Combination, Modulation and Interplay of Modern Radiotherapy with the Tumor Microenvironment and Targeted Therapies in Pancreatic Cancer: Which Candidates to Boost Radiotherapy?

Abstract

Pancreatic ductal adenocarcinoma cancer (PDAC) is a highly diverse disease with low tumor immunogenicity. PDAC is also one of the deadliest solid tumor and will remain a common cause of cancer death in the future. Treatment options are limited, and tumors frequently develop resistance to current treatment modalities. Since PDAC patients do not respond well to immune checkpoint inhibitors (ICIs), novel methods for overcoming resistance are being explored. Compared to other solid tumors, the PDAC’s tumor microenvironment (TME) is unique and complex and prevents systemic agents from effectively penetrating and killing tumor cells. Radiotherapy (RT) has the potential to modulate the TME (e.g., by exposing tumor-specific antigens, recruiting, and infiltrating immune cells) and, therefore, enhance the effectiveness of targeted systemic therapies. Interestingly, combining ICI with RT and/or chemotherapy has yielded promising preclinical results which were not successful when translated into clinical trials. In this context, current standards of care need to be challenged and transformed with modern treatment techniques and novel therapeutic combinations. One way to reconcile these findings is to abandon the concept that the TME is a well-compartmented population with spatial, temporal, physical, and chemical elements acting independently. This review will focus on the most interesting advancements of RT and describe the main components of the TME and their known modulation after RT in PDAC. Furthermore, we will provide a summary of current clinical data for combinations of RT/targeted therapy (tRT) and give an overview of the most promising future directions.

Favorable histo-molecular remodeling of pancreatic ductal adenocarcinoma after Total Neoadjuvant Therapy including Stereotactic Body Radiotherapy

“…Nonetheless, further well-designed trials, combining these treatments with targeted therapies and stratified treatment approaches, are urgently needed to improve the dismal patients’ prognosis. [5] For this purpose, we hereby investigated for the first time the histo-molecular modulations induced by FFX alone and FFX followed by iHD-SBRT (TNT group).…”

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma or a Metaphor for Heterogeneity: From Single-Cell Analysis to Whole-Body Imaging

“…This complexity arises from extensive interactions among various TME components, providing numerous avenues for resistance and heightened tumor aggressiveness. The TME in PDAC plays a significant role in the pronounced resistance observed against conventional and immune therapies [ 3 , 4 ]. PDAC tumors are characterized by prominent stromal desmoplastic reactions surrounding cancer cells, resulting in an acidified and hypoxic microenvironment with elevated interstitial pressure.…”

“…PDAC tumors are characterized by prominent stromal desmoplastic reactions surrounding cancer cells, resulting in an acidified and hypoxic microenvironment with elevated interstitial pressure. This creates a drug-resistant sanctuary and poses a physical barrier to immune cells recruitment [ 4 , 5 , 6 , 7 ]. Central to the desmoplastic reaction are cancer-associated fibroblasts (CAFs), representing a significant component of the TME, accounting for up to 90% of the tumor tissue in PDAC.…”

The footprint of gut microbiota in gallbladder cancer: a mechanistic review

“…Incidental GBC cases are often found by pathological examination after cholecystectomy, requiring secondary surgery ( Ethun et al., 2017 ), while symptomatic patients are usually at an advanced stage who are not suitable for surgery or have poor surgical outcomes ( Liu et al., 2022b ). Unfortunately, regardless of whether GBC is known or unknown preoperatively, the R0 resection rate remains suboptimal even with aggressive radical surgical resection ( Benkhaled et al., 2023 ). Chemoradiotherapy is the preferred treatment for advanced GBC, but the lack of chemotherapy options and the insensitivity of radiotherapy lead to poor patient outcomes ( Hakeem et al., 2019 ).…”