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Peer-reviewedCC BYCancers

PP2A Activation as a Senotherapeutic in Neuroblastoma.

  • Nazia Nazam1
  • Sorina N Shirley1
  • Joel C Opara1
  • Shamza Manzoor2
  • Maryam G Shaikh1
  • Morgan L Brown1
  • Pranava Nande1
  • Ali M Eakes1
  • Abdulraheem Kaimari1
  • Jianmei W Leavenworth2,3
  • Michael Ohlmeyer4
  • Elizabeth A Beierle1,3
4 affiliations
  1. 1Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  2. 2Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  3. 3O'Neal Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  4. 4Atux Iskay, LLC, Plainsboro, NJ 08536, USA.
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Abstract

Background/Objectives: Therapy-induced senescence (TIS), while initially growth-suppressive, may promote tumor recurrence through the persistence of senescent cells and the senescence-associated secretory phenotype (SASP). Topotecan, a topoisomerase inhibitor and a key component in the treatment of neuroblastoma (NBL), is known to lead to TIS. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that has been linked to cellular senescence. PP2A is downregulated in NBL, primarily through upregulation of its endogenous inhibitors. We have previously shown that a novel small molecule, ATUX-1215, activates PP2A in NBL cells. Methods: The current study investigates the PP2A activator, ATUX-1215, as a senotherapeutic strategy in NBL. Results: We demonstrate that combining ATUX-1215 with topotecan leads to a reduction in senescent cell burden. Combination therapy suppressed PAI-1 and CCL2, key components of the SASP secretome, and enhanced apoptosis. PP2A activation reduced viability, stemness, and clonogenic survival post-TIS. In vivo, the combination of ATUX-1215 treatment with topotecan significantly delayed tumor growth and attenuated the pro-tumorigenic serum SASP. Conclusions: Our findings position PP2A activation as a senotherapeutic approach, transforming the tumor-promoting TIS program into a therapeutic vulnerability, offering a promising avenue to mitigate therapy resistance and improve outcomes in NBL.

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Cite

BibTeXRIS
BibTeX
@article{nazam2026pp2a,
  title = {{PP2A Activation as a Senotherapeutic in Neuroblastoma.}},
  author = {Nazia Nazam and Sorina N Shirley and Joel C Opara and Shamza Manzoor and Maryam G Shaikh and Morgan L Brown and Pranava Nande and Ali M Eakes and Abdulraheem Kaimari and Jianmei W Leavenworth and Michael Ohlmeyer and Elizabeth A Beierle},
  journal = {Cancers},
  year = {2026},
  month = sep,
  doi = {10.3390/cancers18193088},
  url = {https://europepmc.org/article/MED/42882783},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - PP2A Activation as a Senotherapeutic in Neuroblastoma.
AU  - Nazia Nazam
AU  - Sorina N Shirley
AU  - Joel C Opara
AU  - Shamza Manzoor
AU  - Maryam G Shaikh
AU  - Morgan L Brown
AU  - Pranava Nande
AU  - Ali M Eakes
AU  - Abdulraheem Kaimari
AU  - Jianmei W Leavenworth
AU  - Michael Ohlmeyer
AU  - Elizabeth A Beierle
PY  - 2026
DA  - 2026/09/23
JO  - Cancers
DO  - 10.3390/cancers18193088
UR  - https://europepmc.org/article/MED/42882783
AB  - Background/Objectives: Therapy-induced senescence (TIS), while initially growth-suppressive, may promote tumor recurrence through the persistence of senescent cells and the senescence-associated secretory phenotype (SASP). Topotecan, a topoisomerase inhibitor and a key component in the treatment of neuroblastoma (NBL), is known to lead to TIS. Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that has been linked to cellular senescence. PP2A is downregulated in NBL, primarily through upregulation of its endogenous inhibitors. We have previously shown that a novel small molecule, ATUX-1215, activates PP2A in NBL cells. Methods: The current study investigates the PP2A activator, ATUX-1215, as a senotherapeutic strategy in NBL. Results: We demonstrate that combining ATUX-1215 with topotecan leads to a reduction in senescent cell burden. Combination therapy suppressed PAI-1 and CCL2, key components of the SASP secretome, and enhanced apoptosis. PP2A activation reduced viability, stemness, and clonogenic survival post-TIS. In vivo, the combination of ATUX-1215 treatment with topotecan significantly delayed tumor growth and attenuated the pro-tumorigenic serum SASP. Conclusions: Our findings position PP2A activation as a senotherapeutic approach, transforming the tumor-promoting TIS program into a therapeutic vulnerability, offering a promising avenue to mitigate therapy resistance and improve outcomes in NBL.
SN  - 2072-6694
ER  -