Modulation of breast cancer growth by modulation of XBP1 activity

• US 10,655,130 B2
• Filed: 02/23/2017
• Issued: 05/19/2020
• Est. Priority Date: 03/09/2012
• Status: Active Grant

• Current Assignee: Cornell University
• Original Assignee: Cornell University
• Inventors: Glimcher, Laurie H., Chen, Xi
• Primary Examiner(s): Yakovleva, Galina M.
• Application Number:
  US15/441,103
• Publication Number:
  US 20170240903A1
• Time in Patent Office: 1,181 Days
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C12N 15/113 Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing when used in plants C12N15/8218
• CPC Class Codes: C12N 15/1135 against oncogenes or tumor suppressor genes
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/531 Stem-loop; Hairpin
• CPC Class Codes: C12N 2320/30 Special therapeutic applications
• CPC Class Codes: C12N 2320/31 Combination therapy
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Y 207/11001 Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• 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 33/57415 of breast

Abstract

Described herein is a previously unknown function of XBP1 in triple-negative breast cancer (TNBC). It is shown that XBP1 is preferentially spliced and activated in TNBC, and that deletion of XBP1 significantly blocks triple negative breast tumor growth. Strikingly, XBP1 is required for the self-renewal of breast tumor initiating cells (TICs). Genome-wide mapping of the XBP1 transcriptional regulatory network identified a fundamental role for XBP1 in regulating the response to hypoxia via the transcription factor hypoxia-inducible factor 1α (HIF1α). Importantly, activation of this pathway appears to carry prognostic implications, as expression of the XBP1-dependent signature is associated with shorter survival times in human TNBC.

Claims

1. A method for treating triple negative breast cancer (TNBC) in a subject, the method comprising administering to the subject a direct inhibitor of X-box binding protein 1 (XBP1) and doxorubicin each in an amount effective to inhibit growth of cancer cells in said subject, such that TNBC in the subject is treated;

wherein the direct inhibitor of XBP1 is an XBP1 shRNA.

2. The method of claim 1, wherein the direct inhibitor of XBP1 is administered to breast tissue of said subject.

3. The method of claim 2, wherein the direct inhibitor of XBP1 is administered directly to the breast tissue of the subject.

4. The method of claim 1, wherein the treatment promotes longer relapse-free survival of the subject.

5. The method of claim 1, wherein the treating comprises reducing the population of chemotherapy-resistant tumor initiating breast cancer cells in the subject.

6. The method of claim 1, wherein the comprises depleting breast tumor initiating breast cancer cells in the subject.