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US-20260125675-A1 - DOWNREGULATING TROLLS USING NOVEL ANTISENSE OLIGONUCLEOTIDES TO OVERCOME RESISTANCE TO CHEMOTHERAPY

US20260125675A1US 20260125675 A1US20260125675 A1US 20260125675A1US-20260125675-A1

Abstract

Disclosed herein are 2 novel long non-coding RNAs (lncRNAs). TROLL-2C and TROLL-3A. It is shown herein that lncRNAs TROLL-2C and TROLL-3A are suitable targets for cancer therapies and can be used to make prognostic determinations about a cancer and determine if immune checkpoint inhibitors should be used to treat a cancer.

Inventors

  • Elsa FLORES
  • Marco Napoli

Assignees

  • H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE, INC.

Dates

Publication Date
20260507
Application Date
20231013

Claims (17)

  1. 1 . A method of treating a cancer in a subject comprising knocking down expression of TROLL-2C and/or TROLL-3A in the subject.
  2. 2 . The method of claim 1 , wherein the cancer comprises breast cancer, lung cancer, ovarian cancer, colon cancer, or melanoma.
  3. 3 . The method of claim 2 , wherein the lung cancer comprises lung adenocarcinoma or lung squamous cell carcinoma.
  4. 4 . The method of claim 2 , wherein the breast cancer comprises triple negative breast cancer.
  5. 5 . The method of claim 2 , wherein the cancer comprises a p53 mutation.
  6. 6 . The method of claim 2 , wherein the cancer is Tap63 regulated.
  7. 7 . The method of claim 1 , wherein expression of TROLL-2C and/or TROLL-3A is knocked down through the administration of one or more RNA-targeted therapeutics.
  8. 8 . The method of claim 7 , wherein the one or more RNA-targeted therapeutics selected from antisense oligonucleotides, siRNA, shRNA, ribozymes, transcription activator-like effector nucleases (TALEN), zinc finger nucleases (ZFNs) or clustered regularly interspaced short palindromic repeats/associated (CRISPR/Cas) nucleases.
  9. 9 . The method of claim 8 , wherein the expression of TROLL-2 is knocked down by administering to the subject the antisense oligonucleotide as set forth in SEQ ID NO: 2, and/or SEQ ID NO: 4.
  10. 10 . The method of claim 7 , wherein the expression of TROLL-2 is knocked down by targeting the RPSAP52/NR_026825.2 isoform.
  11. 11 . The method of claim 8 , wherein the expression of TROLL-3 is knocked down by administering to the subject the antisense oligonucleotide as set forth in SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, or a combination thereof.
  12. 12 . The method of claim 7 , wherein the expression of TROLL-3 is knocked down by targeting the TRAF3IP2-AS1/NR_034108.1, TRAF3IP2-AS1/NR_034109.1, TRAF3IP2-AS1/NR_034110.1, TRAF3IP2-AS1/NR_034111.1 isoform, or a combination thereof.
  13. 13 . The method of claim 1 , wherein the cancer is already established in the subject prior to the initiation of treatment.
  14. 14 . The method of claim 1 , wherein the cancer is metastatic.
  15. 15 . An antisense oligonucleotide comprising SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7.
  16. 16 . A pharmaceutical composition comprising a therapeutically effective amount of one or more of an antisense oligonucleotide as set forth in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7, or a combination thereof, and a pharmaceutically acceptable carrier.
  17. 17 . The pharmaceutical composition of claim 16 , comprising any combination at least 2, 3, 4, 5, or all 6 of the antisense oligonucleotides.

Description

II. CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/445,137, filed on Feb. 13, 2023, and U.S. Provisional Application No. 63/415,977, filed on Oct. 13, 2022, applications which are incorporated herein by reference in their entirety. I. STATEMENT OF GOVERNMENT SUPPORT This invention was made with government support under Grant No. CA197452 awarded by National Institutes of Health. The government has certain rights in the invention. III. REFERENCE TO SEQUENCE LISTING The sequence listing submitted on Oct. 13, 2023, as an .XML file entitled “10110-417WO1_ST26.xml” created on Oct. 13, 2023, and having a file size of 10,001 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52 (e) (5). IV. BACKGROUND 1. Cancer metastasis is the leading cause of death in cancer patients. Multiple pathways have been found to increase cancer progression and metastasis including the activation of the PI3K/AKT pathway and the gain-of-function mutation of the tumor suppressor TP53, which are the two most frequent driving mutations in a broad variety of human cancers. Therefore, investigating the mechanistic interplay between these pathways is of the utmost importance for the identification of novel therapeutic opportunities against the progression of metastatic cancers. V. SUMMARY 2. Disclosed are antisense oligonucleotides that target TROLL-2C or TROLL-3A and methods of their use in treating cancer. 3. In one aspect, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example, breast cancer (including, but not limited to triple negative breast cancer), lung cancer (including, but not limited to lung adenocarcinoma or lung squamous cell carcinoma), ovarian cancer, liver cancer, colon cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or melanoma) in a subject comprising knocking down expression of TROLL-2C and/or TROLL-3A in the subject. In some aspects, the cancer comprises a p53 or KRAS mutation. In some aspects the cancer is Tap63 regulated. In some aspects, the cancer is already established in the subject prior to the initiation of treatment. 4. Also disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis of any preceding aspect, wherein expression of TROLL-2C and/or TROLL-3A is knocked down through the administration of one or more RNA-targeted therapeutics (such as, for example antisense oligonucleotides, siRNA, shRNA, ribozymes, transcription activator-like effector nucleases (TALEN), zinc finger nucleases (ZFNs) and/or clustered regularly interspaced short palindromic repeats/associated (CRISPR/Cas) nucleases). 5. In one aspect, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis of any preceding aspect, wherein the expression of TROLL-2 is knocked down by administering to the subject the antisense oligonucleotide as set forth in SEQ ID NO: 2, and/or SEQ ID NO: 4; and/or wherein the expression of TROLL-3 is knocked down by administering to the subject the antisense oligonucleotide as set forth in SEQ ID NO: 5, SEQ ID NO: 6, and/or SEQ ID NO: 7. In some aspects, the expression of TROLL-2 is knocked down by targeting the RPSAP52/NR_026825.2 isoform. In some aspects the expression of TROLL-3 is knocked down by targeting the TRAF3IP2-AS1/NR_034108.1, TRAF3IP2-AS1/NR_034109.1, TRAF3IP2-AS1/NR_034110.1, and/or TRAF3IP2-AS1/NR_034111.1 isoform. 6. In one aspect, disclosed herein are antisense oligonucleotides comprising SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7. 7. Also disclosed herein are pharmaceutical composition comprising a therapeutically effective amount of 1 or any combination of 2, 3, 4, 5, or 6 of antisense oligonucleotides of any preceding aspect. 8. In one aspect, disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis (such as, for example, breast cancer (including, but not limited to triple negative breast cancer), lung cancer (including, but not limited to lung adenocarcinoma or lung squamous cell carcinoma), ovarian cancer, liver cancer, colon cancer, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or melanoma) in a subject comprising knocking down expression of TROLL-2C and/or TROLL-3A in the subject by administering to the subject the antisense oligonucleotide or pharmaceutical composition of any preceding aspect. 9. Also disclosed herein are methods of treating, inhibiting, reducing, decreasing, ameliorating, and/or preventing a cancer and/or metastasis further comprising administering to the subject Adriamycin, docetaxel, paclitaxel, cyclophosphamide, carboplatin, and capecitabine. VI. BRIEF DESCRIPTION OF THE DRAWINGS 10.