Everybody working in cancer research dreams of the ideal cancer drug that could attack cancer cells, but not normal tissues. However, the majority of our targets so far are in the most redundant compartments of cells that can quickly rewire to compensate for our attacks. Hence, novel opportunities might lie in the identification of less evolutionarily degenerate nodes in cancer. Some of these functions might be identified in the nuclei of cells (a compartment less accessible to standard drugs), where many proteins are intrinsically disordered, lacking a defined three-dimensional structure amenable to attack by canonical small molecule inhibitors. But are these challenges sufficient to dismiss these targets as “undruggable”? Our answer is definitely not.

In our last publication in Science Translational Medicine [1], we established the feasibility of pharmacologically targeting MYC, the most infamous “undruggable target” deregulated in the majority of human cancers, by making use of a cell-penetrating polypeptide called Omomyc. I designed Omomyc when I was still a student, and I used it in genetically engineered models to establish the therapeutic potential of MYC inhibition to stop tumor progression. However, Omomyc was deemed too bulky and unfit to ever become a drug. And this is where our last publication is really proving this assumption wrong.  In [1], we showed that a purified, recombinantly produced Omomyc polypeptide has cell-penetrating properties and is disruptive in multiple ways: not only can Omomyc sequester MYC in complexes unable to recognize DNA, but it shows a dramatic therapeutic effect in Non-Small lung cancer, while displaying safety and lack of toxicity even upon long term treatment.

Overall, our results provide the first evidence and preclinical validation of the Omomyc mini-protein as an excellent candidate for clinical development. Indeed, clinical trials are now planned for Q1 2021 to test its clinical value in patients.

Mutations in DNA can disrupt protein synthesis, sometimes causing truncated proteins which don’t work as intended. Known as nonsense mutations, these types of alterations can give rise to hereditary diseases and different types of cancer. To keep the number of truncated proteins to a minimum, human cells recognise and remove RNAs with nonsense mutations through a quality control process known as nonsense-mediated mRNA decay (NMD).

To better understand the effect of NMD on human disease, we have built NMDetective, a tool describing every possible nonsense mutation that can occur in the human and mouse genomes.  Developed by large-scale statistical analyses based on machine learning, the algorithm identifies which mutations in the genome are susceptible to NMD.

As described in Nature Genetics, we used NMDetective to analyse thousands of genetic variants that are known to give rise to hereditary diseases in humans. We were surprised to observe that, in many cases, NMD activity was actually predicted to lead to a greater severity of the disease. This suggests that pharmacological NMD inhibition could slow the progression of many different genetic diseases. To distinguish which patients would benefit from this therapy, it is necessary to apply a precision medicine approach to determine the mutation responsible for the disease and the effect of NMD on this mutation, and this is precisely where NMDetective comes into play.

We also studied the role of NMD in cancer and the interaction between the tumour and the immune system. Remarkably, there is robust genomic evidence that NMD activity is important for the prediction of success of immunotherapy in cancer, because NMD hides mutations that would otherwise trigger the immune system. Therefore, NMDetective can be used to analyse the mutations present in the tumour, in order to better distinguish between cancer patients that respond to immunotherapy from those who do not respond to immunotherapy.