Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene sequence information alone. Recent human clinical data have demonstrated the potent activity of systemically administered ASOs targeted to genes expressed in the liver. Here, we describe the preclinical activity and initial clinical evaluation of a class of ASOs containing constrained ethyl modifications for targeting the gene encoding the transcription factor STAT3, a notoriously difficult protein to inhibit therapeutically. Systemic delivery of the unformulated ASO, AZD9150, decreased STAT3 expression in a broad range of preclinical cancer models and showed antitumor activity in lymphoma and lung cancer models. AZD9150 preclinical activity translated into single-agent antitumor activity in patients with highly treatment-refractory lymphoma and non-small cell lung cancer in a phase I dose escalation study.

BackgroundThe Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin’s lymphoma population, primarily consisting of patients with DLBCL.MethodsPatients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.ResultsThirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.ConclusionsAZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.Trial registrationRegistered at ClinicalTrials.gov: NCT01563302. First submitted 2/13/2012.Electronic supplementary materialThe online version of this article (10.1186/s40425-018-0436-5) contains supplementary material, which is available to authorized users.

The Ace-1 xenograft is a useful model for investigating the pathogenesis of prostate cancer invasion and mixed osteoblastic/osteolytic bone metastases.

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Prostate carcinoma and transitional cell carcinoma (TCC) occur in the prostate gland of older dogs and have morphologic similarities when evaluated by light microscopy. The dog is a commonly used animal model for studying human prostate carcinoma; therefore, it is important to accurately differentiate canine prostate carcinomas from TCCs. We investigated whether keratin 7 (K7) and arginine esterase (AE) would aid differentiation of canine prostate carcinoma from TCC. K7 expression was evaluated in normal and neoplastic canine prostate and bladder tissues using immunohistochemistry. The expression of AE messenger ribonucleic acid (mRNA) in normal and neoplastic canine prostate and bladder was detected using northern blots and reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, AE enzyme activity was measured in normal and neoplastic canine prostate and bladder tissues. We found marked similarities in K7 expression in prostate carcinomas and TCCs. AE mRNA was present in high levels in normal prostatic tissue but was reduced in prostate carcinoma by northern blot assay. Nested RT-PCR detected AE mRNA both in TCCs (13 of 15) and in prostate carcinomas (13 of 13). Enzymatic activity of AE was high in normal prostate gland and in some prostate carcinomas, whereas normal bladder and TCCs produced lower levels of AE. In conclusion, K7 and AE cannot be used to differentiate TCC from prostate carcinoma in dogs.