Florian Perner: Physician Scientist Uncovers Epigenetic Mechanisms of Drug Resistance in Leukemia.
By studying the mechanisms of cancer resistance in childhood leukemia, Florian Perner, MD has discovered that targeting the epigenetic changes in therapy-resistant cancers could be an effective new therapeutic approach.
Perner, a physician scientist at the Dana Farber Cancer Institute, is zeroing in on a subset of leukemias marked by chromosomal rearrangements in an oncogene called MLL1. While most acute childhood leukemias initially respond well to chemotherapy, the survival rate of those with rearranged MLL1 is devastating. Therefore, efficient targeted therapies that improve patient outcomes and limit treatment-related toxicity are urgently needed. In 2018, Perner received a Momentum fellowship from the Mark Foundation to investigate the molecular mechanisms underlying drug sensitivity in this hard-to-treat type of leukemia with the aim of discovering more effective treatments.
Chromosomal abnormalities in leukemia can lead to the fusion of MLL1 with other proteins, which drives cells to become cancerous. Although direct targeting of MLL1 fusions is not yet possible, MLL1 forms a larger complex with other proteins, and these interactions represent opportunities for therapies.
Recent efforts in drug development have led to the establishment of novel molecules that target the MLL1 protein complex to disrupt its oncogenic function. A number of these molecules have recently entered early-phase clinical trials and show promise in leukemia patients whose cancers are refractory to conventional types of treatment. Unfortunately, in several patients, the long-term clinical success of these new therapies is limited by the development of drug resistance.
Perner found that epigenetic plasticity allows leukemia cells to escape targeted treatment by changing their molecular vulnerabilities. Using a comprehensive CRISPR–Cas9-based screening approach, Perner was able to identify an Achilles’ heel in these resistant leukemia cells that allowed the group at Dana-Farber to re-program the cells toward a drug sensitive state by targeting a histone acetyltransferase. According to Perner, this is one of the first times scientists have seen this type of drug resistance in cancer. “If you read up on textbook examples of drug resistance, you won’t find this one,” he said.
Perner has established this novel concept of epigenetic drug resistance in the setting of two different classes of molecules. The first is an inhibitor that blocks the activity of the enzyme DOT1L, a methyltransferase that associates with the MLL1 complex and activates genes by histone methylation. The other class of molecules blocks the interaction between MLL1 and the adaptor protein Menin, leading to physical disruption of the oncogenic protein complex. Remarkably, resistance towards these two very different types of drugs seems to follow similar principles.
Currently, three different Menin inhibitors are investigated in phase-1 clinical trials for leukemia. The progress toward the establishment of DOT1L inhibitors, on the other hand, was hampered by poor pharmacological properties of the available compounds. In October 2020, Perner published in the journal Blood a novel set of DOT1L inhibitors, which are orally available, have favorable pharmacokinetics, and show promise in combating leukemia in patient-derived xenografts, putting this class of drugs back onto the pre-clinical landscape.
Now, the race is on to establish efficient pharmacologic combination treatment approaches to leverage the novel concepts derived from this project and translate the pre-clinical findings to improve patient care in the future.
Perner credits the Mark Foundation for helping him forge ahead in this emerging field.
“The Mark Foundation lifted us to a point where we had a freedom to generate data on a high-risk project and to prove that what we are working on is actually relevant,” he says.
Next year, Perner will start his own lab in the Department of Hematology and Medical Oncology at University Medical Center in Greifswald, Germany. He hopes to use the new insights about the epigenetic mechanisms of resistance to further develop and optimize novel therapies for blood cancer.
“We were really ahead of the game,” he says. “And now, I want to use these findings to improve clinical care.”