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D. Gao
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.14 - The Aurora Kinase B Inhibitor AZD1152-HQPA Inhibitor in Small Cell Lung Cancer (SCLC) (ID 2161)
16:45 - 18:15 | Author(s): D. Gao
- Abstract
- Presentation
Background:
Aurora kinase expression has been associated with a poor prognosis in non-small cell lung cancer (NSCLC) and aurora kinase inhibitors have activity in preclinical lung models. Aurora kinases are required for mitosis and cell division. Small cell lung cancer cells have rapid proliferation and higher rates of MYC family amplification, which makes aurora kinase inhibition a natural target.
Methods:
23-SCLC lines with known MYC family amplification and MYC family gene expression were exposed to varying concentrations of the specific aurora kinase B inhibitor AZD1152-HQPA. The percentage growth inhibition compared to control was determined in MTS assays at 120 hours. Cell lines were classified as “sensitive” if the GI50 concentration was < 50 nM and with ≥ 80% growth inhibition at 100 nM. Fisher’s exact test was used to determine the correlation between amplification of MYC family members and sensitivity of the cell lines to growth inhibition by AZD1152-HQPA. A two-group t-test (gene expression as a continuous variable) and an odds ratio estimate (dichotomized gene expression level) were used to determine a correlation between MYC family gene expression and growth inhibition by AZD1152-HQPA. To determine whether growth inhibition correlated with the published MYC-signature gene expression, we used Fisher’s exact test. In vivo growth inhibition by AZD1152 (prodrug) was evaluated on SCLC xenografts in nude mice.
Results:
Nine (39%) of the 23 cell lines were sensitive to AZD1152-HQPA with IC50 values < 50 nM. There was a significant association between sensitivity to growth inhibition by AZD1152-HQPA and cMYC amplification (p = 0.018). The odds of being sensitive is 16 (95% CI, 1.4, 183) times higher for cMYC amplified compared to non-cMYC amplified cell lines. By a two-group t-test, the mean cMYC gene expression of 10.9 (std 4) in sensitive lines compared to 7.2 (std 3.3) in resistant lines was also significant (p = 0.026). Cell lines were separated into two groups based on cMYC gene expression > 12.9 vs < 12.9. The odds of being sensitive is 11 (95% CI, 1.2, 103) time higher for cell lines with cMYC gene expression > 12.9 compared to cell lines with cMYC gene expression < 12.9. Sensitive cell lines were enriched in a published MYC-signature of gene expression (p = 0.042). AZD1152 (prodrug) caused significant growth delay in vivo in two of these lines. The doses of AZD1152-HQPA used in this study are within the range reported to be clinically achievable.
Conclusion:
Aurora kinase inhibitors have promise in SCLC therapy. Questions that currently need answering in translating aurora kinase inhibitors in the clinical setting are: (1) the dosing schedule to avoid myelosupression, (2) should aurora kinase inhibitors be used in maintenance therapy and (3) should the aurora kinase inhibitors be evaluating in combination with chemotherapy.
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P2.07 - Poster Session/ Small Cell Lung Cancer (ID 222)
- Event: WCLC 2015
- Type: Poster
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.07-002 - Effects of Eribulin and Radiation on a Panel of Small Cell Lung Cancer (SCLC) Cell Lines (ID 2154)
09:30 - 17:00 | Author(s): D. Gao
- Abstract
Background:
Background: Chemotherapy produces high response rates in extensive stage SCLC and a modest improvement in 5-year survival rates when combined with chest radiation in limited stage SCLC. Chemotherapeutic agents for SCLC have not changed in 20 years. Eribulin is a microtubule inhibitor that arrests cells in the G2/M fraction of the cell cycle with established activity in breast cancer. Radiobiological studies demonstrated that cells in the G2/M phase of the cell cycle are less efficient at repairing radiation induced DNA damage. Thus, we investigated the effects of eribulin, radiation and the combination on growth and cell cycle distribution in a panel of SCLC cell lines.
Methods:
Methods: Growth inhibition (GI) by varying concentrations of eribulin alone, radiation alone and the combination was assessed by MTS assay at 5 days post-treatment. Growth inhibition or fraction affected (FA) was determined by 1-(x/y) where x is the MTS signal for the experimental condition and y is the MTS signal for the untreated control cells. Our goal was to use a dose of radiation that alone induced a FA of about 0.5 allowing determination of the combination effects with eribulin. Changes in the G2/M distribution of cells treated with eribulin alone, radiation alone and the combination were evaluated at 24 and 48 hours post treatment by propidium iodine staining and analysis by FACS.
Results:
Results: Four of the eight SCLC cell lines were very sensitive to eribulin with half maximal growth inhibitory concentration (FA<0.5) of < 2nM. Four lines had 0.5 FA values > 2nM. 2 Gy radiation produced 32% to 58% growth inhibition in all 8 lines irrespective of their eribulin sensitivity. Low eribulin concentrations (≤ 1.25nM) and 2Gy radiation produced >70% growth inhibition in the 4 sensitive lines, which was significantly more growth inhibition than either alone. Eribulin concentrations of >2.5nM were required to increase growth inhibition over either alone in the 4 more resistant lines and the maximal GI was less in these lines (48%-70%) even at higher concentrations. With respect to G2/M, in the 4 most sensitive eribulin lines, there was a significant increase in the G2/M fraction following eribulin alone (0.625-1.25nM), radiation alone (2 or 3Gy) and a further increase occurred with the combination treatment. In these eribulin sensitive lines, 59% to 93% of the cells were in the G2/M phase by 48 hours. In 3 of the 4 less sensitive eribulin lines, higher concentrations of eribulin (>2.5nM) were required to increase the G2/M fraction to >50% and 2 or 3 Gy irradiation increased the G2/M fraction to 59% to 64%. The combination produced maximal G2/M fractions of 64%-79%. The one most eribulin resistance line never had more than 50% GI or > 40% of cells in G2/M at any concentration or radiation dose up to 4 Gy.
Conclusion:
Conclusions: SCLC cell lines are sensitive to eribulin and radiation and the combination produced significantly more growth inhibition and cell cycle arrest then either alone. The combination warrants further evaluation in in vivo models and potentially clinical trial study in patients with SCLC.
