bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient Offline Waveform Design Using Quincunx/Hexagonal Time-Frequency Lattices
Authors: Ayadi Raouia , Kammoun Inès , Siala Mohamed
Published: November 2017

Conventional orthogonal frequency division multiplexing (OFDM) may turn to be inappropriate for future wireless cellular systems services, because of extreme natural and artificial impairments they are expected to generate. Natural impairments result from higher Doppler and delay spreads, while artificial impairments result from multisource transmissions and synchronization relaxation for closed-loop signaling overhead reduction. These severe impairments induce a dramatic loss in orthogonality between subcarriers and OFDM symbols and lead to a strong increase in intercarrier interference (ICI) and intersymbol interference (ISI). To fight against these impairments, we propose here an optimization of the transmit/receive waveforms for filter-bank multicarrier (FBMC) systems, with hexagonal time-frequency (TF) lattices, operating over severe doubly dispersive channels. For this, we exploit the Ping-pong Optimized Pulse Shaping (POPS) paradigm, recently applied to rectangular TF lattices, to design waveforms maximizing the signal-to-interference-plus-noise ratio (SINR) for hexagonal TF lattices. We show that FBMC, with hexagonal lattices, offers a strong improvement in SINR with respect to conventional OFDM and an improvement of around 1 dB with respect to POPS-FBMC, with rectangular lattices. Furthermore, we show that hexagonal POPS-FBMC brings more robustness to frequency synchronization errors and offers a 10 dB reduction in out-of-band (OOB) emissions, with respect to rectangular POPS-FBMC.
Myelodysplasia and Mast Cell Leukemia with t(9;22)
Authors: Lago Kathryn J. , Shupe Matthew P. , Hannah William N. , Velagaleti Gopalrao V. N. , Mendiola Christina , Ortega Veronica , Haney Brian R.
Published: November 2017

Introduction. Mast cell leukemia (MCL) is a rare variant of systemic mastocytosis. Most cases of mast cell leukemia do not have cytogenics performed. Furthermore, there is no consistent chromosomal abnormality identified in MCL. This is the first reported case of MCL with a (9;22) translocation. Case Report. An 80-year-old female presented with pancytopenia and was diagnosed with MDS. Over time, she required hospitalizations for platelet transfusions with increased frequency. She developed fatigue and weakness along with gastrointestinal symptoms. On exam, she had diffuse abdominal tenderness and a maculopapular rash. Her lab results revealed a new basophilia. A bone marrow biopsy showed 100% cellularity with many aggregates of mast cells. Chromosomal analysis showed t(9;22) with confirmed BCR/ABL1 fusion by fluorescence in situ hybridization (FISH). Discussion. MCL has a poor prognosis due to the aggressive nature of the disease and ineffective therapies. Translocation (9;22) is known to be associated with MDS transformations to acute leukemia; however, this translocation has never been reported in MCL. Further research on the relationship between t(9;22) and MCL could lead to development of improved therapeutic options.
A Novel Technique for Bulk-Fill Resin-Based Restorations: Achieving Function and Esthetics in Posterior Teeth
Authors: Durán Ojeda Gerardo , Henríquez Gutiérrez Ismael , Tisi José Pablo , Báez Rosales Abelardo
Published: November 2017

Advances in the mechanical properties of composite resins have allowed for their use in posterior teeth. Conventional resins have several problems associated with polymerization shrinkage stress. The development of “bulk-fill” resins has allowed for their use in single increments up to depths of 4 mm, with very low polymerization shrinkage stress. Nevertheless, differences in anatomy and the desire for optimal esthetics present unique difficulties. This article describes a step-by-step technique using flowable bulk-fill resin as a substitute for dentin in a single increment, together with a high-reflective-index resin to restore enamel and decrease clinical time, obtaining anatomically and esthetically acceptable results without detriment to the mechanical properties required to restore the functionality of the posterior teeth.
Effect of Different HTM Layers and Electrical Parameters on ZnO Nanorod-Based Lead-Free Perovskite Solar Cell for High-Efficiency Performance
Authors: Anwar Farhana , Mahbub Rafee , Satter Sakin Sarwar , Ullah Saeed Mahmud
Published: November 2017

Simulation has been done using SCAPS-1D to examine the efficiency of CH3NH3SnI3-based solar cells including various HTM layers such as spiro-OMeTAD, Cu2O, and CuSCN. ZnO nanorod array has been considered as an ETM layer. Device parameters such as thickness of the CH3NH3SnI3 layer, defect density of interfaces, density of states, and metal work function were studied. For optimum parameters of all three structures, efficiency of 20.21%, 20.23%, and 18.34% has been achieved for spiro-OMeTAD, Cu2O, and CuSCN, respectively. From the simulations, an alternative lead-free perovskite solar cell is introduced with the CH3NH3SnI3 absorber layer, ZnO nanorod ETM layer, and Cu2O HTM layer.
Abstract A08: Hyperthermia plus radiotherapy in Estrogen receptor positive (ER+) breast cancer; before or after?
Authors: Joveini Zahra , Behrouzkia Zhaleh , Aghdam Reza Zohdi
Published: December 2017

Background: Breast cancer is the most common cancer among women. Hyperthermia is a new cancer treatment modality which is used in addition to other treatments to improve patient's survival. The clinical use of Hyperthermia in the combination of radiotherapy is debatable and shows important technical challenges. But the most challenge in this case is the order of this combination. We aimed to explore that in ER+ breast cancer applying hyperthermia before radiotherapy is better or after it.

Methods and Material: The anti-proliferative activity of Hyperthermia alone and in combination with Radiotherapy in T47D human breast cancer cell line was assessed by the standard 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium bromide (MTT) method. We also used Acridine Orange/ Propidium Iodide fluorescent staining for approving the inhibitory effect. We exposed the cells to 43±0.2°C for 30 minutes in a regular incubator, as Hyperthermia treatment and also exposing into 4Gy Gamma irradiation as Radiotherapy. We applied Hyperthermia before and after Radiotherapy to detect the differences. In two modality treatments the time interval was two hours. Then the viability rates of cells were determined after 24, 48 and 72 hours. All data are expressed as the mean ± standard deviation. We used Kruskal-Wallis and Mann-Whitney for statistical analysis. P-values of less than 0/05 were considered to be statistically significant.

Results: The findings indicated that adding hyperthermia after Radiotherapy showed 43.75±3.86, 40.75±3.09 and 38.25±2.21 viability rate after 24,48 and 72 hours, respectively; while applying it after Radiotherapy showed 47.5±5.12, 45.25±2.21 and 42.75±3.59 viability rate after 24,48 and 72 hours.

Conclusions: It was concluded that in ER-positive breast cancer applying hyperthermia after radiotherapy is more efficient.

Note: This abstract was not presented at the conference.

Citation Format: Zahra Joveini, Zhaleh Behrouzkia, Reza Zohdi Aghdam. Hyperthermia plus radiotherapy in Estrogen receptor positive (ER+) breast cancer; before or after? [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A08.
Abstract A36: The cytolytic and anti-leukemic potential of ex vivo differentiated NK cells is confined in the CD94 positive population
Authors: Chouaib Salem , Khalifé Nadine Saleh , Hasmim Meriem , Zhang Yanyan , Doldur Manale , Bouhris Jean Henri , Louache Fawzia
Published: December 2017

Adoptive transfer of allogeneic natural killer (NK) cells represents a promising treatment approach against acute myeloid leukemia (AML). We developed a cytokine-based culture method for the generation of NK cells derived from CD34+hematopoietic progenitor cells (HPC) isolated from fresh umbilical cord blood (UCB). Immuno-phenotyping of ex vivo expanded NK cells showed typical inhibitory and activating NK receptors except for CD16 and the KIR receptors. CB-derived NK cells displayed good cytolytic activity and phenotypic analysis showed that the lytic potential of these ex vivo differentiated NK was associated with their expression level of CD94. We further characterized UCB-derived NK cells by investigating in vivo their toxicity, biodistribution, and anti-leukemic potential. For this purpose, immune deficient mice were engrafted with a patient derived AML strain. We showed that in vivo only the CD94+ NK cells survive and form conjugate with leukemic blasts. The characterization of CD94+ cells and the involvement of CD94 and its ligand in the regulation of these ex vivo differentiated allogenic NK cells lytic activity will be discussed. Our findings suggest that CD94+ NK selection could be a pertinent approach to select highly functional expanded NK cells before therapeutic use.

Citation Format: Salem Chouaib, Nadine Saleh Khalifé, Meriem Hasmim, Yanyan Zhang, Manale Doldur, Jean Henri Bouhris, Fawzia Louache. The cytolytic and anti-leukemic potential of ex vivo differentiated NK cells is confined in the CD94 positive population [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr A36.
Abstract B28: Baseline prostate-specific antigen (PSA) levels in midlife predict aggressive prostate cancer in African-American men
Authors: Preston Mark , Gerke Travis , Carlsson Sigrid V. , Signorello Lisa , Sjoberg Daniel D. , Markt Sarah C. , Kibel Adam S. , Trinh Quoc-Dien , Steinwandel Mark , Blot William , Vickers Andrew J. , Lilja Hans , Mucci Lorelei A. , Wilson Kathryn M.
Published: December 2017

Background: Baseline prostate specific antigen (PSA) levels measured in midlife predict future prostate cancer mortality among white men. There are minimal data on whether a baseline PSA in African-American men, who experience the highest incidence and mortality of this disease, predicts future aggressive prostate cancer.

Methods: We undertook a nested case-control study among African-American men age 40 to 64 years who gave prediagnostic blood at enrollment in the Southern Community Cohort Study between 2002-2009 and were followed a median of 9 years for cancer incidence and mortality through 2015. Baseline total and free PSA levels were available for 197 prostate cancer cases (55 aggressive cases, Gleason ≥4+3=7, AJCC Stage III or IV, or cancer-specific death) and 569 age-matched controls. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs) for the association between baseline PSA levels and risk of total and aggressive prostate cancer.

Results: Median PSA among controls was 0.72, 0.80, 0.94, and 1.03 ng/mL for men aged 40 to 49, 50 to 54, 55 to 59, and 60 to 64 years, respectively. Relative risk of total prostate cancer was strongly associated with baseline PSA levels in midlife: ORs (95% CIs) comparing PSA levels in the >90th percentile vs. ≤median were 93.7 (22.5-390) at 40 to 54 years and 77.0 (24.9-238) at 55 to 64 years. Risk of aggressive prostate cancer was also strongly associated with baseline PSA levels in midlife: ORs (95% CIs) comparing PSA levels in the >90th percentile vs. ≤median were 80.8 (14.7 to infinity) at 40-54 years

Citation Format: Mark Preston, Travis Gerke, Sigrid V. Carlsson, Lisa Signorello, Daniel D. Sjoberg, Sarah C. Markt, Adam S. Kibel, Quoc-Dien Trinh, Mark Steinwandel, William Blot, Andrew J. Vickers, Hans Lilja, Lorelei A. Mucci, Kathryn M. Wilson. Baseline prostate-specific antigen (PSA) levels in midlife predict aggressive prostate cancer in African-American men [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B28.
Abstract IA12: Targeting DNA repair in cancer therapy
Authors: D'Andrea Alan D.
Published: December 2017

Human cancer cells have genomic instability resulting from germline or acquired defects in DNA repair. One DNA repair pathway - the Fanconi Anemia/BRCA pathway (D'Andrea, A., N Engl J Med 362:1909, 2010) - is defective in many human cancers, including breast, ovarian, and pancreatic neoplasms. Disruption of the FA/BRCA Pathway results in the characteristic chromosome instability and radiation/crosslinker hypersensitivity of these tumors. In general, loss of one DNA repair pathway often leads to hyperdependence on another pathway for tumor cell survival. This hyperdependence offers a unique opportunity for the development of anticancer therapeutics. For instance, FA/BRCA pathway deficient tumors are hyperdependent on Base Excision Repair (BER) and, accordingly, these tumors are hypersensitive to single agent treatment with PARP1 inhibitors, which block BER, or with ATM inhibitors. Our research program is focused on profiling the FA/BRCA pathway and the other five major DNA repair pathways in tumor cells (Kennedy and D'Andrea, JCO 24: 3799, 2006). Each DNA repair pathway has a characteristic biomarker and repairs a specific type of DNA lesion. By profiling these pathways in primary tumor samples with activation-specific antibodies to DNA repair proteins, we have been able (1) to predict the sensitivity of tumors to conventional chemotherapy and radiation (2) to subset tumors for their sensitivity to novel classes of DNA repair inhibitors, (i.e., PARP1, Chk1, ATM, and proteasome inhibitors) and (3) to screen for new small molecule inhibitors of other DNA repair pathways. This combination of novel DNA repair inhibitors, conventional DNA damaging agents, and DNA repair biomarkers offers new opportunities for developing more effective anticancer therapy. In my presentation, I will also discuss novel approaches to sensitizing Triple Negative Breast Cancers (TNBCs) and Ovarian Tumors (OCs) to PARP1 inhibitors. We have previously shown that exposure of these tumors to either a CDK inhibitor or a proteasome inhibitor can block homologous recombination (HR) repair and thereby sensitize the tumor cells to PARP1 inhibitor. The CDK inhibitor/PARP1 inhibitor combination has been examined in orthotopic primary TNBC and OC xenograft models. Finally, we have identified an additional PARP1-dependent DNA repair mechanism in TNBCs and OCs. This pathway is driven by a novel alternative end-joining polymerase, POL. These tumors are hypersensitive to inhibitors of this new pathway, suggesting a new target for DNA repair therapies.

Citation Format: Alan D. D'Andrea. Targeting DNA repair in cancer therapy [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA12.
Abstract IA30: CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer
Authors: DuBois Raymond N.
Published: December 2017

Emerging evidence suggests that once a primary tumor forms it can then influence the development of a supportive metastatic microenvironment, referred to as pre-metastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A that stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruits CXCR2-positive myeloid-derived suppressor cells (MDSCs) to form a pre-metastatic niche that ultimately promotes liver metastases. Importantly, we found that pre-metastatic liver-infiltrating MDSCs induce tumor cell survival without involvement of the innate or adaptive immune responses. Our study provides the first evidence we know of showing that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1 that recruits CXCR2-positive MDSCs to form a pre-metastatic niche which promotes liver metastases. Our findings not only reveal a novel mechanism by which the interactions of malignant cells with their stromal counterparts in the primary tumor contribute to the formation of a pre-metastatic niche that favors tumor cell survival, but also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease.

Citation Format: Raymond N. DuBois. CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA30.
Abstract A23: Multi-parametric genetic interactions map dynamic genetic network rewiring upon anti-proliferative treatment
Authors: Heigwer Florian , Scheeder Christian , Miersch Thilo , Blass Claudia , Boutros Michael
Published: December 2017

Signaling pathways are often characterized as rather static networks whose outcome is the result of state changes of pathway components, e.g. by protein phosphorylation or other post-translational modifications. These state changes along signaling networks have been systematically studied using, for example proteomics methods. However it remained unknown how networks rewire under the influence of external stimuli, such as anti-cancer drug treatment. To analyze dynamic rewiring of a signaling network, we performed an arrayed high-throughput co-RNAi screen in a Drosophila melanogaster cell line (Dmel-2). Therin, we assessed statistic genetic interactions measured by 26 880 pairwise RNAi experiments under MEK1/2 inhibitor treatment over the time course of 96 hours. As phenotypic readout we conducted high-content imaging of DNA, cytoskeleton and microtubule markers and extracted >150 cellular features from 4 423 680 images each representing a specific condition, and marker. Together these features precisely characterize ~100 000 alleviating and 160 000 aggravating synergistic effects resulting from combinatorial perturbations. While only 2 % of all interactions are explained by cell viability the vast majority of dynamic differential interactions is explained by other features. Correlation of genetic interaction profiles across those features allows us to precisely how genes change pathway affiliation under different conditions. Our results show that, among others, key signaling nodes e.g. ERK1/2 or the Mediator complex build different connections within genetic networks depending on the environmental conditions and reveal yet unknown synthetic interactions. Using the confidence we gain from time resolved measurements of different cellular features we could identify numerous interactions which could resolve mechanisms of resistance to MEK inhibitor driven treatments and reveal potential new therapeutic targets.

Citation Format: Florian Heigwer, Christian Scheeder, Thilo Miersch, Claudia Blass, Michael Boutros. Multi-parametric genetic interactions map dynamic genetic network rewiring upon anti-proliferative treatment [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A23.
Abstract B07: Analysis of allele specific expression in esophageal squamous cell carcinoma with combination of exome sequencing and mRNA Sequencing
Authors: Takahashi Masahiko , Nakaoka Hirofumi , Akutsu Yasunori , Hanari Naoyuki , Murakami Kentaro , Kano Masayuki , Matsumoto Yasunori , Otsuka Ryota , Sekino Nobufumi , Yokoyama Masaya , Inoue Itsuro , Matsubara Hisahiro
Published: December 2017

In recent years, large-scale international studies have provide comprehensive catalogues of genomic alterations in cancers including Esophageal Squamous Cell Cancer(ESCC). They revealed that some gene associated with cell cycle/apoptosis pathway, NOTCH pathway, WNT pathway, such as TP53 and NOTCH1, harbored genetic abnormalities frequently. As the next step clinical sequencing studies are starting to evaluate efficacy of using targeted agents to patients with specific molecular aberrations.

We performed exome sequencing and RNA sequencing for 25 Japanese patients with esophageal squamous cell carcinoma (ESCC) to provide a comprehensive catalogue of genomic abnormalities in ESCC and found TP53 and ZNF750 significantly mutated genes. Additionally, we performed allele specific expression analysis of TP53, integrating mRNA sequencing data into the information of genomic abnormality. This analysis revealed that levels of expression changes depending on mutation types and nearly mono-allelic expression of TP53 was a common signature of ESCC patients with somatic mutations. And pattern of mono-allelic expression was dependent on mutation types. We expanded this analysis to all genes with somatic SNV mutations and revealed that mutant allele specific expression was observed in other genes including ZNF750, and many of them were belonged to cancer pathway in KEGG database.

About TP53, our investigation might provide better understanding of the involvement of somatic mutations. And fluctuations in transcriptional regulation of TP53 could be predicted based on type of somatic mutation. In addition to this, analysis of allele specific expression suggested that not only somatic mutation of DNA, but also mutant allele expression should be considered to understand cancer genetic pathophysiology better and build more effective therapeutic strategies.

Citation Format: Masahiko Takahashi, Hirofumi Nakaoka, Yasunori Akutsu, Naoyuki Hanari, Kentaro Murakami, Masayuki Kano, Yasunori Matsumoto, Ryota Otsuka, Nobufumi Sekino, Masaya Yokoyama, Itsuro Inoue, Hisahiro Matsubara. Analysis of allele specific expression in esophageal squamous cell carcinoma with combination of exome sequencing and mRNA Sequencing [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B07.
Abstract B13: Synthetic vulnerabilities in MLL3 deficient pancreatic tumors
Authors: Gupta Sonal , Ferri-Borgogno Sammy , Reisenauer Mary R. , Gupta Anvita k. , Maitra Anirban
Published: December 2017

Myeloid/lymphoid or mixed-lineage leukemia 3 (MLL3) is a histone 3-lysine 4 methyltransferase, frequently mutated in a variety of solid tumors including pancreatic ductal adenocarcinoma (PDAC), a nearly lethal disease due to our current inability to therapeutically target major oncogenic proteins driving this cancer. Like other tumor suppressor genes, direct targeting of MLL3 is not feasible, and thus our objective was to find biological pathways which are synthetic lethal targets in MLL3-deficient PDAC tumors. Identification of drug targets in such a specific genetic context could potentially dictate stratification of patients based on the mutational profile of their tumor. To achieve this, we generated a novel genetically engineered mouse model (GEMM) of pancreatic cancer, in which targeted mutation of Kras (G12D) and loss of functional MLL3 was driven by Cre-recombination from early pancreatic lineage-specific transcription factor, Pdx1. Our unpublished data suggests that loss of MLL3 function in exocrine pancreas cooperates with mutant Kras to accelerate the progression of invasive pancreatic neoplasia. Using cell lines generated from spontaneous tumors arising in KC (KrasG12D alone) and KMC (KrasG12D; MLL3δ/δ) mice, we performed functional genomic analyses and found several key oncogenic pathways upregulated in MLL3-deficient cells. We selected two well-known oncogenic pathways and through a series of cellular and biochemical assays, further validated their selectively activation in KMC cells, in contrast with KC cells. Next, we picked multiple pharmacological inhibitors of these pathways, which are already approved at various phases of clinical trials, and tested for their efficacy on growth of KC and KMC cells in both two- and three-dimensional growth assays. In agreement with our data showing preferential activation in KMC cells, we found KMC cells to be significantly more sensitive than KC cells to the effect of these inhibitors. Thus, identification of synthetic lethal hits in context of MLL3 functional loss could potentially enable us to design strategies to limit metastasis in patients with surgically-resectable tumors.

Citation Format: Sonal Gupta, Sammy Ferri-Borgogno, Mary R. Reisenauer, Anvita k. Gupta, Anirban Maitra. Synthetic vulnerabilities in MLL3 deficient pancreatic tumors [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B13.
Abstract B15: Comprehensive cistromic characterization of SOX10, a lineage-specific genetic dependency in melanoma, via the integration of functional genomic approaches
Authors: Wong Terence , Johannessen Cory , Fan Jingyu , Long Henry , Liu Shirley , Garraway Levi
Published: December 2017

Melanoma accounts for less than 5% of skin cancers, but a majority of skin cancer deaths. Genomic studies and drug discovery programs have led to the development of targeted therapies, including BRAF and MEK inhibitors, but the inevitable resistance to these targeted agents necessitates a greater understanding of melanoma biology and genetics. By integrating genome-wide functional genomic and transcriptomic data, we have identified SOX10 as a lineage-specific genetic dependency in melanoma independent of BRAF or NRAS mutation status. Subsequent analyses indicate that SOX10 dependency is highly correlated with SOX10 gene expression and functional in vitro experiments have confirmed the role of SOX10 in the proliferation and growth of melanoma cell lines regardless of their sensitivity to MAPK pathway inhibitors. Chromatin immunoprecipitation of endogenous SOX10 followed by sequencing (SOX10 ChIP-seq) combined with transcriptomic profiling (RNA-seq) following SOX10 depletion by shRNA in a panel of melanoma cell lines determined the SOX10 cistrome, the set of SOX10 target genes across the melanoma genome. Integration of the SOX10 cistrome with genetic dependency data may lead to novel therapeutic approaches in melanoma.

Citation Format: Terence Wong, Cory Johannessen, Jingyu Fan, Henry Long, Shirley Liu, Levi Garraway. Comprehensive cistromic characterization of SOX10, a lineage-specific genetic dependency in melanoma, via the integration of functional genomic approaches [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B15.
Abstract B17: Identification of Druggable Targets through Functional Multi-Omics in Renal Medullary Carcinoma
Authors: Hong Andrew L. , Tseng Yuen-Yi , Kynnap Bryan D. , Doshi Mihir B. , Sandoval Gabriel , Oh Coyin , Sayeed Abeer , Shubhroz Gill , Church Alanna J. , Keskula Paula , Peng Anson , Clemons Paul A. , Tsherniak Aviad , Vazquez Francisca , Rodriguez-Galindo Carlos , Janeway Katherine A. , Garraway Levi A. , Schreiber Stuart L. , Root David E. , Mullen Elizabeth , Stegmaier Kimberly , Kadoch Cigall , Roberts Charles W.M. , Boehm Jesse S. , Hahn William C.
Published: December 2017

Renal medullary carcinoma is a rare kidney cancer that is primarily seen in adolescent and young adult African American patients with sickle cell trait. Prognosis is poor and treatment options are limited. We have developed several cell line models that recapitulate the primary and relapsed metastatic samples from a patient who succumbed to this disease. We have confirmed by whole exome sequencing that our models have sickle cell trait and loss of heterozygosity of the SMARCB1 loci, both hallmarks of this disease. By RNA-sequencing, we see a lack of SMARCB1 transcription. We have further shown dependency of our models to SMARCB1 re-expression thus suggesting that this cancer is indeed driven by loss of SMARCB1 at a functional level. We performed pooled CRISPR-Cas9 and RNAi loss of function screens and a small molecule screen focused on druggable cancer targets based on our previous work in parallel to a genome-wide pooled CRISPR-Cas9 loss of function screen. Integrating these complementary and orthogonal methods, we identified a number of targets for further validation. These targets, when combined may provide a rational approach to therapeutic targeting for this rare kidney cancer.

Citation Format: Andrew L. Hong, Yuen-Yi Tseng, Bryan D. Kynnap, Mihir B. Doshi, Gabriel Sandoval, Coyin Oh, Abeer Sayeed, Gill Shubhroz, Alanna J. Church, Paula Keskula, Anson Peng, Paul A. Clemons, Aviad Tsherniak, Francisca Vazquez, Carlos Rodriguez-Galindo, Katherine A. Janeway, Levi A. Garraway, Stuart L. Schreiber, David E. Root, Elizabeth Mullen, Kimberly Stegmaier, Cigall Kadoch, Charles W.M. Roberts, Jesse S. Boehm, William C. Hahn. Identification of Druggable Targets through Functional Multi-Omics in Renal Medullary Carcinoma [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B17.
Abstract B39: Small Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA Deficient Cancers
Authors: Pomerantz Richard T.
Published: December 2017

Suppression of RAD52 causes synthetic lethality in BRCA deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 recruitment and recombination activity in cells with negligible effects on other double-strand break repair pathways. Importantly, we show that 6-OH-dopa selectively inhibits the proliferation of BRCA deficient cancer cells, including those obtained from leukemia patients. Taken together, these data demonstrate small molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA deficient cancers.

Citation Format: Richard T. Pomerantz. Small Molecule Disruption of RAD52 Rings as a Mechanism for Precision Medicine in BRCA Deficient Cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr B39.
Abstract IA09: Genome-wide CRISPR screens illuminate lymphoma pathogenesis and therapeutic resistance
Authors: Staudt Louis M.
Published: December 2017

While the genetic aberrations in cancer cells have been revealing, many malignant phenotypes are regulated by genes that are not genetically altered. To gain insight into these pathways, we have employed genome-wide genetic screens using CRISPR-Cas9 technology. In one type of screen, lentiviral libraries expressing small guide RNAs (sgRNAs) are used to direct the endonuclease Cas9 to particular genomic locations, leading to the cutting and inactivation of the targeted gene. An alternative approach, called CRISPRi, uses a catalytically-dead Cas9 isoform fused to a KRAB transcriptional repressor domain. sgRNAs are used to guide this fusion protein to gene promoters, leading to their silencing. We are utilizing both screening methodologies in a variety of cell line models of various genetic subtypes of diffuse large B cell lymphoma, T cell lymphomas, and multiple myeloma, looking for essential genes that control proliferation and/or survival in a cancer subtype-specific fashion. We are also using these screens to uncover genes that synergize or antagonize targeted agents that are in clinical development in these lymphoid malignancies. I will present new Insights from these screens into the mechanisms by which lymphomas acquire sensitivity to therapeutic agents targeting B cell receptor signaling, such as ibrutinib, and how they subsequently may develop resistance.

Citation Format: Louis M. Staudt. Genome-wide CRISPR screens illuminate lymphoma pathogenesis and therapeutic resistance [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA09.
Abstract PR18: Leveraging synthetic lethality to target convergent therapeutic resistance
Authors: Wood Kris C.
Published: December 2017

Our laboratory uses genomic and pharmacological methods to define the pathways of resistance to targeted anticancer therapies. Toward this end, we recently developed a technique in which engineered lentiviral cDNAs encoding activators of major oncogenic signaling pathways are introduced into cells and then profiled to identify those capable of conferring resistance to drugs. In parallel, we have also developed analogous loss-of-function screening approaches based on CRISPR/Cas9 gene editing, and have used these approaches to map the pathways supporting intrinsic resistance to targeted therapies. Using these tools in conjunction with data and mouse models derived from human tumors, we recently discovered that major pathways of resistance frequently converge onto common downstream effectors, the targeting of which can forestall resistance. Here, I will describe the discovery of common resistance effectors in JAK2-driven myeloproliferative neoplasms, EGFR-driven colorectal cancers, and BRAF-driven melanomas. Focusing particularly on melanoma, I will describe the discovery that major pathways of resistance converge to activate the transcription factor c-MYC (MYC). MYC expression and gene signatures were suppressed following initial drug treatment, then rebounded during tumor progression in each member of a large panel of human patients, independent of the upstream pathway driving resistance. MYC suppression using either genetic approaches or BET bromodomain inhibition was sufficient to both resensitize diverse BRAFi/MEKi-resistant models and delay resistance in treatment naïve models. Although direct pharmacological inhibition of MYC remains difficult, the BRAFi/MEKi-resistant, MYC-activated state harbors synthetic lethal signaling and metabolic dependencies, including those involving SRC family and c-KIT tyrosine kinases and glucose, glutamine, and serine pathways, that can be targeted to create combination therapies that uniquely select against resistance evolution.

Citation Format: Kris C. Wood. Leveraging synthetic lethality to target convergent therapeutic resistance [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR18.
Abstract 13: Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients
Authors: Porter Ashleigh , Daniels Gregory A. , Patel Sandip Pravin , Sacco Assuntina , Banks Kimberly C. , Cohen Ezra E. W.
Published: December 2017

Background: Head and neck squamous cell carcinoma (HNSCC) is an increasingly prevalent disease but effective targeted therapy is lacking. The use of next generation sequencing (NGS) in the identification of novel targets has been suggested as a way to potentially expand therapeutic options and thereby improve outcomes.

Methods: Data were collected on patients with recurrent and metastatic (R/M) head and neck cancers who underwent molecular profiling of blood samples utilizing Guardant360, a 70-gene circulating tumor DNA (ctDNA) NGS platform. CtDNA sequencing data was compared to tumor NGS data, when available. Best response to therapy was assessed using RECIST measures.

Results: 60 HNSCC patients were evaluated from February 2015 to June 2016. The most common tumor type and histology was oropharyngeal squamous cell carcinoma (n=21), which was commonly human papillomavirus (HPV) positive (n=15). Other cancer types included salivary gland and thyroid cancers. The most common mutations identified by ctDNA analysis were TP53 (98%), PIK3CA (43%), NOTCH1 (38%), and ARID1A (36%). These findings were consistent with results from tumor sequencing data (n=29) where TP53 (48%) and PIK3CA (24%) were also reported with the highest frequency. Importantly, 73% (n=22) of patients had alterations identified in ctDNA that were not present in tumor specimens. Actionable mutations were identified in 66% of HNSCC and in 50% salivary gland cancer patients. Of patients with actionable mutations, 10% (n=6) received matched targeted therapy (MTT): 3 (50%) had stable disease (SD), 1 had progressive disease (PD), and 2 were not evaluated. Of those who did not receive targeted therapy (n=23), 1 (4.3%) patient had a complete response treated with immunotherapy, 11 (47%) had SD, and 11 (47%) had PD.

Conclusions: Analysis of ctDNA may play a role in management decisions in R/M HNSCC. The majority of patients had unique mutations identified on ctDNA. The utility of ctDNA NGS and its role in patient management should be explored in future studies.

Citation Format: Ashleigh Porter, Gregory A. Daniels, Sandip Pravin Patel, Assuntina Sacco, Kimberly C. Banks, Ezra E. W. Cohen. Next generation sequencing of cell free circulating tumor DNA in blood samples of recurrent and metastatic head and neck cancer patients [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 13.
Abstract 15: Utility of chemoradioselection for the optimization of treatment intensity in advanced hypopharyngeal and laryngeal carcinoma
Authors: Masuda Muneyuki , Toh Satoshi , Rikimaru Hidefumi , Kunitake Naonobu , Higaki Yuichiro
Published: December 2017

Background: Definitive concomitant chemoradiotherapy (CRT) with high-dose cis-platinum (CDDP) is a current standard protocol for advanced laryngeal and hypopharyngeal cancer sparing surgery for salvage. However, this modality is associated with limited feasibility and frequent sever toxicities. We have developed a “chemoradioselection” protocol with minimal toxicity using initial response to CRT as a biomarker for patient selection.

Materials and Methods: From 2000 to 2012, 123 patients with stage III (44), IV (79) laryngeal (64) and hypopharyngeal carcinoma (59) excluding T4 cases were enrolled to this protocol. Two cycles of split (15 mg/m2 x 5 days, 2000-2008) or bolus (80 mg/m2, 2009-present) CDDP was concurrently administered.

Results: Tumor responses were evaluated after 40 Gy of CRT and 64 responders (i.e., chemoradioselected, CRS) received further CRT up to 70 Gy, while radical surgery was recommended for the 59 non-responders (N-CRS), and 34 underwent surgery (N-CRS-ope). The remaining 25 patients who refused surgery (N-CRS-refu) were treated with continuous CRT. The 5-yr overall survival (OS) and disease-specific survival (DSS) were 67% and 77%, respectively. The CRS demonstrated quite favorable 5-yr OS (73%) and 5-yr laryngo-esophageal dysfunction-free survival (LEDFS, 69%). In contrast, the N-CRS-refu showed significantly (P = 0.0193) lower 5-yr OS (47%) than CRS (73%) and N-CRS-ope (70%), and significantly (P < 0.0001) lower 5-yr LEDFS (20%) than the CRS (69%). On multivariate analyses including T, N, primary site, and planned treatment (CRS + N-CRS-ope) or not (N-CRS-refu), unplanned treatment alone showed a significant correlation with poor OS (Hazard ratio [HR]: 2.584, 95% CI: 1.313–4.354, P = 0.007).

Conclusions: Chemoradioselection reflects the biological aggressiveness of each tumor, and can segregate patients for functional laryngeal preservation with moderate intensity CRT (150-160 mg/m2 of CDDP) from those who would be better treated with surgery. This strategy may be useful for the optimization of the therapeutic intensity.

Citation Format: Muneyuki Masuda, Satoshi Toh, Hidefumi Rikimaru, Naonobu Kunitake, Yuichiro Higaki. Utility of chemoradioselection for the optimization of treatment intensity in advanced hypopharyngeal and laryngeal carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 15.
Abstract 61: Overcoming acquired resistance to PI3K inhibitors in head and neck squamous cell carcinoma with combination treatment
Authors: Mizrachi Aviram , Dunn Lara , Ho Alan , Scaltriti Maurizio
Published: December 2017

Purpose: Activating mutations in PIK3CA, the gene coding for the catalytic subunit of phosphoinositide-3-kinase (PI3K), are prevalent in both HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC). These mutations are therapeutic targets and selection for PIK3CA mutations leads to superior activity of PI3K inhibitors. However, early clinical trials have been disappointing, mainly because the durability of activity of these drugs is limited. Recent preclinical data suggest that acquired resistance to PI3K inhibition is a result of activation of alternative pathways such as mTORC1 and the Cyclin D1 complex.

Experimental Design: We challenged two different mechanisms by which PIK3CA-mutated tumors develop resistance to PI3K inhibitors by combining PI3K inhibitors with either mTORC1 inhibitor or CDK 4/6 inhibitor. Using patient-derived xenograft models of HNSCC, we tested whether these therapeutic strategies can overcome drug resistance and result in durable response.

Results: Administration of the PI3K inhibitor BYL719 together with the mTORC inhibitor RAD001 delayed tumor growth in comparison with either of these drugs alone. Similarly, treatment with another PI3K inhibitor GDC-0032 and the CDK4/6 inhibitor abemaciclib was superior to single-agent treatments.

Conclusions: Co-suppression of PI3K and either mTORC1 or CDK4/6 is effective in preclinical models of HNSCC. These results may provide the rationale to test these therapeutic strategies in the clinic.

Citation Format: Aviram Mizrachi, Lara Dunn, Alan Ho, Maurizio Scaltriti. Overcoming acquired resistance to PI3K inhibitors in head and neck squamous cell carcinoma with combination treatment [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 61.
Abstract 62: Loss of PERP p53/p63 target gene may indicate tumorigenesis at the margin and local recurrence
Authors: Simmons Amanda , Kong Christina , Eyben Rie von , Attardi Laura , Ma Xiaohui , Le Quynh-Thu , Nathan Cherie-Ann
Published: December 2017

Objectives: PERP (p53 apoptosis effector related to PMP22) localizes to the desmosomal adhesion complexes and is involved in suppressing squamous cell carcinoma (SCC) development. Loss of PERP expression leads to destabilization of desmosome complexes, resulting in enhanced tumor aggressiveness and worse local control in head and neck SCC (HNSCC). We had previously examined PERP loss at surgical margins in a small cohort of HNSCC patients. Results suggested that the loss of PERP may serve as a marker for persistent tumor and predictive of local relapse. Here we validate these findings in an independent patient cohort and report on the combined results of both groups.

Materials and Methods: We previously examined the PERP protein expression by immunohistochemistry (IHC) in the surgical mucosal margins of 17 HNSCC patients. The validation cohort consists of 31 patients (15 oral cavity, 11 hypopharynx, 5 larynx). PERP expression was similarly assessed by IHC in the surgical margins of these patients. Finally, we combined the results of both groups to yield 48 patients with HNSCC (18 oral cavity, 12 hypopharynx, 4 oral pharynx, 14 larynx) for competing risk analysis. The relationship between local relapse and PERP expression (positive or negative) was analyzed in a competing risk model with death as a competing risk.

Results: In the initial cohort, the 2-year cumulative incidence rate of local relapse was 37.5% for the negative PERP group compared to a 20% for the positive PERP group (p = 0.177). In the validation cohort, the 2-year cumulative incidence rate of local relapse was 50% for the negative PERP group compared to a 15% for the positive PERP group (p = 0.063). Since the results were similar between two groups, we combined them together for additional analyses. In this combined dataset, PERP expression was negative in 18, positive in 26, and not assessable in three patients. Of the 45 analyzable patients, the 2-year cumulative incidence rate of local relapse was 44.4% for the negative PERP group compared to a 16.4% for the positive PERP group (p = 0.010). There was also a trend for worse progression-free survival (p = 0.059) and overall survival (p = 0.085) with the loss of PERP.

Conclusions: PERP loss at the surgical margins appears to be associated with a higher risk of local recurrence in HNSCC. These promising results need to be tested in a larger prospective study.

Citation Format: Amanda Simmons, Christina Kong, Rie von Eyben, Laura Attardi, Xiaohui Ma, Quynh-Thu Le, Cherie-Ann Nathan. Loss of PERP p53/p63 target gene may indicate tumorigenesis at the margin and local recurrence [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 62.