- Suna Gulay
Advanced stage cancers are typically marked by metastases of the primary cancer to secondary sites such as lungs, liver, and bones. Such metastatic cancers result in strikingly low 5-year survival rates, underscoring the need for novel therapeutics. For example, bone metastasis of primary breast cancer has a 5-year survival rate of 13%, lung cancer only 1%. There is a need for targeted therapy options specific to metastases. One approach to targeting metastases is to reduce cancer cell migration and invasion.
Several mRNAs become localized to subcellular destinations during the metastatic process. These mRNAs may play roles in cell and organelle development – either through corresponding increases in encoded protein concentration or through dynamic interactions with the extracellular environment. Their activities may be modulated via antisense oligonucleotides. One example is the mRNA localization at the protrusions extended by mesenchymal migrating cells, partially under control of the adenomatous polyposis coli (APC) tumor suppressor. Regulation of the mRNAs localized to these protrusions may be usurped to target cancer cell migration and invasion and, ultimately, metastasis. RAB13 and NET1 are especially promising mRNA targets as they are overexpressed in multiple cancer types and contributory to cell motility in vitro.
Researchers at the National Cancer Institute (NCI), Laboratory of Cellular and Molecular Biology, have shown that mRNA localization at protrusive regions of migrating cells depends on specific signals within the 3’-untranslated regions of these mRNAs. These signals may be modulated by antisense oligonucleotides as a novel mechanism to target cancer metastasis. The inventors have designed chemically modified antisense oligonucleotides against RAB13 and NET1, delivered these into cancer cells, and observed inhibition of cell migration and invasion in two-dimensional and three-dimensional in vitro assays. These oligonucleotides specifically target RNAs at protrusions without broadly affecting expression of encoded proteins, so they are expected to have minimal effects on non-migrating cells. In vivo studies with xenograft tumor models are currently taking place to optimize delivery of the oligonucleotides.
NCI is seeking parties interested in co-developing and/or licensing these therapeutic antisense oligonucleotides that target cell migration and cancer metastasis.
- Metastatic cancer therapeutic
- Targeted cancer therapeutic
- Cardiovascular and neurodegenerative diseases, as well as genetic disorders
- Regulatory approval pathway exists following FDA/EMA approval of the first antisense-based molecule (Tegsedi™) in 2018
- Targeting cancer metastasis and inhibition of cell movement through antisense oligonucleotides is a novel approach
- Antisense oligonucleotides specifically target RNAs at cell protrusions without broadly affecting cellular protein expression
- Antisense oligonucleotides can be highly specific, permitting induction at advanced stages of cancer growth – as compared with chemotherapy
- Pre-clinical (in vivo)
Moissoglu K, et al. Local RNA translation controls cell migration and Rab GTPase function. [Local RNA translation controls cell migration and Rab GTPase function | bioRxiv]
Moissoglu K, et al. Translational regulation of protrusion-localized RNAs involves silencing and clustering after transport. [PMID 31290739]
Mili S, et al. Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions. [PMID 18451862]
- U.S. Provisional: U.S. Provisional Patent Application Number 62/966,204 , Filed 27 Jan 2020