The transition from castration-resistant prostate adenocarcinoma (CRPC) to neuroendocrine prostate cancer (NEPC) has emerged as an important mechanism of treatment resistance. NEPC is associated with ...overexpression and gene amplification of MYCN (encoding N-Myc). N-Myc is an established oncogene in several rare pediatric tumors, but its role in prostate cancer progression is not well established. Integrating a genetically engineered mouse model and human prostate cancer transcriptome data, we show that N-Myc overexpression leads to the development of poorly differentiated, invasive prostate cancer that is molecularly similar to human NEPC. This includes an abrogation of androgen receptor signaling and induction of Polycomb Repressive Complex 2 signaling. Altogether, our data establishes N-Myc as an oncogenic driver of NEPC.
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•N-Myc drives the NEPC phenotype and associated molecular program•N-Myc abrogates AR signaling, which results in enhanced AKT activity•N-Myc redirects EZH2 activity and sensitizes cells to EZH2 inhibitors•N-Myc interacts with Aurora-A, which facilitates N-Myc target gene expression
Dardenne et al. demonstrate that N-Myc overexpression in pre-clinical models drives aggressive prostate cancer that mimics human neuroendocrine prostate cancer, including reduced AR signaling and enhanced PRC2 target gene repression, and sensitizes cells to an Aurora-A inhibitor and EZH2 SET domain inhibitors.
The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to ...epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.
BACKGROUNDProstate cancer is multifocal with distinct molecular subtypes. The utility of genomic subtyping has been challenged due to inter- and intrafocal heterogeneity. We sought to characterize ...the subtype-defining molecular alterations of primary prostate cancer across all tumor foci within radical prostatectomy (RP) specimens and determine the prevalence of collision tumors.METHODSFrom the Early Detection Research Network cohort, we identified 333 prospectively collected RPs from 2010 to 2014 and assessed ETS-related gene (ERG), serine peptidase inhibitor Kazal type 1 (SPINK1), phosphatase and tensin homolog (PTEN), and speckle type BTB/POZ protein (SPOP) molecular status. We utilized dual ERG/SPINK1 immunohistochemistry and fluorescence in situ hybridization to confirm ERG rearrangements and characterize PTEN deletion, as well as high-resolution melting curve analysis and Sanger sequencing to determine SPOP mutation status.RESULTSBased on index focus alone, ERG, SPINK1, PTEN, and SPOP alterations were identified in 47.5%, 10.8%, 14.3%, and 5.1% of RP specimens, respectively. In 233 multifocal RPs with ERG/SPINK1 status in all foci, 139 (59.7%) had discordant molecular alterations between foci. Collision tumors, as defined by discrepant ERG/SPINK1 status within a single focus, were identified in 29 (9.4%) RP specimens.CONCLUSIONInterfocal molecular heterogeneity was identified in about 60% of multifocal RP specimens, and collision tumors were present in about 10%. We present this phenomenon as a model for the intrafocal heterogeneity observed in previous studies and propose that future genomic studies screen for collision tumors to better characterize molecular heterogeneity.FUNDINGEarly Detection Research Network US National Cancer Institute (NCI) 5U01 CA111275-09, Center for Translational Pathology at Weill Cornell Medicine (WCM) Department of Pathology and Laboratory Medicine, US NCI (WCM SPORE in Prostate Cancer, P50CA211024-01), R37CA215040, Damon Runyon Cancer Research Foundation, US MetLife Foundation Family Clinical Investigator Award, Norwegian Cancer Society (grant 208197), and South-Eastern Norway Regional Health Authority (grant 2019016 and 2020063).
The epichaperome is a new cancer target defined, in part, by changes in the interaction strength between chaperone and co-chaperone proteins to form stable hyperconnected networks that support ...oncoprotein stability and are vital for tumor survival (Nature 2016, Nature Rev Cancer 2018 and Nature Med 2018). Cancers with this altered chaperone configuration may become susceptible to drugs that target the epichaperome, such as the inhibitor PU-H71. We have developed a novel flow cytometry-based test, the PU-FITC binding assay, to evaluate epichaperome levels at the single cell level and identify patients who are most likely to respond to PU-H71 treatment.
A 61-year-old woman was diagnosed with an accelerated phase myeloproliferative neoplasm in 2013 after years of leukocytosis, arthritis, urticaria, and vasculitis. Cytogenetic analysis revealed t(9;15) involving the PML gene. Molecular studies were negative for BCR-ABL, PDGFRA/B and FGFR1 rearrangements as well as JAK2 mutation. Mutations in ETV6 and multiple ASXL1 subclones were present. She was treated with hydroxyurea and in Aug 2013 underwent matched unrelated donor allogeneic stem cell transplantation conditioned with Fludarabine/Melphalan, followed by 3 cycles of vidaza in 2014 for early recurrence. In Jan 2016, she relapsed and was treated with hydroxyurea. She also had painful ulcerations of toes, thought to be an atypical presentation of graft versus host disease complicated by her underlying Raynaud's disease and treated successfully with ruxolitinib. During 2017, she had bone marrow (BM) evidence of recurrent disease, skin lesions consistent with recurrent disease, and significant splenomegaly, but since neutrophils and platelets were preserved, she did not require transfusions and she had no bleeding or infections, she was maintained on hydrea, prednisone and ruxolitinib. In 2017, BM biopsy showed progression to AML with fibrosis. She developed progressive splenomegaly and weight loss and was treated with 2 cycles of decitabine without response. The patient was sent for precision medicine evaluation. Whole-exome sequencing and RNA-seq was performed with a control buccal swab. No somatic alterations in clinically relevant genes were found. However, a novel fusion protein, PML-SYK, was detected and validated by FISH and PCR. We found constitutive Syk, Stat5, Erk and ribosomal S6 kinase phosphorylation. Elevated epichaperome levels were found in the cell populations bearing the translocation, suggesting sensitivity to PU-H71. Also, invitro treatment of patient's cells with PU-H71 resulted in cell death and decreased colony formation. These findings confirm preclinical data in AML in which a relationship between a hyperactive signalosome and epichaperome expression was observed (Cell Reports 2015). Based on the poor prognosis, lack of effective therapies, and laboratory data suggesting sensitivity to PU-H71, the patient was granted compassionate access to this medication by the FDA. After 16 doses of PU-H71 at 300 mg/m2 over 3 months, the patient has attained complete remission, with normalization of peripheral blood counts and <5% marrow blasts. Splenomegaly and all constitutional symptoms have completely resolved. Therapy is ongoing. Phosphorylation of SYK in blast as stem cell populations decreased after treatment.
In summary, a novel flow cytometry-based PU-FITC binding assay to evaluate epichaperome levels at the single cell level successfully identified a patient predicted to respond to treatment with PU-H71. This poor prognosis AML patient who had relapsed after allogeneic stem cell transplantation is presently in remission and the assay is being used to screen other potential patients.
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Roboz:Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Sandoz: Consultancy; Celgene Corporation: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Otsuka: Consultancy; Astex Pharmaceuticals: Consultancy; Otsuka: Consultancy; Argenx: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Astex Pharmaceuticals: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Celltrion: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy. Morgan:Samus Therapeutics, Inc: Employment, Equity Ownership. Chiosis:Samus Therapeutics, Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Guzman:Cellectis: Research Funding.
Mammary myofibroblastoma is a benign spindle cell tumor that can show variable morphologic patterns and lines of differentiation. Myofibroblastoma belongs to a family of CD34-positive tumors with ...similar morphology that show a deletion of 13q14, which includes RB1 and FOXO1A genes. A subset of these tumors demonstrates distinct smooth muscle differentiation which can be confused with other smooth muscle tumors of the breast, itself constituting a rarified morphological subgroup. We aimed to characterize 4 cases of the leiomyomatous variant of myofibroblastoma arising in the breast by clinicopathological, immunohistochemical, and molecular means. All 4 examples arose in women aged 41–62 years (median, 46.5 years). Tumors ranged in size from 1.7 to 2.5 cm (median, 2.2 cm). Morphologically, all tumors were characterized by bundles of smooth muscle cells with elongated cigar-shaped nuclei and eosinophilic cytoplasm. All four tumors showed diffuse positive staining with desmin, caldesmon, smooth muscle actin (SMA), estrogen receptor (ER), and Bcl-2. CD34 staining was diffusely positive in two cases, weak and patchy in one case, and was negative in one case. Two of four (50%) tumors showed deletion of RB1 by fluorescence in situ hybridization (FISH). Loss of Rb staining was seen in one tumor with RB1 deletion by FISH, while intact Rb staining was observed in one non-deleted case studied. In conclusion, this rare variant of myofibroblastoma is a distinct subgroup of tumors among an already uncommon category of (smooth muscle) breast tumors. Some reported examples of “parenchymal leiomyoma” may represent the leiomyomatous variant of myofibroblastoma.
A 68-year-old woman sustained an isolated type III left coronoid fracture after mechanical ground-level fall. The patient underwent left elbow arthroscopy with minimally invasive arthroscopic ...reduction and internal fixation of the coronoid fracture using Arthrex Mini TightRope. The patient achieved successful elbow stabilization with a postoperative Mayo Elbow Score of 100.
We present a case report of a novel technique in coronoid fracture management with stable fixation, minimal soft-tissue violation, and restoration of highly functional elbow range of motion. Minimal soft-tissue violation with use of arthroscopy and suture button was the key element in successful surgical treatment and outcome.
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