Recurrent mutations in the spliceosome are observed in several human cancers, but their functional and therapeutic significance remains elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3' splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3' ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3' ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer.
Muscle-invasive bladder cancer (MIBC) is an aggressive disease with limited therapeutic options. Although immunotherapies are approved for MIBC, the majority of patients fail to respond, suggesting existence of complementary immune evasion mechanisms. Here, we report that the PPARγ/RXRα pathway constitutes a tumor-intrinsic mechanism underlying immune evasion in MIBC. Recurrent mutations in RXRα at serine 427 (S427F/Y), through conformational activation of the PPARγ/RXRα heterodimer, and focal amplification/overexpression of PPARγ converge to modulate PPARγ/RXRα-dependent transcription programs. Immune cell-infiltration is controlled by activated PPARγ/RXRα that inhibits expression/secretion of inflammatory cytokines. Clinical data sets and an in vivo tumor model indicate that PPARγHigh/RXRαS427F/Y impairs CD8+ T-cell infiltration and confers partial resistance to immunotherapies. Knockdown of PPARγ or RXRα and pharmacological inhibition of PPARγ significantly increase cytokine expression suggesting therapeutic approaches to reviving immunosurveillance and sensitivity to immunotherapies. Our study reveals a class of tumor cell-intrinsic “immuno-oncogenes” that modulate the immune microenvironment of cancer.
The lenvatinib PFS benefit was maintained regardless of baseline CAF or BRAF/RAS status. Baseline Ang2 was predictive of PFS in a subgroup of lenvatinib-treated patients, indicating that Ang2 may be predictive of lenvatinib sensitivity. BRAF may be a poor prognostic factor in patients with radioiodine-refractory papillary thyroid cancer. Improved PFS associated with upregulated FGF23 suggests that lenvatinib-induced FGF receptor inhibition contributes to lenvatinib efficacy. Trial registration ID of the main study, SELECT: ClinicalTrials.gov: NCT01321554.
BACKGROUND: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor. METHODS: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines. RESULTS: Forty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50-800-mg oral dosing. CONCLUSION: The results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov code: NCT01618136.
A phase II trial was conducted in subjects with human papillomavirus (HPV) associated high-grade cervical dysplasia testing the safety and efficacy of a microparticle encapsulated pDNA vaccine. Amolimogene expresses T cell epitopes from E6 and E7 proteins of HPV types 16 and 18. An analysis was performed on a subset of HLA-A2+ subjects to test whether CD8+ T cells specific to HPV 16, 18, 6 and 11 were increased in response to amolimogene immunization. Of the 21 subjects receiving amolimogene, 11 had elevated CD8+ T cell responses to HPV 16 and/or 18 peptides and seven of these also had increases to corresponding HPV 6 and/or 11 peptides. In addition, T cells primed and expanded in vitro with an HPV 18 peptide demonstrated cross-reactivity to the corresponding HPV 11 peptide. These data demonstrate that treatment with amolimogene elicits T cell responses to HPV 16, 18, 6 and 11.
Schweinfurthins, a class of natural products, have attracted considerable interest for novel therapy development because of their selective and potent anti-proliferative activity against human cancer cells. However, the underlying mechanism is not well understood. Herein, we demonstrated that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Intracellularly, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, likely by binding to oxysterol-binding proteins, leading to an effective inhibition of mTOR/AKT signaling through inducing endoplasmic reticulum stress and suppressing both lipid raft-mediated PI3K activation and mTOR/RheB complex formation. Moreover, schweinfurthins were found to be highly potent toward PTEN-deficient B cell lymphoma cells, and displayed two orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in trans-Golgi-network trafficking and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest a new opportunity to modulate oncogenic signaling by interfering with TGN trafficking to treat mTOR/AKT-dependent human cancers.
5518 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In a phase II study of lenvatinib, 58 patients (pts) with DTC were enrolled and a response rate of 50% was observed (Sherman, ASCO 2011). Methods: Pts received lenvatinib at a starting dose of 24 mg oral once daily in 28-day cycles. Serum was collected at baseline (BL), on day 8 and on day 36 and concentrations of 47 CAFs were measured using multiplex bead arrays and enzyme-linked immunosorbent assay (ELISA). 33 genes (443 mutations) were examined in archival tumor tissues (n=25). Association of baseline CAF, changes in CAF levels upon treatment and gene mutation status with treatment outcomes was investigated. Results: Combination of low baseline VEGF and ANG-2 (p=0.02 and HR=0.386) correlated with longer PFS. Both baseline and changes in CAF levels demonstrated an association with gene mutation status. High baseline levels of VEGF were observed in pts with wild type RAS and BRAF (p=0.035) whereas high baseline sTIE-2 levels associated with RAS mutation (p=0.023). Supporting pre-clinical mouse xenograft tumor model developed using ANG2-overexpressing human thyroid cancer cell line FTC-286 demonstrated reduced sensitivity to lenvatinib treatment. Increased levels of IL-10 and FGF-2 8-day post-treatment (8d post-tx) significantly associated with RAS (N- or K-) and BRAF mutation. Combination of gene mutation status with baseline CAF levels provided better prediction of longer PFS compared to gene mutation alone. Hierarchical clustering modeling using changes in CAF levels 8d post-tx with tumor shrinkage identified a set of CAFs that could predict two categories of lenvatinib response: longer PFS and greater tumor shrinkage or longer PFS in the absence of significant tumor shrinkage. Conclusions: CAF profiling identified potential predictive biomarkers of lenvatinib treatment outcomes in DTC. Combination of RAS and BRAF mutation with baseline VEGF and ANG-2 or treatment-associated changes in FGF-2 and IL-10 level correlated with lenvatinib treatment response.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.