If elephants have evolved a natural anti‑cancer armour, can pieces of that armour be repurposed as medicine? A growing cadre of researchers believes the answer is yes, and they are now trying to bottle elephant p53 biology for human use.
One promising lead is p53‑R9, a truncated protein encoded by one of the elephant TP53 retrogenes. In 2023, a team led by scientists at the University of Utah and the University of Rochester characterised p53‑R9’s behaviour in human cancer cell lines. They found that when p53‑R9 is expressed in TP53‑deficient osteosarcoma cells, it travels to the mitochondria, binds the pro‑apoptotic protein Bax, triggers cytochrome c release and activates caspases – the molecular executioners of apoptosis. In other words, a single elephant retrogene product is sufficient to re‑install a powerful death programme in human tumour cells that have lost their own p53.
This mitochondrial route is particularly attractive pharmacologically. Unlike canonical p53, which functions largely as a transcription factor in the nucleus, p53‑R9 can induce cell death independent of DNA binding, potentially sidestepping some resistance mechanisms cancers evolve against nuclear p53 signalling. The study’s authors argue that understanding this non‑canonical pathway could open up new classes of pro‑apoptotic drugs inspired directly by elephant proteins.
A parallel translational effort focuses on delivering elephant p53 proteins systemically. The Angular Cancer Foundation has funded preclinical development of Elephant P53 Lipid Nanoparticles (EP53‑LNPs) – formulations designed to ferry elephant p53 variants into human and veterinary tumours using the same mRNA‑LNP technology that underpinned COVID‑19 vaccines. Early work is exploring whether these particles can flood cancer cells with functional tumour suppressor protein, pushing them over the threshold into apoptosis while sparing normal tissues. If successful, such an approach would represent one of the first direct imports of a non‑human tumour suppressor into human oncology.
At the same time, mainstream drug developers are attacking the problem from the opposite angle: reactivating or liberating our own p53. A wave of molecules now in clinical and preclinical development aim to restore function to mutant p53, disrupt the inhibitory MDM2/MDMX proteins that degrade p53, or modulate downstream signalling to favour cell death over survival. Aileron Therapeutics’ stapled peptide ALRN‑6924, for example, was designed to block both MDM2 and MDMX, thereby re‑engaging wild‑type p53 in tumours that retain the gene but keep it shackled. Early trials showed acceptable safety and hints of activity across several solid tumours, although subsequent breast cancer chemoprotection studies were disappointing and the programme has been wound down.
What elephants add to this crowded field is proof that super‑p53 systems can operate in a whole organism without catastrophic side‑effects. Comparative genomics reveals that some elephant p53 isoforms have evolved to escape negative regulation by MDM2, effectively uncoupling cell‑death decisions from the usual brakes that restrain p53 in humans. Drug designers are now asking whether small molecules can mimic these elephant‑style escape mutations or allosteric configurations to push human p53 closer to the elephant regime of rapid, decisive apoptosis.
None of these elephant‑inspired approaches has yet reached late‑stage clinical trials. But together they mark a conceptual shift: from treating p53 as a fragile human safeguard to treating it as an engineered module that evolution has already stress‑tested at scale in giant mammals. The hope is that, by copying the right design principles, human oncology can borrow some of that resilience.
– Dr Nithin Katragadda
