Methods and compositions for the diagnosis of cancer susceptibilities and defective DNA repair mechanisms and treatment thereof

• US 9,354,224 B2
• Filed: 10/21/2014
• Issued: 05/31/2016
• Est. Priority Date: 11/03/2000
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute, Oregon Health & Science University
• Original Assignee: Dana-Farber Cancer Institute, Oregon Health & Science University
• Inventors: D'Andrea, Alan D., Taniguchi, Toshiyasu, Fox, Edward A., Timmers, Cynthia, Grompe, Markus
• Primary Examiner(s): Goddard, Laura B
• Application Number:
  US14/520,055
• Publication Number:
  US 20160084821A1
• Time in Patent Office: 588 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A01K 2217/05 Animals comprising random inserted nucleic acids (transgenic)
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 16/18 against material from animals or humans
• CPC Class Codes: C12Q 1/025 for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics antimicrobial activity C12Q1/18
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2333/47 Assays involving proteins of known structure or function as defined in the subgroups
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/5011 for testing antineoplastic activity
• CPC Class Codes: G01N 33/5091 for testing the pathological state of an organism
• CPC Class Codes: G01N 33/574 for cancer
• CPC Class Codes: G01N 33/57484 involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

Methods and compositions for the diagnosis of cancer susceptibilities, defective DNA repair mechanisms and treatments thereof are provided. Among sequences provided here, the FANCD2 gene has been identified, and probes and primers are provided for screening patients in genetic-based tests and for diagnosing Fanconi Anemia and cancer. The FANCD2 gene can be targeted in vivo for preparing experimental mouse models for use in screening new therapeutic agents for treating conditions involving defective DNA repair. The FANCD2 polypeptide has been sequenced and has been shown to exist in two isoforms identified as FANCD2-S and the monoubiquinated FANCD-L form. Antibodies including polyclonal and monoclonal antibodies have been prepared that distinguish the two isoforms and have been used in diagnostic tests to determine whether a subject has an intact Fanconi Anemia/BRCA pathway.

Claims

1. An in vitro method of predicting the efficacy of a therapeutic agent in a cancer patient, comprising the steps of:

a) taking a tissue sample from said cancer patient who is being treated with said therapeutic agent;

b) inducing DNA damage in the cells of said tissue sample; and

c) detecting the presence of FANCD2-L protein in said cells,

wherein the presence of FANCD2-L protein is indicative of a reduced efficacy of said therapeutic agent in said cancer patient, and wherein said therapeutic agent is cisplatin.

2. The method of claim 1, wherein said cancer is breast cancer, ovarian cancer, or prostate cancer.