BackgroundAdenoid cystic carcinoma (ACC) is a rare tumor of secretory glands. In this study, recent advances in molecular characterization and in therapeutics are reviewed.MethodsA search of articles in PubMed and of abstracts from national meetings was performed regarding ACC.ResultsRecent genetic analyses found that recurrent chromosome 6:9 translocations in ACC generate an MYB:NFIB gene fusion resulting in overexpression of the MYB oncoprotein. Several other frequent mutations are recently published that may be relevant for drug development. Several trials of targeted drugs are reviewed. Some agents delay tumor progression, but tumor responses remain rare.ConclusionACCs have a characteristic chromosomal translocation, but also frequently pick up additional mutations. Clinical research is limited by the rarity and slow growth of ACC. Several ongoing trials are testing agents that inhibit fibroblast growth factor receptor signaling or other signaling pathways. Novel treatments based on the recently sequenced tumor genome are under development. © 2015 The Authors Head & Neck Published by Wiley Periodicals, Inc. 38: 620–627, 2016

HRS/J inbred mice carry a mutant autosomal recessive gene (hr), which in homozygotes coincides with susceptibility to spontaneous thymic leukemia. Unlike their heterozygote (hr/+) littermates, hr/hr homozygotes express high levels of xenotropic virus during the preleukemic period, and viruses with a broadened host range (termed polytropic viruses) can be isolated from their preleukemic and leukemic tissues. Because hr/hr and hr/+ mice are otherwise genetically identical, the virological differences between them support the role of polytropic viruses in the generation of thymic leukemia. In the present report we show that the HRS/J polytropic viruses are env gene recombinants with unique oligonucleotide and peptide maps. These polytropic viruses appear to arise by recombination between ecotropic virus and an unidentified genome related, but not identical to, the endogenous xenotropic viruses. Moreover, polytropic viruses not only accelerate leukemogenesis in HRS/J mice, but also induce thymic leukemia in the low leukemia strain CBA/J. By contrast, cloned ecotropic and xenotropic viruses have no leukemogenic action.

Tl-oligonucleotide fingerprinting and mapping were used to study the expression of RNA leukemia viruses in leukemic and preleukemic AKR/J mice, with techniques designed to minimize the loss or inadvertent selection of viruses in vitro before biochemical analysis. In leukemic animals, complex mixtures of ecotropic and mink-tropic viruses were expressed. Unique but similar polytropic virus-like genomes were present in each tumor isolate. In preleukemic mice, viral isolates from the thymus that were grown on NIH3T3 fibroblasts contained genomes with non-Akv polytropic virus-related oligonucleotides. This phenomenon was not evident in fingerprints of viruses from the spleen and bone marrow of the same animals. Remarkably, the non-Akv oligonucleotides located in the 3' portion of the P15E gene, the U3 noncoding region, and the 5' part of the gp7O gene were often expressed independently. Our results suggest the following. (i) Recombinant viruses can be detected in the thymuses of young preleukemic AKR mice and increase in relative abundance with age. (ii) During in vivo generation of the recombinant leukemogenic viruses, the selection of polytropic virus-related sequences in the 3' part of pl5E and the U3 region and the 5' portion of gp70 occurs independently. (iii) Independent biological properties encoded in the gp7O and pl5E regions of env of the recombinant viruses may mediate viral selection or leukemogenicity. (iv) The leukemogenic polytropic viruses of AKRIJ mice arise via genetic recombination involving at least three endogenous viral sequences.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have poor efficacy in head and neck squamous cell carcinoma (HNSCC). Because the insulin-like growth factor-1 receptor (IGF1R) generates potent prosurvival signals and has been implicated in therapeutic resistance, its ability to induce resistance to EGFR-TKIs was studied in vitro. Five HNSCC cell lines demonstrated reduced sensitivity to the EGFR-TKI gefitinib when the IGF1R was activated. In SCC-25 and Cal27 cells, gefitinib inhibited basal and EGF-stimulated EGFR, Erk and Akt phosphorylation and reduced cell number. This correlated with initiation of apoptosis based on a 4-fold increase poly-(ADP-ribose) polymerase (PARP) cleavage and a 2.5-fold increase in Annexin V positivity. The apoptotic response and reduction in cell number were blocked by IGF1R activation, which resulted in phosphorylation of both Erk and Akt. In both cell lines, IGF1R-induced Erk but not Akt activation was eliminated by gefitinib. IGF1R-induced gefitinib resistance was unaffected by MEK inhibition with U0126, but was partially impaired by inhibition of phosphatidylinositol 3′-kinase (PI3K) with LY294002. The IGF1R-TKI PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib. Thus the IGF1R can make HNSCC cells resistant to EGFR-TKI treatment via a prosurvival mechanism. Of 8 studied, all HNSCC tumor samples expressed the IGF1R and 5 demonstrated detectable IGF1R phosphorylation, suggesting that this receptor may be relevant in vivo, and thus combined EGFR/IGF1R inhibition may be necessary in some patients for effective targeted molecular therapy.

BACKGROUND To identify novel effectors and markers of localized but potentially life-threatening prostate cancer (PCa), we evaluated chromosomal copy number alterations (CNAs) in tumors from patients who underwent prostatectomy and correlated these with clinicopathologic features and outcome. METHODS CNAs in tumor DNAs from 125 prostatectomy patients in the discovery cohort were assayed with high resolution Affymetrix 6.0 SNP microarrays and then analyzed using the Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm. RESULTS The assays revealed twenty significant regions of CNAs, four of them novel, and identified the target genes of four of the alterations. By univariate analysis, seven CNAs were significantly associated with early PCa-specific mortality. These included gains of chromosomal regions that contain the genes MYC, ADAR, or TPD52 and losses of sequences that incorporate SERPINB5, USP10, PTEN, or TP53. On multivariate analysis, only the CNAs of PTEN and MYC contributed additional prognostic information independent of that provided by pathologic stage, Gleason score, and initial PSA level. Patients whose tumors had alterations of both genes had a markedly elevated risk of PCa-specific mortality (OR = 53; C.I.= 6.92–405, P = 1 × 10−4). Analyses of 333 tumors from three additional distinct patient cohorts confirmed the relationship between CNAs of PTEN and MYC and lethal PCa. CONCLUSION This study identified new CNAs and genes that likely contribute to the pathogenesis of localized PCa and suggests that patients whose tumors have acquired CNAs of PTEN, MYC, or both have an increased risk of early PCa-specific mortality.