Neuroendocrine Tumor SPORE Research

Investigators are analyzing human pancreatic neuroendocrine tumor specimens from collaborating institutions, including Rutgers Cancer Institute and the University of Iowa.

Using multiplex immunohistochemistry, immunofluorescence, RNA sequencing, and B-cell and T-cell receptor profiling, researchers are characterizing immune-cell populations, including plasma cells, B cells, T cells, and immune checkpoint proteins such as B7x and PD-L1.

These findings will be correlated with tumor characteristics, metastasis, molecular signatures, and patient outcomes to identify potential prognostic and predictive biomarkers.

Researchers are evaluating CDK4/6 inhibitors, MEK inhibitors, and immune checkpoint blockade, individually and in combination, using immunocompetent mouse models of pNETs.

At Rutgers Cancer Institute, Dr. Libutti's laboratory is investigating these treatments using genetically engineered mouse models with deletion of the tumor suppressor genes MEN1 and PTEN. These mice develop functional pancreatic neuroendocrine tumors and can develop metastatic disease.

The studies examine tumor progression, survival, immune-cell infiltration, plasma-cell responses, and changes in the tumor immune microenvironment.

The clinical research component is designed to evaluate whether short-term treatment with the CDK4/6 inhibitor palbociclib and PD-L1 immune checkpoint blockade can increase immune-cell infiltration and activation in patients with pNETs before surgery.

Investigators plan to compare pretreatment tumor biopsies with surgically removed tumors to assess immune activation, plasma-cell infiltration, tumor-cell proliferation, and treatment-related biological changes.

This translational approach may help identify biomarkers that predict which patients are most likely to benefit from combination therapy.

Researchers in Dr. Libutti's laboratory evaluated the therapeutic efficacy of the MEK inhibitor mirdametinib and the CDK4/6 inhibitor palbociclib, alone or in combination with anti-PD-1 immunotherapy, using genetically engineered MEN1/PTEN-deficient mouse models of pancreatic neuroendocrine tumors.

Preliminary results demonstrated that combination treatments significantly prolonged survival compared with vehicle-treated controls. At approximately three months after treatment initiation, 71.4% of mice receiving mirdametinib plus palbociclib, mirdametinib plus anti-PD-1, or triple combination therapy remained alive, compared with 0% in the control group.

These encouraging findings support the potential of combining targeted kinase inhibitors with immune checkpoint blockade to improve therapeutic outcomes in pNETs.

During the first year, Rutgers Cancer Institute investigators have also been performing extensive immunohistochemistry (IHC) and immunofluorescence (IF) staining on human pancreatic neuroendocrine tumor specimens to characterize the tumor immune microenvironment.

These studies focus on identifying and quantifying immune-cell populations, including B cells, plasma cells, CD4+ and CD8+ T cells, and other tumor-associated immune cells, as well as evaluating the expression and spatial distribution of immune checkpoint proteins, including B7x and PD-L1.

Using multiple IHC and multiplex IF staining approaches, researchers are investigating the relationships among immune-cell infiltration, plasma-cell accumulation, and the potential formation of tertiary lymphoid structures within human pNETs.

These ongoing analyses aim to identify immune signatures associated with tumor progression, metastatic potential, and clinical outcomes. The findings may also help identify biomarkers that predict patient responses to targeted therapies and immunotherapy.