Research in the Nevalainen laboratory focuses on therapy development for prostate cancer which is the most common non-skin cancer in men in Western countries with the prevalence of more than 3 million currently in the US. Localized prostate cancer is typically treated by surgery or radiation therapy. However, approximately 30% of prostate cancers treated with curative intent recur – often as systemic (metastatic) disease. If prostate cancer has metastasized at the time of diagnosis, the treatment options often focus on hormone therapy (androgen deprivation) or chemotherapy as palliative treatment strategies. Therapy resistance develops relatively rapidly through multiple complex molecular mechanisms leading to a lethal disease. Our work is focused on understanding mechanisms underlying resistance to hormone therapy and radiation therapy with particular interest in Jak-Stat5 signaling with the goal of development of secondary therapies for recurrent prostate cancer after the initial treatment strategies fail.

The studies focus on understanding the mechanisms of Jak-Stat5 regulation of AR gene transcription in prostate cancer and utilization of second-generation Jak2 inhibitors as a therapeutic strategy to shut down or suppress AR signaling in preclinical in vitro and xenograft tumor models in mice as well as in ex vivo tumor explant cultures of patient-derived prostate cancers.

This theme includes access to liquid and tumor biopsies from a phase 2 clinical trial of a Jak2-inhibitor in AR signaling inhibitor (ARSI)-resistant prostate cancer.

The goal is to evaluate the utilization of the second-generation Jak2 inhibitors in sensitization of prostate cancer to radiation therapy by compromising Homologous Recombination DNA-repair of radiation-induced double-strand DNA breaks. This theme includes development of phase 1 clinical trial. In addition, we will evaluate the potential and efficacies of combining Jak-Stat inhibitors with select Parp-inhibitors as radiation-sensitizers or stand-alone therapeutic strategy

• The Nevalainen Lab developed unique and novel family of direct Stat5 inhibitor compounds. The project involves two medicinal chemists and lead optimization of these Stat5 inhibitors with potency, efficacy and toxicity testing in preclinical prostate cancer models.
• The Nevalainen Lab demonstrated in previous work that Jak2-Stat5 signaling is a direct inducer of epithelial-to-mesenchymal transition (EMT) and metastatic behavior of prostate cancer in vitro and in vivo. In addition, the previous studies showed that activated Jak2-Stat5 signaling is a predictor of development of metastatic disease in prostate cancer patients in a cohort of more than 1,000 patients). This developmental theme will investigate Jak2-Stat5-signaling involvement in interaction of prostate cancer cells with tumor microenvironment in metastatic niches in bone.