Stapled Oncolytic Peptides for Treatment-Resistant Pediatric Leukemias
When pediatric leukemias recur, they are often harder to treat because they have developed resistance to the broad spectrum of standard treatments, such as chemotherapy, radiation, and modern cellular and immunotherapies. Most pediatric leukemia treatments target either the cancer cell’s DNA or protein, but often cannot distinguish between leukemia cells and normal cells, leading to unwanted side effects and toxicities. For our proposed Innovator project, we will focus on a distinct target of the leukemia cell – its membrane coating or “plasma membrane”. There are hundreds of peptides found in nature that protect against infection by literally poking holes in the plasma membranes of bacteria. Although such peptides can overcome even the most drug-resistant bacteria, they could not be used as antibiotics because they also destroy the plasma membranes of normal cells. The Walensky laboratory discovered how to engineer stapled antimicrobial peptides or StAMPs so that they selectively kill bacteria but not normal cells, enabling their development into prototype antibiotics for the treatment of human infections. Now, we propose to harness this know-how to generate stapled oncolytic peptides or StOPs that selectively target pediatric leukemia cells based on the unique properties of their plasma membranes.
Project Goal:
The Walensky group will apply their unique peptide stapling technology that recapitulates and stabilizes the natural coiled shape of bioactive peptides to produce stapled oncolytic peptides that can selectively destroy the plasma membranes of treatment-resistant pediatric leukemia cells. To achieve this goal, we will generate a large series of stapled peptides based on membrane-disrupting antimicrobial peptide sequences from nature and then examine their capacity to lyse pediatric leukemia cells but not normal blood cells. We will then test the best compounds that emerge from our studies against leukemia cells collected from pediatric patients. Our ultimate goal is to advance a new therapeutic strategy for eliminating the hardest-to-treat leukemias by literally destroying their otherwise protective membrane coating. We envision that mechanical disruption of the leukemia cell membrane will provide an opportunity to bypass treatment resistance and extend the lives of children confronting refractory disease by suppressing, and ideally eliminating, circulating leukemic blasts, including in the palliative care setting where maximizing quality and quantity of life is paramount.
