Sowalsky, Adam G
Mayo Clinic
Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
Citations 2
TMPRSS2-ERG confers resistance to antiandrogens: mechanism and therapeutic implications
Chatterjee, Rishita , Selvadurai, Boobash Raj , Verma, Aakanksha , Giri, Suvendu , Genna, Alessandro , Karatekin, Feride , Zerbib, Mirie , Vinik, Yaron , Avioz, Tamir, Weizman, Eviatar , Pan, Yunqian , Hunt, Hazel , Ku, Anson T. , Kartal, Sumeyra, Bright, Jack R., Dahut, William L. , Sowalsky, Adam G. , Yarden, Yosef, Sowalsky, Adam G , Sekar, Arunachalam , Pal, Lipika R. , Nataraj, Nishanth Belugali , Garcia, Diana Drago , Gupta, Nitin, Weizman, Eviatar , David, Eyal , Schäffer, Alejandro A. , Huang, Haojie , Weerden, Wytske M. van , Corey, Eva , Greenstein, Andrew E. , Blecher‐Gonen, Ronnie , Oren, Roni , Afek, Ariel , Amit, Ido , Lev, Sima , Kartal, Sumeyra , Bright, Jack R., Lis, Rosina T. , Ruppin, Eytan
No container title available | January 20, 2025 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG , remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacies of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in fusion-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG -positine patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.
Immune niches in brain metastases contain TCF1+ stem-like T cells, are associated with disease control and are modulated by preoperative SRS
Jansen, Caroline S. , Chappa, Prasanthi, Zhou, Chengjing , Prokhnevska, Nataliya , Hoang, Kimberley B., Zhong, Jim , Torres, Mylin A. , Logan, Suzanna , Balzo, Luke del , Patel, Kirtesh R., Burri, Stuart H., Wilkinson, Scott , Lake, Ross , Patel, Pretesh, Dhere, Vishal R. , Sowalsky, Adam G. , Khan, Mohammad K. , Kissick, Haydn , Buchwald, Zachary S. , Wilkinson, Scott , Sowalsky, Adam G , Kissick, Haydn , Prabhu, Roshan S. , Pagadala, Meghana S. , Goyal, Subir , Neill, Stewart G. , Cardenas, Maria Andrea , Olson, Jeffrey J. , Nduom, Edjah Kweku-Ebura , Asher, Anthony L., Higgins, Kristin Ann
No container title available | March 22, 2023 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The CD8 + T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1 + TCF1 + stem-like CD8 + T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS’s impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8 + T cells at 3 days. However, CD8 + T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1 + stem-like population.