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An immune competent orthotopic model of endometrial cancer with metastasis.

ABSTRACT: Endometrial cancer is the most common gynecologic malignancy in the U.S. with metastatic disease remaining the major cause of patient death. Therapeutic strategies have remained essentially unchanged for decades. A significant barrier to progression in treatment modalities stems from a lack of clinically applicable in vivo models to accurately mimic endometrial cancer; specifically, ones that form distant metastases and maintain an intact immune system. To address this problem, we have established the first immune competent murine orthotopic tumor model for metastatic endometrial cancer by creating a green fluorescent protein labeled cell line from an endometrial cancer that developed in a Pgr cre/+ Pten f/f Kras G12D genetically engineered mouse. These cancer cells were grafted into the abraded uterine lumen of ovariectomized recipient mice treated with estrogen and subsequently developed local and metastatic endometrial tumors. We noted primary tumor formation in 59% mixed background and 86% of C57BL/6 animals at 4 weeks and distant lung metastases in 78% of mice after 2 months. This immunocompetent orthotopic tumor model closely resembles some human metastatic endometrial cancer, modeling both local metastasis and hematogenous spread to lung and has significant potential to advance the study of endometrial cancer and its metastasis.

SUBMITTER: Fedorko AM

PROVIDER: S-EPMC7260377 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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An immune competent orthotopic model of endometrial cancer with metastasis.

Fedorko Alyssa M AM Kim Tae Hoon TH Broaddus Russell R Schmandt Rosemarie R Chandramouli Gadisetti V R GVR Kim Hong Im HI Jeong Jae-Wook JW Risinger John I JI

Heliyon 20200527 5

Endometrial cancer is the most common gynecologic malignancy in the U.S. with metastatic disease remaining the major cause of patient death. Therapeutic strategies have remained essentially unchanged for decades. A significant barrier to progression in treatment modalities stems from a lack of clinically applicable <i>in vivo</i> models to accurately mimic endometrial cancer; specifically, ones that form distant metastases and maintain an intact immune system. To address this problem, we have es ...[more]

PMID: 32490257

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Project description:Toca 511 (vocimagene amiretrorepvec), a nonlytic, amphotropic retroviral replicating vector (RRV), encodes and delivers a functionally optimized yeast cytosine deaminase (CD) gene to tumors. In orthotopic glioma models treated with Toca 511 and 5-fluorocytosine (5-FC) the CD enzyme within infected cells converts 5-FC to 5-fluorouracil (5-FU), resulting in tumor killing. Toca 511, delivered locally either by intratumoral injection or by injection into the resection bed, in combination with subsequent oral extended-release 5-FC (Toca FC), is under clinical investigation in patients with recurrent high-grade glioma (HGG). If feasible, intravenous administration of vectors is less invasive, can easily be repeated if desired, and may be applicable to other tumor types. Here, we present preclinical data that support the development of an intravenous administration protocol. First we show that intravenous administration of Toca 511 in a preclinical model did not lead to widespread or uncontrolled replication of the RVV. No, or low, viral DNA was found in the blood and most of the tissues examined 180 days after Toca 511 administration. We also show that RRV administered intravenously leads to efficient infection and spread of the vector carrying the green fluorescent protein (GFP)-encoding gene (Toca GFP) through tumors in both immune-competent and immune-compromised animal models. However, initial vector localization within the tumor appeared to depend on the mode of administration. Long-term survival was observed in immune-competent mice when Toca 511 was administered intravenously or intracranially in combination with 5-FC treatment, and this combination was well tolerated in the preclinical models. Enhanced survival could also be achieved in animals with preexisting immune response to vector, supporting the potential for repeated administration. On the basis of these and other supporting data, a clinical trial investigating intravenous administration of Toca 511 in patients with recurrent HGG is currently open and enrolling.

Dataset Information

An immune competent orthotopic model of endometrial cancer with metastasis.

Publications

An immune competent orthotopic model of endometrial cancer with metastasis.

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