Focal radiation in the murine 4T1-luc2 mammary cancer model

AUTHOR:

Chris Bull, Senior Scientific Advisor, Imaging

DATE:

August 2017

免疫肿瘤学疗法的使用在过去五年中存在显着进展，目前正在与各种药剂组合进行临床试验，包括放射治疗（RT）。¹RT is a main-stay in clinical oncology treatments with approximately 60 percent of cancer patients receiving RT at some point during their care. The clinical prevalence of RT underpins the need for effective testing of radiation combinations in the preclinical setting. In order to do this, baseline sensitivity of mouse tumor models to radiation is required.

乳腺癌最常用的同工小鼠模型之一是4T1。在景气，我们已经表征了我们的4T1-Luc2模型，以支持具有新型免疫肿瘤学代理的研究。我们之前报道了4T1-Luc2肿瘤的广泛免疫分析以及抗CTLA-4治疗后缺乏鲁棒的抗肿瘤活性（4T1-Luc2: An Orthotopic Mammary Cancer Model To Support Novel Immuno-Oncology Drug Discovery). In this month’s Model Spotlight we highlight the dose responsiveness of 4T1-luc2 tumors to focal beam radiation treatment.

At Covance we utilize theSmall Animal Radiation Research Platform (SARRP)from Xstrahl to allow for precise radiation delivery to an exact anatomic target (Figure 1).

Figure 1: Following placement onto the treatment bed, a CBCT is performed for treatment planning. The resultant CT is loaded into the treatment planning software and a treatment plan is optimized for each animal. This example shows the isocenter and isodose for a mouse with a subcutaneous tumor.

我在这个工作中,小鼠植入n the lower mammary fat pad with 4T1-luc2 tumor cells and radiation treatment performed on day 7 utilizing the SARRP instrument. We found that a single dose of focal radiation with 5Gy did not result in any anti-tumor effects whereas both 10 and 20Gy resulted in a dose dependent reduction of tumor volume over time (Figure 2). At 10Gy we found an approximate 10 day growth delay compared to the untreated group while 20Gy resulted in just over 15 days growth delay. However, neither dose resulted in any tumor free survivors.

Dose Response Following Focal Radiation of 4T1-luc2 Tumors

Figure 2: Tumor cells were implanted into the mammary fat pad of female Balb/C mice. At a mean tumor volume of ~100-150mm3 mice were untreated or treated with a single dose of 5, 10 or 20Gy as indicated on day 7. A, group mean tumor volumes over time. B, individual tumor volumes for untreated control mice over time. C, individual tumor volumes for 5Gy treated mice over time. D, individual tumor volumes for 10Gy treated mice over time. E, individual tumor volumes for 20Gy treated mice over time. In B-E the black dashed line indicates mean tumor volume of untreated group over time. In C-E, the colored dashed line is the mean tumor volume of the indicated group.

Body weight loss was only observed in mice that exhibited advanced disease associated with lung and/or thoracic area metastasis that the model is known to produce. In Figure 3, percent change in body weights over time showed toleration of all three doses of radiation during the course of the study. In order to best utilize this model for radiation combination studies, Covance recommends using the moderately active 10Gy dose which allows for an ample therapeutic window to combine with novel therapies.

Figure 3: Percent Change in Body Weight Over Time

The combination of precision radiation delivery and Covance’s expertise in immuno-oncology allows for the execution of complex and powerful study designs.接触Covance和与我们的一个科学家发现how our 4T1-luc2 or other syngeneic models can be used with our targeted radiation therapy technology and techniques.

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¹Kang et al. Journal for ImmunoTherapy of Cancer (2016) 4:51.

Note: Studies were performed in accordance with applicable animal welfare regulations in an AAALAC-accredited facility