An Epigenetic Epiphany
When genetics yielded unsatisfactory answers about pancreatic cancer’s persistent survival, researchers looked beyond the genome – and found telling epigenetic changes
Many researchers have investigated the genetics of pancreatic cancer, hoping to find answers to the disease’s mysteries. Some studies have struck gold with oncogenic events like KRAS mutations (1), which occur in almost all cases of pancreatic ductal adenocarcinoma (PDAC) – but then discovered that treatments targeting those mutations are hampered by dose-limited toxicity or disease resistance. More recently, next-generation sequencing has revealed mutations in several genes that code for chromatin regulators (2,3), suggesting that epigenetic factors might be responsible for some properties of PDAC tumors – perhaps even their persistent survival.
Based on their knowledge of the properties of proteins in the BET (bromodomain and extraterminal) family, researchers from the Technical University of Munich and Stanford University decided to use them to investigate the possibility of an epigenetics-based therapy for PDAC. BET proteins use their bromodomains to recognize acetylated lysines on histones, the proteins involved in DNA packaging in the cell. Histone acetylation is associated with increased transcription and a more open, accessible chromatin structure – including in oncogenes like MYC, thereby increasing the survival and proliferation of abnormal cells that would otherwise undergo apoptosis.
To generate their treatment, the researchers examined the expression of BET proteins in PDAC tumors and found three proteins – BRD2, BRD3 and BRD4 – in preneoplastic and neoplastic lesions. They then used a mouse model to test a small molecule known as JQ1, which inhibits the function of those proteins (4). By inhibiting the BET proteins, the researchers were able to decrease both MYC activity and inflammatory signaling, suppressing PDAC development. But JQ1 alone wasn’t effective enough – the mice still ultimately succumbed to their disease. So the researchers investigated agents that could be used alongside the small molecule to improve treatment and discovered that the addition of the small molecule SAHA – which inhibits histone deacetylation – had a synergistic effect.
This is an especially promising start because JQ1 (as TEN-010) is already in clinical trials and SAHA (as vorinostat) has been approved by the US Food and Drug Administration for use in cutaneous T cell lymphoma. Because the researchers don’t need to start from scratch, their treatment may reach the clinic more quickly than a brand new combination. With that in mind, they’ve already begun investigating potential biomarkers – like the gene p57, which may be a key mediator of the drugs’ function and a predictor of treatment success.
Mission: Impossible by Michael Schubert
Tapping a Rich Vein by Christopher Chapman
New Ab-ilities in Imaging by Michael Schubert
Surprising Subtypes by Michael Schubert
Friend or Foe? by Anne Marie Lennon
(Chemo)resistance Is Futile by Michael Schubert
Breaching Cancer’s Defenses by Ingunn Stromnes
Building a Better Mousetrap by Michael Schubert
- MA Collins, M Pasca di Magliano, “Kras as a key oncogene and therapeutic target in pancreatic cancer”, Front Physiol, 4, 407 (2014). PMID: 24478710.
- AV Biankin et al., “Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes”, Nature, 491, 399–405 (2012). PMID: 23103869.
- AK Witkiewicz et al., “Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets”, Nat Commun, 6, 6744 (2015). PMID: 25855536.
- PK Mazur et al., “Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma”, Nat Med, 21, 1163–1171 (2015). PMID: 26390243.
While obtaining degrees in biology from the University of Alberta and biochemistry from Penn State College of Medicine, I worked as a freelance science and medical writer. I was able to hone my skills in research, presentation and scientific writing by assembling grants and journal articles, speaking at international conferences, and consulting on topics ranging from medical education to comic book science. As much as I’ve enjoyed designing new bacteria and plausible superheroes, though, I’m more pleased than ever to be at Texere, using my writing and editing skills to create great content for a professional audience.