Targeting Leukemia Stem Cells with Small Molecule Heat Shock Transcription Factor 1 Degrader

Project Summary_Abstract Acute myeloid leukemia (AML) thrives through the persistence of self-renewing leukemic stem cells (LSCs). A central challenge in AML treatment lies in the failure of conventional therapies to eradicate LSCs, which can trigger AML reoccurrence. The promise of AML eradication hinges on identifying and targeting pivotal molecules driving LSC self-renewal. Heat shock transcription factor 1 (HSF1) is a stress-responsive transcription factor pivotal in shielding cells from stress-induced demise. It aids cancer cells in managing stress, facilitating oncogenic signaling, DNA/protein synthesis, oncogenic energy metabolism, and immune evasion. Our studies using Hsf1 knockout mice underscore HSF1’s unique role in AML stem cell maintenance, while sparing normal hematopoiesis. Importantly, AML prognosis worsens with elevated HSF1 levels per TCGA data and our data show that nuclear HSF1 levels correlate with therapeutic responses and AML progression. While HSF1 inhibitors have been tested in cellular and mouse xenograft cancer models, many either indirectly affect the HSF1 pathway or have an unknown mechanism of action. SISU-102, a direct and selective small-molecule nuclear HSF1 degrader, physically engages HSF1 and selectively promotes the degradation of its active, nuclear form. Importantly, our research has shown that SISU-102 effectively targets human AML LSCs. More recently, Sisu Pharma has developed new more potent HSF1 nuclear degraders with better drug-like properties. Our preliminary data indicate that these advanced HSF1 degraders exhibit enhanced binding to HSF1 and effectively suppress the proliferation of human LSCs. The aim of this proposal is to further investigate the impacts of these newly developed HSF1 degraders on LSC self-renewal, identify sensitive and resistant AML subtypes, and explore the underlying mechanisms, facilitating their translation into clinical use. Our working hypothesis posits that nuclear-specific HSF1 degraders have broad therapeutic potential against AML stem cells by disrupting multifaceted molecules and pathways driven by HSF1 that are critical for LSC maintenance. Aim 1: Determine the cellular impact of the newly developed small molecule nuclear HSF1 degraders on human AML stem cell self-renewal. Aim 2: Elucidate the mechanism of action of HSF1 degraders in LSCs and identify associated biomarkers that can identify AML patients susceptible to HSF1 degrader therapeutics. This research could advance HSF1 degraders for clinical trials in treating AML patients.