HSP70 as an actionable cancer-specific target

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is projected to become the second leading cause of cancer-related deaths in the United States by 2030. Despite recent advances in targeted therapies and immune checkpoint inhibitors for other solid tumors, PDAC remains largely refractory to treatment. As a result, PDAC is among the deadliest malignancies, with a five-year survival rate of only 13%. These challenges underscore the urgent and unmet need for innovative therapeutic strategies to improve clinical outcomes for the nearly 52,000 Americans who die from PDAC every year. Our research has identified the heat shock protein 70 (HSP70), a stress-inducible molecular chaperone, as a promising and selective therapeutic target in PDAC. We found that HSP70 is markedly overexpressed in both primary and metastatic PDAC, is associated with poor prognosis, and is minimally expressed in normal cells and tissues. We also discovered that the stress-induced, cytosolic HSP70 is significantly enriched in the mitochondria of PDAC cells and patient tumor biopsies, a feature that is rarely observed in non-malignant cells. This tumor-specific mitochondrial localization highlights a previously unrecognized role for HSP70 in PDAC and reveals a novel therapeutic vulnerability. Based on these findings, we developed a potent and highly selective small-molecule HSP70 inhibitor conjugated to a mitochondrial-targeting moiety. We hypothesize that HSP70 inhibition suppresses PDAC growth and metastasis by inducing oxidative stress and reprogramming the tumor immune microenvironment (TIME) to activate antitumor immunity. In Aim 1, we will use genetically engineered mouse models, patient-derived xenografts, and orthotopic models to determine the tumor cell-intrinsic mechanisms by which HSP70 inhibition attenuates PDAC progression and metastasis. In Aim 2, we will leverage integrative multi-omics approaches, including single-cell RNA-seq and spatial transcriptomics, to elucidate how HSP70 inhibition remodels the PDAC TIME. We will also investigate the mechanisms by which HSP70 inhibition promotes immune cell infiltration into the PDAC TIME. Vertebrate animal models are required for these studies to recapitulate PDAC tumor-host interactions, metastatic progression, and immune microenvironment dynamics within an intact physiological system that cannot be fully modeled in vitro or ex vivo. To successfully complete the proposed studies, we have assembled a strong and collaborative team at the Medical University of South Carolina with complementary expertise in (1) mouse models of PDAC, (2) drug discovery, and (3) cancer immunology. These studies are well supported by preliminary data and will address fundamental gaps in the field by improving the efficacy of HSP70 inhibitors, investigating the immunomodulatory roles of HSP70, and developing mechanism-based combination therapies. Ultimately, this proposal will lay the mechanistic groundwork for the clinical advancement of HSP70 inhibitors in PDAC.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is a lethal malignancy with no curative treatment options. This proposal leverages a newly developed HSP70 inhibitor with a unique mechanism of action to investigate tumor cell-intrinsic and extrinsic pathways by which it attenuates PDAC. We will also evaluate rational combination strategies to enhance the anti-tumor efficacy of HSP70 inhibition, with the long-term goal of translating these findings into therapies that improve outcomes for patients with PDAC.