Pancreatic cancer: Early detection and novel therapies

PC is a heterogeneous disease, with PDAC accounting for 90% of cases. Despite its relatively low incidence, PC is the third leading cause of cancer-related deaths in the United States, with 66,440 new cases and 51,750 deaths estimated in 2024. The deep retroperitoneal location of the pancreas and nonspecific symptoms often delay diagnosis, with over 80% of patients presenting with unresectable tumors at diagnosis. Premalignant lesions, such as intraductal papillary mucinous neoplasms (IPMNs), offer screening opportunities, but current methods are limited to high-risk populations.

Imaging Techniques for Diagnosis

Imaging plays a pivotal role in PC diagnosis and staging:

• Endoscopic Ultrasound (EUS): Highly sensitive for detecting small tumors (<2 cm), with modifications like EUS elastography and contrast-enhanced EUS improving diagnostic accuracy.

• Multi-Detector CT (MDCT): The primary imaging tool, offering 85–95% accuracy for tumor detection and surgical planning.

• MRI and PET: Useful for differentiating ambiguous lesions and assessing metabolic activity, respectively, though PET’s spatial resolution limits local staging.

Blood and Tissue-Based Diagnostic Tests

Advancements in biomarkers and molecular diagnostics include:

• CA 19-9: The most widely used biomarker, albeit with limited specificity due to elevation in benign conditions.

• Circulating Tumor DNA (ctDNA): Detects tumor-specific mutations non-invasively, aiding in prognosis and monitoring treatment response.

• MicroRNAs (miRNAs): Dysregulated miRNAs like miR-1290 show promise for early detection and distinguishing PDAC from benign conditions.

• Proteomics and Radiomics: These omics technologies analyze protein expression and imaging features, respectively, to identify novel biomarkers and improve diagnostic precision.

Treatment Approaches

Therapeutic strategies target PC’s complex pathophysiology:

1. HRD Pathway Targeting: Platinum-based therapies and PARP inhibitors (e.g., olaparib) benefit patients with homologous recombination deficiency (HRD) mutations.

2. Immunotherapy:

   • Immune Checkpoint Inhibitors (ICIs): Limited efficacy in PDAC due to its immunosuppressive microenvironment, but combinations (e.g., anti-PD-1 + anti-CTLA-4) show promise in HRD-mutant subsets.

   • CAR T-Cell Therapy: Targets antigens like claudin 18.2 and mesothelin, though challenges remain in solid tumor penetration.

   • Cancer Vaccines: GVAX and dendritic cell vaccines aim to stimulate immune responses, with mixed clinical outcomes.

3. Novel Therapies:

   • Oncolytic Viruses: Engineered viruses (e.g., VCN-01) lyse tumor cells and enhance immune activation.

   • CRISPR/Cas9: Gene editing to disrupt immune resistance pathways (e.g., CD73 knockout) and restore drug sensitivity.

Future Directions

Emerging strategies focus on modulating the tumor microenvironment (TME):

• CD40 Agonists: Reprogram the TME to enhance T-cell infiltration.

• Stromal Targeting: Hyaluronidase (PEGPH20) reduces desmoplasia, improving drug delivery.

• Innate Immune Activation: STING agonists and bacterial vectors (e.g., CRS207) aim to convert "cold" tumors into immunogenic ones.

Conclusion

While pancreatic cancer remains a formidable challenge, integrating advanced diagnostics (e.g., ctDNA, radiomics) with innovative therapies (e.g., CAR T-cells, vaccines) offers hope for earlier detection and personalized treatment. Multidisciplinary approaches targeting the TME and immune evasion mechanisms are critical to improving survival outcomes.

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https://www.xiahepublishing.com/2994-8754/JTG-2024-00037

The study was recently published in the Journal of Translational Gastroenterology.

Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.

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