Author of

• 11515

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  P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

  • Event: WCLC 2013
  • Type: Poster Session
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level

  • 11532

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    P2.05-017 - Evaluation of the selective aurora B kinase inhibitor AZD1152 in SCLC lines with and without MYC family amplification. (ID 2877)

    09:30 - 09:30  |  Author(s): X. Li
    • Abstract

    Background
    Background: Small cell lung cancer (SCLC) has an overall 5-year survival rate of < 5% despite initial response rates to first line chemotherapy of 70-90%. MYC family amplification occurs in 30% of SCLC and MYC amplified tumors have been shown to be dependent on aurora kinase B for their survival. Aurora B kinase (AURKB) is a chromosomal passenger protein that plays a critical role in mitosis by regulating chromosome alignment, accurate segregation, and cytokinesis during the mitotic stages. We evaluated the effects of the selective aurora B kinase inhibitor AZD1152-HQPA (active drug) in a panel of 15-SCLC lines.

    Methods
    Methods: Nine lines had MYC-family amplification (MYC-5 lines, MYCL1-2 lines, MYCN-2 lines) and 6-lines had no MYC-family amplification. Growth inhibition by AZD1152-HQPA was assessed by tetrazolium based assays. Apoptosis was determined using the DNA binding dyes YOPRO and propidium iodine (PI) and analysis by flow cytomery. The induction of polyploidy was evaluated by flow cytometry following PI staining of the DNA. The effect of AZD1152-HQPA on anchorage independent growth was determined by soft agar colony forming assays. Finally, we evaluated the in vivo efficacy of AZD1152 (prodrug) on SCLC xenografts in nude mice.

    Results
    Results: AZD1152-HQPA GI50 values for the 4 most sensitive SCLC lines were 11-30 nM and < 25% of untreated control growth was observed at 60 nM. Five lines had GI50 values of 30-60 nM but at 600 nM AZD1152-HQPA cell viability remained at 49-55% of untreated control growth. In the remaining 6-lines cell viability at 600 nM was 60-93% of control growth. Growth inhibition marginally correlated with MYC amplification (p=0.044) and was strongly correlated with MYC + MYCL1 + MYCN amplification (p=0.011). Apoptosis (20-28%) was induced by 30 nM AZD1152-HQPA at 24-48 hours in the most sensitive cell lines. Marked increases in DNA ploidy (8N) was observed after 24 hour exposure to AZD1152-HQPA (30nM) in the most sensitive cell lines and at 48 hours in the 5 intermediate lines and in 2 of the resistant lines. In vivo AZD1152 (i.p. 100 mg/kg/M-F for two weeks) induced tumor regression in nude mice implanted with a sensitive cell line. AZD1152 at 50mg/kg/day inhibited tumor growth; however these tumors began growing following treatment cessation. A resistant line was also implanted into nude mice and AZD1152 at 50 and 100 mg/kg/day caused tumor regression. Polyploidy was induced in this cell line at 48 hours post 30 nM AZD1152-HQPA. Anchorage independent growth in this resistant line was also completely inhibited by AZD1152-HQPA 25 nM. The doses of AZD1152-HQPA used in this study are within the range reported to be clinically achievable.

    Conclusion
    Conclusions: AZD1152-HQPA growth inhibition significantly correlated with MYC-family amplification in SCLC lines but some SCLC lines without MYC-family amplification were also inhibited. Additional biomarkers are needed to identify SCLC patients most likely to respond to AZD1152.