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

Overview

Journal Kidney360

Specialty Nephrology

Date 2022 Feb 28

PMID 35224510

Authors

Josephine F Trott

Omran Abu Aboud

Bridget McLaughlin

Katie L Anderson

Jaime F Modiano

Kyoungmi Kim

Kuang-Yu Jen

William Senapedis

Hua Chang

Yosef Landesman

Erkan Baloglu

Roberto Pili

Robert H Weiss

Affiliations

Soon will be listed here.

Abstract

Background: Kidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer.

Methods: In this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti-programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies.

Results: We demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors.

Conclusions: This study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.

Citing Articles

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death.

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PMID: 38580317 PMC: 11056997. DOI: 10.1021/acs.jmedchem.3c02112.

Advances in NAD-Lowering Agents for Cancer Treatment.

Ghanem M, Monacelli F, Nencioni A Nutrients. 2021; 13(5).

PMID: 34068917 PMC: 8156468. DOI: 10.3390/nu13051665.

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