Project 1: Overcoming therapeutic resistance in pancreatic cancer through epigenetic reprogramming

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PROJECT SUMMARY – Project 1: Epigenetics Pancreatic ductal adenocarcinoma (PDA) is a devastating disease with a disturbing rise in incidence. The poor prognosis of PDA is attributed, in large part, to inherent resistance to conventional chemo- and immuno- therapies. Multifactorial contributions from tumor intrinsic and extrinsic epigenomic programs, an elaborate network of cell-cell communications within the tumor microenvironment (TME), and complex metabolic adaptations compound to make PDA refractory to the current arsenal of therapies. Proposed experiments use both pharmacological and genetic targeting of Class I histone deacetylases (HDACs) to determine the contributions of epigenetically encoded programs to therapeutic resistance. Aim 1 expands on the lab’s finding that HDAC inhibition (HDACi) leads to a downregulation of DNA damage response pathway genes. The ability of HDACi to sensitize both organoid and mouse models of PDA to DNA damaging agents is tested by employing a nanoparticle delivery system that circumvents systemic HDAC inhibitor toxicities in vivo. Given preliminary evidence that HDACi upregulates autophagy, a known mediator of therapeutic resistance, the ability of autophagy inhibition to potentiate responses to HDACi (and combinations with DNA damaging agents) is tested in collaboration with Project 3. Moreover, interrogation of a human organoid bank will delineate how different mutational profiles impact sensitivities to HDACi and DNA damage. Aim 2 delineates the contribution of HDAC- regulated epigenetic programs in cancer-associated fibroblasts (CAFs), a heterogenous cell type within the TME, to PDA outcomes. Preliminary data identifies HDAC1 as the primary HDAC underlying CAF responses to pharmacological HDACi in vitro. Here, a genetic approach is taken to determine how HDAC1 loss in fibroblasts impacts CAF functional heterogeneity, tumor growth, and chemoresistance in vivo. Collaborative efforts with Project 2 elucidate how HDACi influences stromal support of tumor growth and chemoresistance through alterations in CAF-derived soluble factors, including LIF. In addition, the molecular mechanisms by which HDACi rewires the epigenome in specific CAF subpopulations is delineated. Lastly, Aim 3 builds on preliminary findings that HDACi sensitizes PDA mouse models to immune checkpoint inhibition (ICI). In collaboration with Project 3, the ability of HDACi and autophagy blockade to synergize in promoting ICI responses through convergent regulation of MHC-I is tested. The possibility of enhancing anti-tumor immunity by inducing immunological cell death through the combination of HDACi and DNA damaging agents is also explored. In collaboration with Project 2, how STAT signaling in inflammatory CAF populations influences anti-tumor immunity elicited by HDACi and ICI is defined. Finally, to determine how HDACi reprograms immunomodulatory features in human PDA, biopsies from a completed clinical trial combining HDACi and anti-PD-1 ICI are analyzed via digital spatial profiling. Together, these studies provide critical insight into the epigenetic mechanisms underlying therapeutic resistance in PDA and explore novel treatment strategies with the potential to improve patient outcomes.