises information on a role of the HER2 alteration, and/or a wild type HER2 gene or gene product, in micropapillary carcinoma of the urinary tract, bladder, or urothelial cells. 
     
     
         36 . The method of  claim 31 , wherein the report further comprises:
 (a) information on prognosis of the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells in the subject;   (b) information on resistance of the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells in the subject to a treatment;   (c) information on likely effectiveness, acceptability, or advisability of a treatment for the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells in the subject;   (d) information or a recommendation to administer the selected treatment in combination with a second therapeutic agent or a different therapeutic modality; and/or   (e) information or a recommendation on a dosage and/or treatment regimen for the selected treatment.   
     
     
         37 . The method of  claim 31 , further comprising providing the report to the subject. 
     
     
         38 . The method of  claim 31 , further comprising providing the report to another person or entity. 
     
     
         39 . The method of  claim 38 , wherein the other person or entity is a caregiver, a physician, an oncologist, a hospital, a clinic, a third-party payor, an insurance company, or a government office. 
     
     
         40 . The method of  claim 37 , further comprising obtaining the sample, and providing the report within any of about 7 days, about 14 days, or about 21 days from obtaining the sample. 
     
     
         41 . The method of  claim 31 , wherein the report is in an electronic, web-based, or paper form. 
     
     
         42 . The method of  claim 31 , wherein the sample is derived from a tumor sample of the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells in the subject. 
     
     
         43 . The method of  claim 31 , further comprising obtaining the sample from subject. 
     
     
         44 . The method of  claim 31 , further comprising administering the selected treatment to the subject. 
     
     
         45 . The method of  claim 31 , wherein the subject is a human. 
     
     
         46 . The method of  claim 31 , wherein the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells lacks HER2 gene amplification or overexpression of a HER2 gene or gene product. 
     
     
         47 . The method of  claim 31 , wherein the subject does not have or is identified as not having HER2 gene amplification or overexpression of a HER2 gene or gene product. 
     
     
         48 . The method of  claim 31 , wherein the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells does not have, or is identified as not having, an elevated level of a HER2 gene product; or wherein the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells is negative for, or is identified as being negative for, an overexpressed HER2 gene product. 
     
     
         49 . The method of  claim 31 , wherein the subject does not have, or is identified as not having, an elevated level of a HER2 gene product; or wherein the subject is negative for a HER2 gene product. 
     
     
         50 . The method of  claim 31 , wherein the subject is undergoing or has undergone a treatment with a non-HER2 therapeutic agent or therapeutic modality. 
     
     
         51 . The method of  claim 50 , wherein the non-HER2 therapeutic agent or therapeutic modality comprises one or more of: methotrexate, vinblastine, doxorubicin, or cisplatin. 
     
     
         52 . The method of  claim 50 , wherein the non-HER2 therapeutic agent or therapeutic modality comprises one or more of: a chemotherapy, immunotherapy, or a surgical procedure. 
     
     
         53 . The method of  claim 50 , wherein, responsive to detecting the HER2 alteration in the sample, the non-HER2 therapeutic agent or therapeutic modality is discontinued. 
     
     
         54 . The method of  claim 50 , further comprising administering the selected treatment to the subject after cessation of the non-HER2 therapeutic agent or therapeutic modality. 
     
     
         55 . The method of  claim 31 , wherein the one or more agents that inhibit a HER2 gene or gene product comprise one or more of: a kinase inhibitor; a multi-specific kinase inhibitor; a HER2-specific inhibitor; an EGFR inhibitor; a reversible or an irreversible HER2 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. 
     
     
         56 . The method of  claim 31 , wherein the one or more agents that inhibit a HER2 gene or gene product comprise an anti-HER2 antibody molecule, or a conjugate thereof. 
     
     
         57 . The method of  claim 31 , wherein the one or more agents that inhibit a HER2 gene or gene product comprise 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. 
     
     
         58 . The method of  claim 31 , wherein the one or more agents that inhibit a HER2 gene or gene product comprise one or more of: an antisense molecule, a ribozyme, a double stranded RNA, or a triple helix molecule that hybridizes to and/or inhibits a HER2 nucleic acid or a transcription regulatory region that blocks or reduces expression of a HER2 nucleic acid. 
     
     
         59 . The method of  claim 58 , wherein the HER2 nucleic acid comprises the HER2 alteration. 
     
     
         60 . The method of  claim 31 , wherein the selected treatment comprises two or more agents that inhibit a HER2 gene or gene product. 
     
     
         61 . The method of  claim 31 , wherein the HER2 alteration is detected by sequencing. 
     
     
         62 . The method of  claim 61 , wherein the report further comprises one or more nucleotide values indicating the presence in the sample of the HER2 alteration. 
     
     
         63 . The method of  claim 31 , wherein the HER2 alteration is detected in a nucleic acid molecule in the sample. 
     
     
         64 . The method of  claim 63 , wherein the nucleic acid molecule is present in a circulating cell;
 a micropapillary carcinoma of the urinary tract, bladder, or urothelial cells; or a blood or plasma sample.   
     
     
         65 . The method of  claim 31 , wherein the sample is a nucleic acid sample. 
     
     
         66 . The method of  claim 31 , wherein the sample is a tumor nucleic acid sample. 
     
     
         67 . The method of  claim 66 , wherein the tumor nucleic acid sample comprises genomic DNA, cDNA, or RNA derived from a sample of the micropapillary carcinoma of the urinary tract, bladder, or urothelial cells. 
     
     
         68 . The method of  claim 66 , wherein the tumor nucleic acid sample is purified or isolated. 
     
     
         69 . The method of  claim 31 , comprising detecting in the sample from the subject an alteration in a HER2 gene that results in an increased activity of a HER2 gene product, compared to a wild type activity of a HER2 gene product. 
     
     
         70 . The method of  claim 31 , comprising detecting in the sample from the subject an alteration in a HER2 gene or gene product, wherein the alteration is:
 a substitution, a deletion or an insertion in a HER2 gene,   an alteration in the extracellular domain of a HER2 polypeptide,   an alteration in domain II of a HER2 polypeptide,   a missense mutation in a HER2 gene,   a substitution at position 310 of a HER2 polypeptide,
 a substitution of a serine residue at position 310 of a HER2 polypeptide to a phenylalanine or tyrosine residue, 
   a substitution at position 157 of a HER2 polypeptide, or
 a substitution of an arginine residue at position 157 of a HER2 polypeptide to a tryptophan residue. 
   
     
     
         71 . The method of  claim 70 , wherein the alteration results in an increased activity of a HER2 gene product, compared to a wild type activity of a HER2 gene product. 
     
     
         72 . The method of  claim 70 , comprising detecting in the sample from the subject a substitution at position 310 of a HER2 polypeptide, or a substitution at position 157 of a HER2 polypeptide. 
     
     
         73 . The method of  claim 70 , comprising detecting in the sample from the subject a substitution of a serine residue at position 310 of a HER2 polypeptide to a phenylalanine or tyrosine residue. 
     
     
         74 . The method of  claim 70 , comprising detecting in the sample from the subject a substitution of an arginine residue at position 157 of a HER2 polypeptide to a tryptophan residue. 
     
     
         75 . The method of  claim 31 , wherein the HER2 polypeptide comprises the amino acid sequence of SEQ ID NO: 1.