Enhancing Epigenetic and Immunotherapy Efficacy in PDAC through Target Discovery and Tumor Microenvironment Modeling

In this project, I led preclinical drug discovery efforts in pancreatic ductal adenocarcinoma (PDAC), aimed at identifying and validating novel therapeutic targets to enhance the efficacy of epigenetic therapies and immune checkpoint inhibitors. I developed complex co-culture systems incorporating tumor cells and multiple immune cell populations to model the PDAC tumor microenvironment. High-parameter flow cytometry was employed to characterize immune subsets and treatment-induced shifts in the tumor-immune interface. In vivo, I designed and executed numerous treatment studies and survival surgeries using orthotopic and subcutaneous PDAC models. Therapeutic responses were evaluated using cytokine array profiling, survival analysis, and immune phenotyping. I also integrated RNA-seq data to identify pathway-level changes and resistance mechanisms.

Low dose dual epigenetic therapy utilizing hypomethylating agents and HDAC inhibitors prolong survival in an orthotopic PDAC model and alter the tumor microenvironment

Stephen Muzyka, Arturo Orlacchio, Amanda Ackermann, Yasmine Chinda, Yoona Shim, Igor Dolgalev, Tamas Gonda

AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research 2024

Dual epigenetic therapy combined with anti-PD1 rescues HMA-induced suppressive myeloid phenotype and reduces tumor growth in a PDAC model

Arturo Orlacchio; Stephen Muzyka; Catherine Do; Diane M. Simeone; Tamas Gonda

AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research 2023

Hypomethylating therapy induces a potential immuno-suppressive myeloid phenotype by altering cancer cell cytokine secretion in PDAC

Arturo Orlacchio; Daniel Weissinger; Catherine Do; Benjamin Tycko; Diane M. Simeone; Tamas Gonda

AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research 2022

Epigenetic therapeutic strategies in pancreatic cancer

Arturo Orlacchio, Stephen Muzyka, Tamas A Gonda

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 8-11%. Despite significant improvements in PDAC treatment and management, therapeutic alternatives are still limited. One of the main reasons is its high degree of intra- and inter-individual tumor heterogeneity which is established and maintained through a complex network of transcription factors and epigenetic regulators. Epigenetic drugs, have shown promising preclinical results in PDAC and are currently being evaluated in clinical trials both for their ability to sensitize cancer cells to cytotoxic drugs and to counteract the immunosuppressive characteristic of PDAC tumor microenvironment. In this review, we discuss the current status of epigenetic treatment strategies to overcome molecular and cellular PDAC heterogeneity in order to improve response to therapy.

International Review of Cell and Molecular Biology 2024

Understanding Tricky Cellular and Molecular Interactions in Pancreatic Tumor Microenvironment: New Food for Thought

Antonio Agostini, Arturo Orlacchio, Carmine Carbone, Ilaria Guerriero

Abstract

Pancreatic ductal adenocarcinoma (PDAC) represents 90% of all pancreatic cancer cases and shows a high mortality rate among all solid tumors. PDAC is often associated with poor prognosis, due to the late diagnosis that leads to metastasis development, and limited efficacy of available treatments. The tumor microenvironment (TME) represents a reliable source of novel targets for therapy, and even if many of the biological interactions among stromal, immune, and cancer cells that populate the TME have been studied, much more needs to be clarified. The great limitation in the efficacy of current standard chemoterapy is due to both the dense fibrotic inaccessible TME barrier surrounding cancer cells and the immunological evolution from a tumor-suppressor to an immunosuppressive environment. Nevertheless, combinatorial therapies may prove more effective at overcoming resistance mechanisms and achieving tumor cell killing. To achieve this result, a deeper understanding of the pathological mechanisms driving tumor progression and immune escape is required in order to design rationale-based therapeutic strategies. This review aims to summarize the present knowledge about cellular interactions in the TME, with much attention on immunosuppressive functioning and a specific focus on extracellular matrix (ECM) contribution.

Frontiers in Immunology 2022

The Role of Toll-like Receptors (TLRs) Mediated Inflammation in Pancreatic Cancer Pathophysiology

Arturo Orlacchio, Pellegrino Mazzone

Abstract

Pancreatic cancer (PC) is one of the most lethal forms of cancer, characterized by its aggressiveness and metastatic potential. Despite significant improvements in PC treatment and management, the complexity of the molecular pathways underlying its development has severely limited the available therapeutic opportunities. Toll-like receptors (TLRs) play a pivotal role in inflammation and immune response, as they are involved in pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs). Activation of TLRs initiates a signaling cascade, which in turn, leads to the transcription of several genes involved in inflammation and anti-microbial defense. TLRs are also deregulated in several cancers and can be used as prognostic markers and potential targets for cancer-targeted therapy. In this review we discuss the current knowledge about the role of TLRs in PC progression, focusing on the available TLRs-targeting compounds and their possible use in PC therapy.

International Journal of Molecular Sciences 2021