Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease development and progression. This study describes the discovery and characterization of a new class of small molecule ERG antagonists identified through rational in silico methods. These antagonists are designed to sterically block DNA binding by the ETS domain of ERG and thereby disrupt transcriptional activity. We confirmed the direct binding of a lead compound, VPC-18005, with the ERG-ETS domain using biophysical approaches. We then demonstrated VPC-18005 reduced migration and invasion rates of ERG expressing prostate cancer cells, and reduced metastasis in a zebrafish xenograft model. These results demonstrate proof-of-principal that small molecule targeting of the ERG-ETS domain can suppress transcriptional activity and reverse transformed characteristics of prostate cancers aberrantly expressing ERG. Clinical advancement of the developed small molecule inhibitors may provide new therapeutic agents for use as alternatives to, or in combination with, current therapies for men with ERG-expressing metastatic castration-resistant prostate cancer.

Genomic alterations involving translocations of the ETS-related gene ERG occur in approximately half of prostate cancer cases. These alterations result in aberrant, androgen-regulated production of ERG protein variants that directly contribute to disease development and progression. This study describes the discovery and characterization of a new class of small molecule ERG antagonists identified through rational in silico methods. These antagonists are designed to sterically block DNA binding by the ETS domain of ERG and thereby disrupt transcriptional activity. We confirmed the direct binding of a lead compound, VPC-18005, with the ERG-ETS domain using biophysical approaches. We then demonstrated VPC-18005 reduced migration and invasion rates of ERG expressing prostate cancer cells, and reduced metastasis in a zebrafish xenograft model. These results demonstrate proof-of-principal that small molecule targeting of the ERG ETS domain can suppress transcriptional activity and reverse transformed characteristics of prostate cancers aberrantly expressing ERG. Clinical advancement of the developed small molecule inhibitors may provide new therapeutic agents for use as alternatives to, or in combination with, current therapies for men with ERG-expressing metastatic castration-resistant prostate cancer. Citation Format: Miriam S. Butler, Mani Roshan-Moniri, Michael Hsing, Desmond Lau, Ari Kim, Paul Yen, Marta Mroczek, Mannan Nouri, Scott Lien, Peter Axerio-Cilies, Kush Dalal, Clement Yau, Fariba Ghaidi, Yubin Guo, Takeshi Yamazaki, Sam Lawn, Martin Gleave, Cheryl Y. Gregory-Evans, Lawrence P. McIntosh, Paul S. Rennie, Artem Cherkasov, Michael E. Cox. Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 130. doi:10.1158/1538-7445.AM2017-130

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A microtia, or small or abnormally formed pinna, is an uncommon congenital abnormality of the external ear which can present as an isolated defect or as part of an underlying clinical syndrome. External ear reconstruction is a possibility, with either an autologous or non-autologous framework. The Nagata type of autologous reconstruction is a multistage process whereby costal cartilage, temporoparietal fascia, and a full thickness skin graft are used to form a new pinna. Here, we present the unique case of a young female born with mosaic trisomy 22, an extremely rare genetic condition, and a right-sided microtia. Between the first and second stages of her reconstruction, an anterior chest wall deformation was observed, coupled with unusual dystrophic calcifications over the cartilage near the ribs and sternum.

Introduction: We hypothesize that treatment of significant truncal lesions with truncal tissue expanders and subsequent flap surgery in pediatric patients may increase the risk of scoliosis. This study aims to investigate any relationship between tissue expansion (TE) and scoliosis and to compare the prevalence of scoliosis in our tissue expander population to the general population. Methods: Health records of patients who underwent truncal TE at BC Children’s Hospital between 1997 and 2017 were retrospectively reviewed and analyzed. The cross-sectional component of the study consisted of radiological imaging to establish the presence or absence of scoliosis. Results: We identified 28 patients who underwent truncal TE over the study period. Ten had a scoliosis X-ray on their chart or as a part of the study. Three (10.7%) patients were identified as having developed scoliosis after TE. Conclusions: We recommend that pediatric TE patients be made aware of the potential complication of scoliosis and be followed closely in the years during and after their treatment, in order to allow for preventative measures, early diagnosis and early management (if required).