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Antisense Inhibitors of Long Noncoding RNA as Treatment for Multiple Myeloma

Highly selective antisense oligonucleotides that are proven inhibitors of RNA regulators of lipogenesis

  • Therapeutics

Project Overview

  • Recent research has indicated that gene loci harboring long noncoding RNAs (lncRNAs) may play a key role in the progression and survival of multiple myeloma (MM) cells.
  • One important lncRNA, RROL (RNA regulator of Lipogenesis, aka lnc-17-92), has been shown to mediate MM proliferation. The regulatory role of RROL in lipogenesis activation makes it a promising new target for therapeutic inhibition. 
  • Researchers at Dana-Farber have designed antisense oligonucleotides (ASOs) that are proven inhibitors of RROL.
  • Dana-Farber Cancer Institute is to license these assets for further development into new oncology therapeutics.

Technology

Multiple Myeloma (MM) is a largely incurable malignancy of plasma cells that accounts for approximately 10% of all hematologic cancers. Recent research has indicated that gene loci harboring long noncoding RNAs (lncRNAs) may play a key role in the progression and survival of MM cells. Long noncoding RNAs are RNA molecules greater than 200 nucleotides that lack protein coding potential. Among the diverse array of functions associated with lncRNAs are regulatory functions that can be exploited by tumor cells. 

Recently, an important lncRNA, RROL (RNA regulator of Lipogenesis, aka lnc-17-92), has been shown to mediate MM proliferation by accommodating the binding of regulatory transcription factors to the promoter region of a gene associated with de novo lipogenesis. Except for liver and adipose tissue, lipogenesis is a metabolic pathway that is generally not active in healthy cells, but it may be reactivated in energy-hungry cancer cells. The regulatory role of RROL in lipogenesis activation makes it a promising new target for therapeutic inhibition. 

Development of therapeutics for targeted inhibition of RNA molecules is a nascent field of research. Use of complementary nucleic acids provides high selectivity for the RNA target but development of drugs from these molecules has been hindered by their low bioavailability and poor stability in vivo. 

Researchers at Dana-Farber Cancer Institute have designed antisense oligonucleotides (ASOs) that are proven inhibitors of RROL. By incorporating state-of-the-art chemical modifications, the ASOs demonstrate greater bioavailability and resistance to enzymatic degradation while retaining high selectivity to the RROL target. Two classes of ASOs have been designed to inhibit RROL via two different mechanisms: (i) an RNase-based mechanism where binding of the ASO to its RROL target induces degradation of RROL, or (ii) a “steric block” mechanism in which RROL is masked by binding to the ASO thereby impeding its function without its degradation. 

Both classes of modified ASOs show strong anti-proliferative effects (>50% cell growth inhibition) in MM cell lines and patient-derived MM cells, while sparing non-malignant cells. In vivo mouse studies show tumor growth inhibition of >68% in an AMO1-based plasmacytoma xenograft model and >50% in a model of aggressive myeloma. No significant toxicity was observed in any mice after treatment, and both classes of inhibitors produced prolonged survival in the mice. 

The therapeutic promise of this technology has been highlighted in a special commentary article in a a January 2023 issue of Blood, in which the editorial author states: “This [technology] will surely lead to great advances in the treatment of patients with cancer, here MM, and of other human diseases”. (See: Agirre, Xabier. “RROL lncRNA role in multiple myeloma.” Blood, The Journal of the American Society of Hematology 141.4 (2023): 328-330. 

Further Details: 

Team Members: Nikhil Munshi, MD, Sergei Gryaznov, PhD, Eugenio Morelli, MD

Applications

  • Potential new treatment strategy for multiple myeloma and other cancers 
  • Potential new treatment strategy for non-alcoholic steatoHepatitis (NASH) 

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing these assets for further development into new oncology therapeutics.

Get in touch

Team Members

Nikhil Munshi, MD

Director of Basic and Correlative Science, Jerome Lipper Multiple Myeloma Center, Dana-Farber

Kraft Family Chair and Professor of Medicine, Harvard Medical School