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Project 4 - Emerging Therapeutic Targets in Breast Cancer

Amplified kinases and novel targets in breast cancer

Kinase inhibitors have been one of the most successful drugs for cancer treatments, but their efficacies in patients are still not satisfactory. We have identified novel kinases amplified in breast cancer, and are using functional genomic approaches to validate them as therapeutic targets.

Novel therapeutic targets in triple negative breast cancer

We have conducted an shRNA cell viability screen of 1,576 candidate genes differentially expressed between CD44+CD24- stem cell-like and CD44-CD24+ more differentiated luminal breast cancer cells. These shRNA were further tested across 14 breast cancer cell lines, thereby generating a list of 15 genes of high interest as candidate therapeutic targets against CD44+CD24- cells, including IL6, CXCL3, PTGIS, IGFBP7, PFKFB3 and HAS1. We have followed up and validated the Il6/Jak2/Stat3 signaling pathway in further detail and demonstrated that JAK2 inhibitors may effectively inhibit the growth of breast tumors that have activation of this pathway as determined based on expression of phospho-Stat3 (pStat3). Based on our preclinical data, a clinical trial testing the efficacy of Jak2 inhibitors in pStat3+ breast tumors (enriched in BLBC) is being initiated at DFCI. More recently we also found that a high fraction of inflammatory breast cancer (IBC) are also positive for pStat3, and thus, may respond to JAK kinase inhibition. Besides the JAK/Stat3 pathway, other potentially promising targets include CXCR2, PTGIS, and HAS1. We are conducting preclinical studies validating these genes and their combination as potential new therapeutic strategies in breast cancer.

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