Clinical and Preclinical Targeting of Oncogenic Pathways in PDAC: Targeted Therapeutic Approaches for the Deadliest Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death worldwide. It is commonly diagnosed in advanced stages and therapeutic interventions are typically constrained to systemic chemotherapy, which yields only modest clinical outcomes. In this review, we examine recent developments in targeted therapy tailored to address distinct molecular pathway alteration required for PDAC. Our review delineates the principal signaling pathways and molecular mechanisms implicated in the initiation and progression of PDAC. Subsequently, we provide an overview of prevailing guidelines, ongoing investigations, and prospective research trajectories related to targeted therapeutic interventions, drawing insights from randomized clinical trials and other pertinent studies. This review focus on a comprehensive examination of preclinical and clinical data substantiating the efficacy of these therapeutic modalities, emphasizing the potential of combinatorial regimens and novel therapies to enhance the quality of life for individuals afflicted with PDAC. Lastly, the review delves into the contemporary application and ongoing research endeavors concerning targeted therapy for PDAC. This synthesis serves to bridge the molecular elucidation of PDAC with its clinical implications, the evolution of innovative therapeutic strategies, and the changing landscape of treatment approaches.

Keywords: PDAC; clinical; clinical trials; combinational therapy; molecular alterations; oncogenic pathways; preclinical; targeted therapy.

Figure 1

Molecular targets and targeted therapeutic approaches. The main clinically-relevant chemotherapeutic agents and targeted agents are displayed against the main molecular alterations in PDAC, which are KRASG12V, TP53, CDKN2A (p14ARF and p16INK4A) and SMAD4 or their signaling pathways.

Figure 2

Emerging therapeutic approaches. The schematic illustration portrays the intricate milieu of a tumor microenvironment, delineating the extracellular matrix and its pivotal constituents, namely hyaluronic acid, collagen, laminin, and proteoglycans, alongside various cellular elements such as TAMs (tumor-associated macrophages), dendritic cells, T lymphocytes, MDSCs (myeloid-derived suppressor cells), and CAFs (cancer-associated fibroblasts). Within this context, emphasis is placed on elucidating the principal molecules governing immune cell regulation, including CTLA-4, PD-1, and corresponding therapeutic interventions targeting these molecules. The evolution of novel therapies stems from the imperative to breach the stromal barrier, leading to amalgamated formulations encapsulated to enhance targeted therapeutic efficacy; exemplified by the combination of gemcitabine and PEGPH20 (hyaluronidase) confined within nanocapsules.