Abstract P3-06-01: Junctional adhesion molecule-A (JAM-A) as a novel future drug target in ductal carcinoma in situ (DCIS)

Abstract

Abstract Background/Aim: Increased expression of the cell-cell adhesion molecule Junctional Adhesion Molecule-A (JAM-A) has been associated with poor prognosis and HER2 expression in patients with invasive ductal breast cancera,b. However, little is known about the potential role of JAM-A in early breast cancer, specifically ductal carcinoma in situ (DCIS). Therefore the aims of this study were to investigate whether JAM-A is overexpressed in DCIS patient tissues, and whether its pharmacological antagonism could reduce functional behaviours associated with tumorigenesis. To this end, a novel inhibitor of JAM-A (JBS-2), was designed and tested in the SUM-225 cell line model of DCIS, in DCIS patient primary cultures and in two murine in vivo models of DCIS. Results: Firstly, a patient tissue microarray comprising DCIS samples (n=50) and normal adjacent tissue (NAT) (n=26) was stained for JAM-A expression and semi-quantitatively scored. 96% of DCIS tissues had moderate/high JAM-A expression in comparison to 23% of NAT. Using the HER2-positive SUM-225 breast cancer cell line, we investigated the potential value of co-targeting JAM-A and HER2/EGFR. Treatment of SUM-225 cells with JBS-2 or the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib significantly inhibited cellular viability in a concentration-dependent manner. Co-treatment of SUM-225 cells with JBS-2 plus lapatinib additively inhibited cellular viability over either treatment alone. Additionally, JBS-2 reduced cellular viability in an ex vivo primary culture isolated from a DCIS patient. A pharmacokinetic study in female NOD-SCID mice treated with JBS-2 revealed no significant haematological, biochemical or pathological toxicity. Furthermore, daily intra-peritoneal administration of JBS-2 exerted significant anti-tumorigenic effects in a murine model of DCIS using female NOD-SCID mice orthotopically implanted with SUM-225 cells into the mammary fat pad. Reverse phase protein array analysis of mammary tissues post-mortem revealed drug-induced changes in several proteins including phospho-PDK1 and Caspase-8. Finally, direct intra-ductal administration of JBS-2 significantly reduced tumor size in murine xenografts which had been grown by direct intra-ductal instillation of SUM-225 cells. Conclusions: In conclusion, the role of JAM-A in DCIS is largely unknown. Increased expression of JAM-A in DCIS tissues coupled with the responsiveness of two HER2-positive DCIS mouse models to a JAM-A inhibitor suggests novel potential in investigating JAM-A inhibitors alone and in combination with HER2 inhibitors as preventative or therapeutic agents in this setting. Refernces: aBrennan K, McSherry EA, Hudson L, Kay EW, Hill AD, Young LS, Hopkins AM. Oncogene. 2013 May 30;32(22):2799-804.bMurakami M, Giampietro C, Giannotta M, Corada M, Torselli I, Orsenigo F, Cocito A, d'Ario G, Mazzarol G, Confalonieri S, Di Fiore PP, Dejana E. PLoS One. 2011;6(6):e21242. Citation Format: Ann M Hopkins, Yvonne E. Smith, Guannan Wang, Ciara Flynn, Alexander Casucci, Sri HariKrishna Vellanki, Lance Hudson, Kieran Brennan, Mattia Cremona, Saraswati Sukumar. Junctional adhesion molecule-A (JAM-A) as a novel future drug target in ductal carcinoma in situ (DCIS) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-06-01.