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

Animals Apoptosis Regulatory Proteins / pharmacology Carcinoma, Renal Cell / drug therapy Cell Proliferation Kidney Neoplasms / drug therapy Male Mice Nicotinamide Phosphoribosyltransferase

Journal

Kidney360
ISSN: 2641-7650
Titre abrégé: Kidney360
Pays: United States
ID NLM: 101766381

Informations de publication

Date de publication:
28 May 2020
Historique:
entrez: 28 2 2022
pubmed: 28 5 2020
medline: 28 5 2020
Statut: ppublish

Résumé

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. 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. 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) 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.

Sections du résumé

BACKGROUND 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 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 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)
CONCLUSIONS 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.

Identifiants

DOI: 10.34067/kid.0000282019 PMID: 35224510 PMC: PMC8809296
pubmed: 35224510
doi: 10.34067/kid.0000282019
pmc: PMC8809296
mid: NIHMS1603763
doi:

Substances chimiques

Apoptosis Regulatory Proteins 0
Nicotinamide Phosphoribosyltransferase EC 2.4.2.12

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Pagination

376-388

Subventions

Organisme : NCI NIH HHS
ID : P30 CA093373
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA181837
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA195973
Pays : United States
Organisme : NCRR NIH HHS
ID : C06 RR012088
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107416
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK082690
Pays : United States

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Auteurs

Josephine F Trott (JF)

Division of Nephrology, Department of Internal Medicine, University of California, Davis, California.
ORCID: 0000-0002-4506-7685

Omran Abu Aboud (OA)

Division of Nephrology, Department of Internal Medicine, University of California, Davis, California.

Bridget McLaughlin (B)

Comprehensive Cancer Center, University of California, Davis, California.

Katie L Anderson (KL)

Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Center for Immunology, University of Minnesota, Minneapolis, Minnesota.

Jaime F Modiano (JF)

Animal Cancer Care and Research Program, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Center for Immunology, University of Minnesota, Minneapolis, Minnesota.
Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.

Kyoungmi Kim (K)

Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, California.

Kuang-Yu Jen (KY)

Department of Pathology and Laboratory Medicine, University of California, Davis, California.

William Senapedis (W)

Research and Translational Development, Karyopharm Therapeutics Inc., Newton, Massachusetts.

Hua Chang (H)

Research and Translational Development, Karyopharm Therapeutics Inc., Newton, Massachusetts.

Yosef Landesman (Y)

Research and Translational Development, Karyopharm Therapeutics Inc., Newton, Massachusetts.

Erkan Baloglu (E)

Research and Translational Development, Karyopharm Therapeutics Inc., Newton, Massachusetts.

Roberto Pili (R)

Simon Cancer Center, School of Medicine, Indiana University, Indianapolis, Indiana.

Robert H Weiss (RH)

Division of Nephrology, Department of Internal Medicine, University of California, Davis, California.
Comprehensive Cancer Center, University of California, Davis, California.
Medical Service, Veterans Affairs Northern California Health Care System, Sacramento, California.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Anti-Cancer Activity of PAK4/NAMPT Inhibitor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines régulatrices de l'apoptose › Anti-Cancer Activity of PAK4/NAMPT Inhibitor...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs du rein › Néphrocarcinome › Anti-Cancer Activity of PAK4/NAMPT Inhibitor...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Anti-Cancer Activity of PAK4/NAMPT Inhibitor...
questionsmedicales.fr › Maladies urogénitales › Maladies urologiques › Tumeurs urologiques › Tumeurs du rein › Anti-Cancer Activity of PAK4/NAMPT Inhibitor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Anti-Cancer Activity of PAK4/NAMPT Inhibitor...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Glycosyltransferase › Pentosyltransferases › Nicotinamide phosphoribosyltransferase › Anti-Cancer Activity of PAK4/NAMPT Inhibitor...