Integrative Consig: NLK as Attractive Drug Target for Intractable Breast Cancer

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Despite many efforts, no effective therapy exists to overcome breast cancer endocrine resistance. The major drawback is that most of the known oncogenes cannot be matched with potent and safe drugs; for the few with inhibitors, clinical responses are limited and transient due to rapid development of escape pathways not yet understood. It is thus critical to uncover both the missing targets in the unknown survival pathways and the drugs that can tackle this disease. In this study, we apply a unique integrative analysis that identifies key drug targets from the complex cancer signaling network by combining genomic/pharmacological information with cancer-gene concept signatures (ConSig). This analysis has revealed a new target, Nemo-like kinase (NLK), which is amplified and/or overexpressed in ~30% of breast cancers. We have shown that NLK drives more aggressive phenotypes, endows endocrine-resistant growth, and predicts worst outcome in tamoxifen- treated patients. Further investigation suggests that NLK modulates several key molecules in the estrogen receptor (ER) pathway or involved in endocrine resistance, such as STAT3, FOXOs, ERK, and p27. More important, a potent NLK inhibitor has been identified which effectively sensitizes breast cancer cells to tamoxifen. NLK can be activated by multiple growth factors distinct from the well-known breast cancer pathways. We thus hypothesize that this protein may be a hub molecule that drives previously uncharacterized survival signaling in a considerable subset of intractable breast tumors. As the safety of the NLK inhibitor has already been established in other clinical trials, it holds an immediate and high potential to transform th care of a substantial population of breast cancer patients. The following studies are proposed to test the hypothesis: ? Aim 1 will understand how NLK crosstalks with the ER pathway and promotes aggressive phenotypes and hormone resistance in breast cancer. Immunohistochemistry (IHC) assays will be done to study the association of NLK expression with patient survival in the presence or absence of endocrine therapy. ? Aim 2 will establish NLK function in tumor progression and hormone resistance using transplanted NLK inducible genetic perturbation tumor models. The therapeutic value of the NLK inhibitor in sensitizing endocrine therapy will be assessed on mice bearing NLK-high ER+ xenograft breast tumors. ? Aim 3 will continue to develop the integrative analysis to enhance its performance and to reveal additional key targets that may drive NLK-independent survival signaling or identify a distinct molecular subtype of ER+ breast tumors. Lead targets and ablating drugs will be validated in vitro. We expect that these studies will confirm the role of NLK in breast cancer progression and endocrine resistance, elucidate the engaged mechanism, validate the NLK inhibitor as a sensitizing agent to endocrine therapy, and establish the NLK IHC as a predictive assay for personalized medicine. This project will also provide a widely-applicable bioinformatics approach to translate genome data into key drug targets in cancer.