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lncRNA - Long Non-coding RNAs02:39

lncRNA - Long Non-coding RNAs

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In humans, more than 80% of the genome gets transcribed. However, only around 2% of the genome codes for proteins. The remaining part produces non-coding RNAs which includes ribosomal RNAs, transfer RNAs, telomerase RNAs, and regulatory RNAs, among other types. A large number of regulatory non-coding RNAs have been classified into two groups depending upon their length – small non-coding RNAs, such as microRNA, which are less than 200 nucleotides in length, and long non-coding RNA...
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Netrin-1 expression and targeting in multiple myeloma.

David Fahed1, AbdelKamel Chettab1, Doriane Mathe2

  • 1Anticancer Antibodies Team, CRCL, CNRS UMR5286, CLB, UCBL, Lyon, France.

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|September 29, 2021
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Summary

Netrin-1 signaling, involving DCC and UNC5 receptors, shows potential as a new multiple myeloma therapy. An anti-netrin-1 treatment (NP137) enhanced existing therapies and reduced tumor size in mice.

Keywords:
DCCNetrin-1UNC5dependence receptorsmultiple myeloma

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Deleted in colorectal cancer (DCC) and uncoordinated-5 (UNC5) receptors are dependence receptors involved in tumor progression in solid tumors.
  • Netrin-1, their ligand, is a potential therapeutic target, but its role in hematological malignancies is underexplored.
  • Understanding netrin-1 signaling in multiple myeloma is crucial for developing novel treatment strategies.

Purpose of the Study:

  • To investigate the expression of netrin-1 and its receptors (DCC, UNC5H2(B)) in multiple myeloma.
  • To evaluate the anti-myeloma activity of a novel anti-netrin-1 agent (NP137) in vitro and in vivo.
  • To explore netrin-1 signaling as a potential therapeutic target in multiple myeloma.

Main Methods:

  • Screening of human myeloma cell lines and patient bone marrow samples for netrin-1 and its receptors.
  • Immunohistochemistry and flow cytometry to confirm expression.
  • In vitro assays assessing NP137's effect on myeloma cell lines, alone and in combination with bortezomib and dexamethasone.
  • In vivo studies using SCID mice with human myeloma tumors.
  • Ex vivo analysis of bone marrow aspirates from patients treated with NP137.

Main Results:

  • Heterogeneous expression of netrin-1, DCC, and UNC5H2(B) was observed in myeloma cell lines and patient samples.
  • NP137 did not induce apoptosis independently but enhanced the cytotoxicity of bortezomib and dexamethasone in vitro.
  • NP137 treatment reduced tumor size in a mouse model of multiple myeloma.
  • Ex vivo, NP137 decreased plasma cell percentages in a subset of patient samples.

Conclusions:

  • Netrin-1 and its receptors are expressed in multiple myeloma, suggesting a role for this signaling pathway.
  • The anti-netrin-1 agent NP137 shows potential as an adjunct therapy, enhancing existing treatments.
  • Netrin-1 signaling represents a promising novel therapeutic target for multiple myeloma.