Scientists Discover Why Some Cancers May Not Respond to Immunotherapy

Excerpt:

UCLA scientists have discovered that people with cancers containing genetic mutations JAK1 or JAK2, which are known to prevent tumors from recognizing or receiving signals from T cells to stop growing, will have little or no benefit from the immunotherapy drug pembrolizumab. This early-stage research has allowed them to determine for the first time why some people with advanced melanoma or advanced colon cancer will not respond to pembrolizumab, an anti-PD-1 treatment.

“The study, led by Dr. Antoni Ribas, director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, also found that JAK1 or JAK2 genetic mutations led to a loss of reactive PD-L1 expression.  PD-L1 is an immune biomarker expressed on tumor cells and pembrolizumab requires an abundance of it to effectively attack cancer cells.”

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Pharmacological Inhibition of Jak2-Stat5 Signaling by Jak2 Inhibitor AZD1480 Potently Suppresses Growth of Both Primary and Castrate-Resistant Prostate Cancer

“Purpose: Progression of prostate cancer (PC) to the lethal castrate-resistant (CR) stage coincides with loss of responsiveness to androgen deprivation and requires development of novel therapies. We previously provided proof-of-concept that Stat5a/b is a therapeutic target protein for PC. Here we demonstrate that pharmacological targeting of Jak2-dependent Stat5a/b signaling by the Jak2 inhibitor AZD1480 blocks CR growth of PC. Experimental Design: Efficacy of AZD1480 in disrupting Jak2-Stat5a/b signaling and decreasing PC cell viability was evaluated in PC cells. A unique PC xenograft mouse model (CWR22Pc), which mimics PC clinical progression in patients, was used to assess in vivo responsiveness of primary and CR PC to AZD1480. Patient-derived clinical PCs, grown ex vivo in organ explant cultures, were tested for responsiveness to AZD1480. Results: AZD1480 robustly inhibited Stat5a/b phosphorylation, dimerization, nuclear translocation, DNA binding and transcriptional activity in PC cells. AZD1480 reduced PC cell viability sustained by Jak2-Stat5a/b signaling through induction of apoptosis, which was rescued by constitutively active Stat5a/b. In mice, pharmacological targeting of Stat5a/b by AZD1480 potently blocked growth of primary androgen-dependent as well as recurrent CR CWR22Pc xenograft tumors, and prolonged survival of tumor-bearing mice vs. vehicle or docetaxel-treated mice. Finally, 9 of 13 clinical PCs responded to AZD1480 by extensive apoptotic epithelial cell loss, concurrent with reduced levels of nuclear Stat5a/b. Conclusions: We report the first evidence for efficacy of pharmacological targeting of Stat5a/b as a strategy to inhibit CR growth of PC, supporting further clinical development of Stat5a/b inhibitors as therapy for advanced PC.”