Research ArticleCancer

Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer

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Science Translational Medicine  24 Feb 2016:
Vol. 8, Issue 327, pp. 327ra24
DOI: 10.1126/scitranslmed.aad7842
  • Fig. 1. MRI volumetric data for the different treatments applied to MDA-MB-231 preclinical models.

    (A to D) Different cohorts of mice injected at different times. Control (Ctrl) animals did not receive any chemotherapy. The mice in the ST group received the standard high-dose treatment [paclitaxel, 20 mg/kg intraperitoneally, twice a week for 2.5 weeks]. AT groups received different doses depending on the algorithm (AT-1 or AT-2; see Materials and Methods). Data are means ± SD. More detailed results, including ADC values and volumes for individual tumors, are available in fig. S1. Arrows indicate when the treatment in the ST group was stopped.

  • Fig. 2. MRI volumetric data for the different treatments applied to MCF7 preclinical models.

    Ctrl animals did not receive any chemotherapy. The mice in the ST group received the standard high-dose treatment (paclitaxel, 20 mg/kg intraperitoneally, twice a week for 2.5 weeks). AT groups received different doses depending on the algorithm (AT-1 or AT-2; see Materials and Methods). Data are means ± SD. More detailed results, including ADC values and volumes for individual tumors, are available in fig. S1. Arrow indicates when the treatment was stopped in the ST mice.

  • Fig. 3. Survival of animals treated by different therapeutic algorithms.

    The Kaplan-Meier plots show animals with tumor volumes smaller than 1000 mm3 after treatment according to the standard (STD) or adaptive (AT-1 and AT-2) strategies. In the legend, n corresponds to the number of animals under each treatment algorithm. (A and B) Mice injected with MDA-MB-231 (A) and MCF7 (B) cell lines. Statistics were calculated with the Mantel-Cox test.

  • Fig. 4. Total delivered dose of paclitaxel with each algorithm.

    Total delivered dose of paclitaxel for MDA-MB-231 cohort D (upper graph) and MCF7 cohort (lower graph) is shown as the cumulative dose of paclitaxel for each day after MRI monitoring had started. Blue corresponds to mice treated under AT-1; green, mice treated under AT-2; and red, animals under ST treatment. Note that mouse#9 and mouse#13 in the MDA-MB-231 group received two sessions of ST therapy to demonstrate that the cancer cells that recur after standard therapy are drug-resistant. Cumulative dose graphs for MDA-MB-231 cohorts A to C are shown in fig. S2.

  • Fig. 5. Mean percentage of necrotic tissue in tumors under different treatment algorithms as determined by DW MRI.

    The percentages of tissue volume that is necrotic are represented relative to the first day of treatment. The data summarize results for MDA-MB-231 and MCF7, in the left and right graphs, respectively, under different therapies: standard (ST), AT-1, and AT-2. After an initial increase, the necrotic volume decreases in the AT-1 (black diamonds) cohort and increases in the ST and AT-2 cohorts. Results are means ± SE.

  • Fig. 6. Changes in tumor flow and perfusion under different treatments.

    Bar graphs show the changes in area under the curve (AUC) for blood flow and perfusion measurements derived from DCE MRI before (Beginning), during (Middle), and after (End) therapy relative to pretreatment baseline. In this case, only Ctrl, ST, and AT-1 therapies were monitored. The numbers in parentheses correspond to the number of mice analyzed in each group. Results are means ± SE.

  • Fig. 7. Histology of tumors under different therapeutic regimens.

    The graphs show H&E, CD31, and SMA analysis of the indicated tumors under different therapeutic regimens, with MDA-MB-231 in the top row and MCF7 in the bottom row. Tumors treated according to AT-1 developed less necrosis (detected by H&E staining) than those on AT-2, and greater vascular density (CD31 staining) in the case of MDA-MB-231 tumors. In MCF7 tumors, necrosis did not correlate with the stability of the tumors, but increased vascular density was observed in tumors that were treated with AT-2. The AT-1 cohort had a higher microvessel density (CD31) than the Ctrl or ST groups but did not achieve statistical significance. However, the AT-1 group did have significantly higher vessel functionality demonstrated by the SMA staining. Significance testing was performed by Student’s t test. P values are indicated above a line showing each comparison.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/8/327/327ra24/DC1

    Fig. S1. Individual volumetric graphics of all mice used in this work.

    Fig. S2. Total dose of paclitaxel delivered in each mouse.

    Fig. S3. Bar graphs showing paclitaxel doses skipped for all mice under AT-1 therapy.

    Table S1. Total dose of paclitaxel and change in weight of mice in MDA-MB-231 batches A and B (provided in Excel format).

    Table S2. Total dose of paclitaxel and change in weight of mice in MDA-MB-231 batch C (provided in Excel format).

    Table S3. Total dose of paclitaxel and change in weight of mice in MDA-MB-231 batch D (provided in Excel format).

    Table S4. Total dose of paclitaxel and change in weight of mice with MCF7 tumors (provided in Excel format).

  • Supplementary Material for:

    Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer

    Pedro M. Enriquez-Navas, Yoonseok Kam, Tuhin Das, Sabrina Hassan, Ariosto Silva, Parastou Foroutan, Epifanio Ruiz, Gary Martinez, Susan Minton, Robert J. Gillies, Robert A. Gatenby*

    *Corresponding author. E-mail: robert.gatenby{at}moffitt.org

    Published 24 February 2016, Sci. Transl. Med. 8, 327ra24 (2016)
    DOI: 10.1126/scitranslmed.aad7842

    This PDF file includes:

    • Fig. S1. Individual volumetric graphics of all mice used in this work.
    • Fig. S2. Total dose of paclitaxel delivered in each mouse.
    • Fig. S3. Bar graphs showing paclitaxel doses skipped for all mice under AT-1 therapy.

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Table S1. Total dose of paclitaxel and change in weight of mice in MDA-MB-231 batches A and B (provided in Excel format).
    • Table S2. Total dose of paclitaxel and change in weight of mice in MDA-MB-231 batch C (provided in Excel format).
    • Table S3. Total dose of paclitaxel and change in weight of mice in MDA-MB-231 batch D (provided in Excel format).
    • Table S4. Total dose of paclitaxel and change in weight of mice with MCF7 tumors (provided in Excel format).

    [Download Tables S1 to S4]

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