# An in vivo model for CCNE1 amplified tumorigenesis

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $47,900

## Abstract

PROJECT SUMMARY
 High-grade serous ovarian carcinoma (HGSOC) is one of the most devastating cancer-related diseases in
the United States. It is the deadliest gynecological malignancy and a public health burden. Historically, it was
thought that ovarian tumors arise from the ovarian surface epithelium. Recently, this school of thought has
been challenged by the finding of early HGSOC precursors in the fallopian tubes (FT) of women at increased
risk of developing HGSOC due to mutations in the BRCA1 or BRCA2 genes. Most cases were localized to the
fimbriated end of the FT and included serous tubal intraepithelial carcinoma (STIC) as the dominant precursor
lesion. The Cancer Genome Atlas of HGSOC showed that approximately 50% of HGSOCs harbor mutations in
the BRCA genes or other genes in the homologous recombination (HR) pathway of DNA repair. These tumors
tend to respond well to chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Unfortunately, the
remaining 50% of HGSOC are often HR-proficient, do not respond well to standard treatment, and are
associated with worse outcomes. HGSOCs with amplification of the CCNE1 gene represent a significant
fraction of these HR-proficient tumors. CCNE1 makes a protein, cyclinE1, that controls cell division but which
can also damage the cell's genome when present in excess. Women with CCNE1 amplified tumors are unlikely
to respond to PARP inhibitors and thus represent an important unmet need. While there are a number of drugs
currently in development in other solid cancers that may be effective in CCNE1 amplified HGSOC, there are
currently no animal models to study the function of cyclin E1 in HGSOC or the efficacy of candidate inhibitors.
This application describes our aim to develop a mouse model that mimics the human disease, thereby
providing a preclinical platform for testing novel cyclinE1 inhibitors. We will construct transgenic mice where
the Ccne1 gene can be precisely activated when and where we want it. Using well-established technology, we
will engineer mice to express the cyclinE1 protein at high levels in FT secretory epithelial cells, the progenitors
of HGSOC. We are very experienced in the generation of such animals and their analysis. Importantly, TP53 is
always defective in human HGSC and its loss appears to be a requirement for cells to tolerate the presence of
excess cyclinE1. Therefore, our model will incorporate expression of a mutant Tp53. Our laboratory studies
suggest these two genetic alterations – Ccne1 over expression and Tp53 mutation – will be enough to
generate tumors. It is also possible, however, that additional mutations will be needed for the mice to develop
HGSC that mimic the human disease. In the second part of the grant we use data from a genetic screen in FT
cells and information from thousands of cancer genomes to find genes that may cooperate with CCNE1 and
that could be added to the mice. The study is likely to provide a high return on the invested effort, as...

## Key facts

- **NIH application ID:** 9830595
- **Project number:** 5F32CA221093-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Paul T Kroeger
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,900
- **Award type:** 5
- **Project period:** 2017-12-01 → 2020-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830595

## Citation

> US National Institutes of Health, RePORTER application 9830595, An in vivo model for CCNE1 amplified tumorigenesis (5F32CA221093-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9830595. Licensed CC0.

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