Abstract P6-04-01: Identification and targeting of clinically actionable genes in bone metastases
Authors: Watters RJ , Hersh B , Hankins M , Patel V , Martin B , Li Z , Clark KL , Pirosa A , Priedigkeit N , Weiss KR , Lee AV , Tuan RS , Alexander PG , Oesterreich S 
Published: May 2019

BACKGROUND: The most common site of cancer metastases from breast is to bone, which occurs in 65-80% of patients resulting in significant comorbidities caused by pathological fractures, pain, hypercalcemia, and nerve compression. The current standard of care involves surgery, radiation, and treatment with bisphosphonates to target osteoclast driven resorption. These modalities all have limitations, complications, and cannot prevent new bone metastases from developing. There is an obvious unmet need for new therapeutic targets and models to treat and study breast cancer related bone metastasis. A large portion of breast cancer research utilizes cell lines and animal models with tissues taken from early stage, primary breast cancers. Furthermore, endpoints such as tumor size reduction and growth in these studies do not always translate to tumor spread. As a result, these study endpoints are not relevant for individuals that are already living with metastatic disease.

MATERIALS and METHODS: Potential therapeutic targets involved in metastasis and osteomimicry were identified by performing exome-capture RNA-sequencing (ecRNA-seq) on eleven matched primary breast tumor and bone metastases. Expression gains and losses were identified from the clinically actionable gene set obtained using the Drug Gene Interaction Database (DGBIdB 2.0). A unique organotypic bone model comprised of endothelial cells (EC), osteoblasts (OB), and mesenchymal stem cells (MSC) co-cultured with primary metastatic bone samples from breast cancer patients is being utilized to target these genes of interest.

RESULTS: ecRNA-seq of metastatic bone samples revealed expression gains in genes of interest (GOI): EPH Receptor A3 (EPHA3), Protein Tyrosine Phosphatase, Receptor Type D (PTPRD), Patched 1 (PTCH1), and Platelet Derived Growth Factor Receptor Alpha (PDGFRA). The GOI were highly recurrent in patients with endocrine-resistant disease that had developed bone metastases after treatment but were absent in the de novo bone metastasis cases where patients had not yet received endocrine therapy. Analysis for expression of these GOI as well as osteomimicry genes are being assessed in our organotypic bone model.

CONCLUSIONS: The GOI identified in this study have been previously associated with the growth and progression of cancer. Furthermore, these genes may be regulated by the RB1-E2F pathway, which was also found to be upregulated in these same samples, and previous studies have linked this pathway's ability to either directly or indirectly regulate our GOI expression levels. Targeting EPHA3, PTPRD, PTCH1, and PDGFRA in breast cancer recurrences may provide a novel therapeutic approach to treat bone metastases that have developed endocrine resistance in patients. Our organotypic bone scaffold provides a unique model to study the interactions of breast cancer cells with bone cells and to test inhibition of novel target genes. Future development of this model will provide a tool for high-throughput screening of drugs to target bone metastases of breast cancer.

Citation Format: Watters RJ, Hersh B, Hankins M, Patel V, Martin B, Li Z, Clark KL, Pirosa A, Priedigkeit N, Weiss KR, Lee AV, Tuan RS, Alexander PG, Oesterreich S. Identification and targeting of clinically actionable genes in bone metastases [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-04-01.