Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer.
Ablative radiotherapy improves survival but does not cure autochthonous mouse models of prostate and colorectal cancer.
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DOI：
10.1038/s43856-023-00336-3
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发表时间：
2023-08-09
期刊：
影响因子：
--
通讯作者：
Vander Heiden, Matthew G
中科院分区：
文献类型：
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作者：
Schmidt, Daniel R;Gramatikov, Iva Monique T;Sheen, Allison;Williams, Christopher L;Hurwitz, Martina;Dodge, Laura E;Holupka, Edward;Kiger, W S 3rd;Cornwall-Brady, Milton R;Huang, Wei;Mak, Howard H;Cormier, Kathleen S;Condon, Charlene;Dane Wittrup, K;Yilmaz, Omer H;Stevenson, Mary Ann;Down, Julian D;Floyd, Scott R;Roper, Jatin;Vander Heiden, Matthew G
癌症的基因工程小鼠模型(GEMM)是研究疾病进展和治疗反应机制的强大工具，但人们对这些模型对患者使用的多模式治疗的反应知之甚少。放射治疗(RT)经常用于治疗有疗效的局部癌症，延缓寡转移瘤的进展，缓解转移性疾病的症状。在这里，我们报告了一种平台的开发、测试和验证，该平台用于固定和靶向采用立体定向消融放疗(SART)的小鼠肿瘤。异种和自体肿瘤模型采用低分割消融剂量的放射治疗。我们证明，在临床实践中使用的低分馏方案可以在小鼠模型中有效地传递。SART改变了肿瘤间质和免疫环境，提高了原发性前列腺癌和结直肠癌GEM的存活率，并与前列腺癌的雄激素剥夺有协同作用。在异种移植模型中获得了完全的病理反应，但在GEMM中却没有。虽然SART能够完全消融异种移植物，但它无法完全根除GEMM中的疾病，理由是对潜在治愈疗法的耐药性可以在GEMM中模拟。小鼠可以用来模拟在人类身上看到的癌症类型，以研究癌症治疗的效果，如辐射。在这里，我们将能够治愈人类癌症的放射治疗应用到患有前列腺癌或结直肠癌的小鼠身上。我们表明，小鼠没有经历太多副作用，肿瘤体积缩小，但在某些情况下，治疗后出现进展。我们的研究表明，小鼠可以用来更好地了解人类癌症对放射治疗的反应，这可以导致改进治疗和治疗时间表的发展。施密特等人。开发并测试用于向小鼠模型提供立体定向放射治疗的平台。作者确定了照射到小鼠下腹部和骨盆的最大耐受剂量，并表明虽然消融性放射治疗提高了存活率，但它不能治愈固有的前列腺癌和结直肠肿瘤模型。
Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. Here we report the development, testing, and validation of a platform to immobilize and target tumors in mice with stereotactic ablative RT (SART). Xenograft and autochthonous tumor models were treated with hypofractionated ablative doses of radiotherapy. We demonstrate that hypofractionated regimens used in clinical practice can be effectively delivered in mouse models. SART alters tumor stroma and the immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. Complete pathologic responses were achieved in xenograft models, but not in GEMMs. While SART is capable of fully ablating xenografts, it is unable to completely eradicate disease in GEMMs, arguing that resistance to potentially curative therapy can be modeled in GEMMs. Mice can be used to model the types of cancer seen in people to investigate the effects of cancer therapies, such as radiation. Here, we apply radiation therapy treatments that are able to cure cancer in humans to mice that have cancer of the prostate or colorectum. We show that the mice do not experience many side effects and that the tumours reduce in size, but in some cases show progression after treatment. Our study demonstrates that mice can be used to better understand how human cancers respond to radiation treatment, which can lead to the development of improved treatments and treatment schedules. Schmidt et al. develop and test a platform for the delivery of stereotactic radiotherapy to mouse models. The authors identify maximum tolerated doses for radiation delivered to the mouse lower abdomen and pelvis, and show that while ablative radiotherapy improves survival, it does not cure autochthonous prostate and colorectal tumor models.