Our current understanding of genetic changes in glioblastoma — for instance, gene mutations at the DNA level — does not fully explain brain cancer cell behavior, including and especially disease treatment resistance and cancer recurrence. A purely genetically oriented approach does not consider transcriptional variation, i.e., changes in gene expression without new genetic alterations, as a driver of intratumoral heterogeneity.
Our investigators hypothesize that epigenetic changes in the tumor and the tumor environment causes therapy resistance and is responsible for the rapid cellular changes that underlie recurrence and continued treatment resistance. Re-defining patients’ glioblastoma tumors through this new lens of epigenetics offers the exciting prospect of discovering epigenetically based cancer cell vulnerabilities.
Central to these efforts is our team’s capability to monitor epigenetic changes — including the evolving cancer DNA methylome — longitudinally in patient specimens through cutting-edge technology developed in the McDonnell Genome Institute. Investigators will also analyze and assess histone codes using advanced proteomics approaches in our world-class mass spectrometry facility, the Mass Spectrometry Technology Access Center at McDonnell Genome Institute.
- Inhibitors of chromatin and DNA modifiers as brain tumor therapeutics. Our team performs epigenetic drug screens to identify compounds that target the cancer cell epigenome. These drugs will be evaluated for their ability to enhance standard-of-care, targeted and immunotherapies by inhibiting epigenetic adaptability and thus “locking” tumor cells in a treatment-sensitive state.
- Epigenetic control of the non-coding genome. Our investigators have found that > 95% of the human genome, traditionally considered “junk DNA,” contains a huge number of transposable elements (TEs) – pieces of viral DNA that have jumped into our genome during our evolutionary history. Remarkably, TEs have emerged as a rich repertoire of neoantigens and double stranded RNAs, which are subject to precise epigenetic control. We are testing the concept that epigenetic therapies can increase the sensitivity of cancer cells to immunotherapies by triggering the expression of TEs. This, in turn, leads to the production of neoantigens, which can be further leveraged by existing immunotherapies including checkpoint blockade and vaccines.
- Epigenetic changes in response to metabolic adaptation. Various metabolites can impact gene expression through effects on chromatin and DNA post-translational modifications. These modifications, in turn, regulate a diverse range of cellular processes, including maintenance of pluripotency, hypoxic responses, angiogenesis and inflammation, among many others. Our investigators study and pharmacologically target the precise mechanisms, by which metabolites control enzymes involved in DNA and histone modifications and shape the tumor transcriptome and proteome.
- Sexual dimorphism. We are determining sex-specific differences that predict which epigenetic treatments and sensitizers of chemoradiation may be best for specific patients.