Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates PI3K/Akt signalling and has a tumour suppressive role in some types of cancers. However, we have found that it is upregulated in a subset of melanomas. Here we report that INPP4B can function as an oncogenic driver through activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) in melanoma. While INPP4B knockdown inhibited melanoma cell proliferation and retarded melanoma xenograft growth, overexpression of INPP4B enhanced melanoma cell and melanocyte proliferation and triggered anchorage-independent growth of melanocytes. Noticeably, INPP4B-mediated melanoma cell proliferation was not related to activation of Akt, but was mediated by SGK3. Upregulation of INPP4B in melanoma cells was associated with loss of miRNA (miR)-494 and/or miR-599 due to gene copy number reduction. Indeed, overexpression of miR-494 or miR-599 downregulated INPP4B, reduced SGK3 activation, and inhibited melanoma cell proliferation, whereas introduction of anti-miR-494 or anti-miR-599 upregulated INPP4B, enhanced SGK3 activation, and promoted melanoma cell proliferation. Collectively, these results identify upregulation of INPP4B as an oncogenic mechanism through activation of SGK3 in a subset of melanomas, with implications for targeting INPP4B and restoring miR-494 and miR-599 as novel approaches in the treatment of melanomas with high INPP4B expression.
8542 Background: Drugs that target oncogenic mutant BRAF have impressive response rates in MM pts, however resistance usually develops within 12 months. In pts on clinical trials of BRAFi, we investigated mechanisms of action and resistance by analysing MM tissue excised before and after treatment, and on progression. Methods: Pts with V600E or V600K mutant MM enrolled on the Ph 1/2 study of GSK2118436 or the Ph 2 study of RO5185426 had biopsies (bx) ≤7 days prior to (PRE) and 7 days +/-4 after commencing BRAFi (POST), and on progression (PROG). Morphologic and IHC (p27, pAKT, pERK, Ki67, TUNNEL assay) tissue bx features were correlated with clinical outcome data including time to progression (TTP) and overall survival (OS), and measures of response; FDG PET change in SUV max, CT-determined RECIST response and calliper measurement of subcutaneous lesions. Results: 12 pts had paired PRE and POST bx, 7 also had PROG bx. 3 pts had paired PRE and PROG bx only. Of the 15 pts, 2 were treated with RO5185426 and 13 with GSK2118436. Comparing paired PRE and POST bx, there was a marked decrease in Ki67 and mitotic rate in 11/12 pts (p<0.05) regardless of clinical response, and a systematic change in cell type (round to spindle), cell size (decreased), necrosis (increased), intratumoral lymphocytes (ITL) (increased) and apoptosis (increased) on exposure to BRAFi (p<0.05). Peritumoral lymphocytes (PTL) increased (p=0.07). Preliminary data suggest there was no systematic change in p27 or pAKT, however a higher PRE nuclear p27 level maybe associated with a poorer OS (HR 1.5, 95%CI 1.03-2.27, p=0.03) and TTP (HR 1.29, 95%CI 1.06-1.59, p=0.01). Change in calliper measurement of the POST lesion from baseline correlated negatively with changes in necrosis and ITL (p<0.05). For POST to PROG paired bx, apoptosis, ITL and PTL decreased (p<0.05). Conclusions: Specific morphological changes occur in melanoma tissue on exposure to BRAFi, some of which may be associated with clinical outcome. Baseline level of p27 may be prognostic in BRAF mutant pts. Changes in tumoral lymphocytic infiltrates in POST and PROG bx suggest that an immune response may have a role in BRAFi activity.
Murali, Rajmohan MBBS, FRCPA; Thompson, John F. BSc (Med), MBBS, MD, FRACS, FACS; Scolyer, Richard A. MBBS, MD, FRCPA, FRCPath Author Information
Read moreWe report four previously undescribed families with germline BRCA1-associated protein-1 gene (BAP1) mutations and expand the clinical phenotype of this tumor syndrome. The tumor spectrum in these families is predominantly uveal malignant melanoma (UMM), cutaneous malignant melanoma (CMM) and mesothelioma, as previously reported for germline BAP1 mutations. However, mutation carriers from three new families, and one previously reported family, developed basal cell carcinoma (BCC), thus suggesting inclusion of BCC in the phenotypic spectrum of the BAP1 tumor syndrome. This notion is supported by the finding of loss of BAP1 protein expression by immunochemistry in two BCCs from individuals with germline BAP1 mutations and no loss of BAP1 staining in 53 of sporadic BCCs consistent with somatic mutations and loss of heterozygosity of the gene in the BCCs occurring in mutation carriers. Lastly, we identify the first reported recurrent mutation in BAP1 (p.R60X), which occurred in three families from two different continents. In two of the families, the mutation was inherited from a common founder but it arose independently in the third family.
Read moreVilain, Ricardo E. BSc, MBBS, PhD, FRCPA; McCarthy, Stanley W. MBBS, FRCPA; Thompson, John F. MD, FRACS FACS; Scolyer, Richard A. MD FRCPA, FRCPath Author Information
Read moreTaken together, our data indicate that preexisting MEK1(P124) mutations are associated with a reduced response to BRAF inhibitor therapy and identify a subset of patients with BRAF-mutant melanoma likely to benefit from combination therapies involving MEK or ERK inhibitors.
Read moreBACKGROUND: The nuclear transcription factor c-Jun is preferentially expressed in basal-cell carcinoma. Dz13 is a deoxyribozyme that targets JUN messenger RNA and has inhibited the growth of a range of tumours in mice. We did a phase 1 study to assess safety and tolerability in human beings. METHODS: Adults with nodular basal-cell carcinoma were recruited from Royal Prince Alfred Hospital, Sydney, Australia, between September, 2010, and October, 2011. Patients were assigned to receive one intratumoral injected dose of 10, 30, or 100 μg Dz13, in a 50 μL volume of lipid carrier, and were assessed for adverse effects in the first 24 h then at 7, 14, and 28 days after injection. Treated tumours were surgically excised 14 days after injection and compared with the baseline biopsy samples for expression of c-Jun and tumorigenesis markers. FINDINGS: Nine patients were recruited, of whom three received each dose of Dz13. All patients completed the study with no drug-related serious adverse events. No systemic Dz13 exposure was detected. c-Jun expression was reduced in the excised tumours of all nine (100%) patients, compared with baseline, and histological tumour depth had decreased in five (56%) of nine. Proportions of cells positive for caspases 3, 8, and 9 and P53 were increased, but those of cells positive for Bcl-2 and MMP-9 were decreased. Infiltration by inflammatory and immune cells was stimulated. INTERPRETATION: Dz13 was safe and well tolerated after single intratumoral injections at all doses. FUNDING: Cancer Institute NSW, Cancer Council Australia, and National Health and Medical Research Council.
Read moreNote Neoplasms arising from melanocytes in the skin may be benign, in which case they are termed nevi, or malignant, in which case they are termed There are several variants of cutaneous melanocytic tumors, characterized by differing clinical and pathologic features. Spitz tumors include a group of cutaneous melanocytic tumors that share certain histologic features. Spitz tumors may be classified as Spitz nevi [which are benign], spitzoid melanomas [which are malignant], and Spitz tumor [a group of tumors whose biologic behavior cannot be accurately predicted on the basis of their histopathologic features] (Barnhill, 2006a; Barnhill, 2006b). Spitz nevi show characteristic cytologic and architectural features, described below. Only some of these characteristics are seen in atypical Spitz tumors and spitzoid melanomas.
Read moreThese methods and descriptors should help to manage the diagnosis of treatment failure.
Read moreDeregulated glucose metabolism fulfi lls the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefi t in BRAF -mutant melanoma, we exam- ined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consist- ent decreases in glycolytic activity in BRAF -mutant melanoma cells. Moreover, we identifi ed a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably , this network of transcription factors, including hypoxia-inducible factor-1 α, MYC, and MONDOA (MLXIP), drives gly- colysis downstream of BRAF V600 , is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)-resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors. SIGNIFICANCE: BRAFis suppress glycolysis and provide strong clinical benefi t in BRAF V600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors. Cancer Discov; 4(4); 1-11. ©2014 AACR.
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