Poster Presentation 38th Lorne Cancer Conference 2026

Deciphering Mitotic and DNA Damage Pathways Driving Malignant Rhabdoid Tumour: Preclinical and Mechanistic Evaluation of Alisertib, Temozolomide, and Irinotecan Combination Therapy (#141)

Kimberly Dias 1 2 , Gabe Tax 1 2 , Jinhan Xie 1 2 , Loretta MS Lau 1 2 3
  1. Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, New South Wales, Australia
  2. School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, New South Wales, Australia
  3. Kids Cancer Centre, Sydney Children's Hospital Network, Randwick, New South Wales, Australia

Background

Malignant rhabdoid tumour (MRT) is an aggressive paediatric malignancy driven by SMARCB1 loss, leading to chromatin dysregulation and mitotic instability. Aurora kinase A inhibition with alisertib disrupts mitotic spindle dynamics but achieves limited efficacy as monotherapy. Given the intrinsic DNA repair vulnerabilities in MRT, we evaluated whether combining alisertib with the DNA-damaging agents temozolomide (TMZ) and irinotecan (IRN) would enhance therapeutic activity through coordinated disruption of mitotic and DNA damage response pathways. This three-drug combination has a safety profile in paediatrics supporting the rapid clinical translation.

Methods

The in vivo efficacy of the alisertib + IRN + TMZ combination was tested against 4 MRT patient-derived xenograft (PDX) models established from patient samples collected through the ZERO childhood cancer program (ZERO). NSG mice were subcutaneously inoculated, and treatment was started when the tumour reached 100 mm³, and the event was defined as the quadrupling of tumour volume from day 0. Efficacy is determined by the stringent objective response criteria developed from clinical trials. Matrix combination testing was also conducted in 2 PDXs to determine the in vitro activity of alisertib + IRN + TMZ. Leveraging the comprehensive multi-omics data obtained through the ZERO program, molecular analyses were also conducted to explore the mechanism of activity associated with this combination therapy.

Results

The alisertib + IRN + TMZ combination exhibits strong in vivo synergism across all 4 PDXs tested. Significant tumour regressions were observed in animals treated with the triple-drug combination, achieving complete responses, whereas alisertib-only treatment induced only partial responses. In zccs1127 PDX, Median event-free survival in the 3-drug combination cohort is nearly doubled compared to that of alisertib alone, and 10 times more compared to the IRN + TMZ cohort (median EFS in days: vehicle control: 4.76; alisertib: 33.67; IRN+TMZ: 6.96; and alisertib + IRN + TMZ: 63.38). Molecular analyses are currently underway to fully dissect the mechanism of activity.

Conclusion

Combination therapy with alisertib, TMZ and IRN produces potent synergistic efficacy in preclinical MRT PDX models through dual targeting of mitotic and DNA repair pathways. These findings provide compelling preclinical evidence to support the use of this combination in treating paediatric MRT.