Development of antisense morpholino oligonucleotides for the treatment of cancer

The development of traditional drugs such as small molecule inhibitors or monoclonal antibodies is an expensive process often hampered by the development of resistance to therapy. An alternative approach is to target genes directly with antisense oligonucleotides (ASOs). These are based on specific genetic sequences and offer the advantage of being highly selective. There are several different types of ASOs. Morpholino ASOs, invented by our industrial collaborators at GeneTools LLC, Oregon USA, require perfect base pairing over 15 bases, are chemically non-reactive, and very stable in a cellular environment. The drug Eteplirsen, now FDA approved, is a morpholino that corrects the aberrant splicing of the DMD gene and, for the first time, children with this terrible disease are able to walk.
There is now interest in developing morpholinos for the treatment of cancer. We have recently successfully designed ASO morpholinos that target the ERG oncogene, inhibiting cancer cell growth (see Jumbe et al. 2019; PMID:30296658). Some genes are specifically expressed during fetal development and re-activated in cancer cells because they provide growth advantages. These are known as oncofetal genes and are optimal targets for therapy as they are specifically active in cancer cells. These include i) the beta subunit of hCG (human chorionic gonadotropin). The main function of hCG is to protect the fetus from the mother’s immune system. hCG is re-activated in cancer cells to help evade the immune system; ii) MBNL3, an oncofetal splice factor that promotes tumorigenesis by modifying splicing of key cancer genes; and iii) IGF2BP1, an RNA-binding protein that promotes mRNA stability of important oncogenes. With GeneTools we plan to design and test morpholinos that target these and other oncofetal transcripts. It is envisaged that the morpholinos could be developed into effective cancer therapies.
The aim of this PhD is to design and test morpholino ASOs that target oncofetal transcripts in a range of cancer cell line models, evaluating their ability to knockdown their expression, and then testing their effect on key cancer cell biology parameters including proliferative capacity, apoptosis, cell migration and invasion, cell morphology and the expression of EMT markers.