Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Kidney cancer (renal cell carcinoma, RCC) is a growing concern with limited treatment options.
• Existing targeted therapies and immunotherapies show resistance in most RCC cases.
• Novel combination therapies are being explored to overcome treatment resistance.

Purpose of the Study:

• To evaluate the efficacy of combining KPT-9274, a dual PAK4/NAMPT inhibitor, with immune checkpoint inhibitors (CPI) in an immunocompetent kidney cancer model.
• To assess the therapeutic potential of KPT-9274 and anti-PD1 antibody combination in renal cell adenocarcinoma (RENCA).

Main Methods:

• Utilized the spontaneous murine RENCA model for kidney cancer.
• Administered KPT-9274 and/or anti-programmed cell death 1 (PDCD1; PD1) antibody to mice with palpable tumors.
• Monitored tumor growth, animal weight, and performed histological and flow cytometry analyses.

Main Results:

• Combination therapy significantly decreased tumor growth without causing significant weight loss.
• Observed decreased murine Naprt expression, confirming tumor dependence on NAMPT.
• Tumor necrosis was substantial, but enhanced therapeutic effects were not driven by increased T-cell infiltration.

Conclusions:

• The RENCA model is suitable for evaluating immunologic responses to KPT-9274 and CPI combinations.
• This combination therapy may enhance efficacy in renal cell carcinoma beyond CPI treatment alone.