Identification Of Genetic Drivers Research Articles

Emerging noncoding RNAs contained in extracellular vesicles: rising stars as biomarkers in lung cancer liquid biopsy.

Lung cancer has a high morbidity and mortality rate, and affected patients have a poor prognosis and low survival. The therapeutic approaches for lung cancer treatment, including surgery, radiotherapy, and chemotherapy, are not completely effective, due to late diagnosis. Although the identification of genetic drivers has contributed to the improvement of lung cancer clinical management, the discovery of new diagnostic and prognostic tools remains a critical issue. Liquid biopsy (LB) represents a minimally invasive approach and practical alternative source to investigate tumor-derived alterations and to facilitate the selection of targeted therapies. LB allows for the testing of different analytes such as circulating tumor cells, extracellular vesicles (EVs), tumor-educated platelets, and cell-free nucleic acids including DNAs, RNAs, and noncoding RNAs (ncRNAs). Several regulatory factors control the key cellular oncogenic pathways involved in cancers. ncRNAs have a wide range of regulatory effects in lung cancers. This review focuses on emerging regulatory ncRNAs, freely circulating in body fluids or shuttled by EVs, such as circular-RNAs, small nucleolar-RNAs, small nuclear-RNAs, and piwi-RNAs, as new biomarkers for early detection, prognosis, and monitoring of therapeutic strategy of lung cancer treatment.

Abstract 3119: Identification of genetic drivers in HER2enriched/HER2negative breast cancer

Abstract Background: The non-basal triple negative breast cancer (Non Basal-TNBC) tumors, also called the luminal androgen receptor (LAR) subtype, make up ~20% of all new TNBC cases and is limited to multi-agent chemotherapy. TNBC is considered one of the leading causes of cancer-associated mortality amongst women in the USA with a high number of patients dying of metastatic disease. Some metastases that arise from luminal primary tumors lose their luminal features and become a HER2-enriched (HER2E) subtype, but remain clinically HER2 negative (HER2E/HER2-). The molecular features that drive these HER2E/HER2- tumors may also represent key checkpoints of metastatic progression. Within this HER2E/HER2- subtype, besides the androgen receptor (AR), FGFR4 has been shown to be expressed, but its functional role remains unknown. FGFR4 is a tyrosine kinase receptor involved in proliferation, survival and migration during embryonic development and cancer. We hypothesize that in addition to AR, that FGFR4 may be a driver of HER2E/HER2- tumors and that the therapeutic targeting of this gene/protein might improve patient outcomes. Objective: Our objective is to identify the mechanism of action of FGFR4 in HER2E/HER2- tumors as well as additional genetic drivers of HER2E TNBC subtype. Methods: We performed computational analysis of databases (TCGA, METABRIC) and the analysis of matched breast cancer primary tumors and metastases to detect genetic drivers. We ran microarrays on two FGFR4 stably transfected luminal HER2-/ER+ cell lines (MCF7 and T47D) and also treated a Luminal B cell line (MDA-MB-453; HER2high/AR+/ER-) and HER2E cell line (CAMA-1; HER2low/ARmed/ER+/low) with a FGFR4 inhibitor using a time course strategy. Results: Through the analysis of microarrays using all 4 cell lines, we identified a gene expression signature of FGFR4-activity enriched in genes involved in proliferation, cell junctions and cell differentiation. The FGFR4-associated signature of upregulated genes was enriched in HER2E and Basal-like subtypes and the downregulated genes enriched in the Luminal subtypes. To identify predictors of chemotherapy response, we evaluated FGFR4-associated gene signatures in the diagnostic (pre-treatment) samples of MDACC neoadjuvant dataset of 500 tumors. The high expression of the FGFR4- induced gene signature predicted pathological complete response (T.test P <0.001). Conclusions: FGFR4 may play an important role in the progression of Luminal disease and has been identified as a new genetic driver of HER2E/HER2- subtype making it an attractive option as a therapeutic target. We are further testing these genetic predictions using Patient Derived Xenograft (PDX) mouse models. Citation Format: Susana Garcia Recio, Cheng Fan, Marni Siegel, Joel S. Parker, Gina N. Duronio, Aleix Prat, Charles M. Perou. Identification of genetic drivers in HER2enriched/HER2negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3119. doi:10.1158/1538-7445.AM2017-3119

Medulloblastoma: Tumor Biology and Relevance to Treatment and Prognosis Paradigm.

Medulloblastoma is a malignant embryonic brain tumor arising in the posterior fossa and typically occurring in pediatric patients. Current multimodal treatment regimes have significantly improved the survival rates; however, a marked heterogeneity in therapy response is observed, and one third of all patients die within 5 years after diagnosis. Large-scale genetic and transcriptome analysis revealed four medulloblastoma subgroups (WNT, SHH, Group 3, and Group 4) associated with different demographic parameters, tumor manifestation, and clinical behavior. Future treatment protocols will integrate molecular classification schemes to evaluate subgroup-specific intensification or de-escalation of adjuvant therapies aimed to increase tumor control and reduce iatrogenic induced morbidity. Furthermore, the identification of genetic drivers allows assessing target therapies in order to increase the chemotherapeutic armamentarium. This review highlights the biology behind the current classification system and elucidates relevant aspects of the disease influencing forthcoming clinical trials.

Abstract 2623: PI3K/mTOR dual inhibitor PF-5212384 inhibits aberrant NF-kB activation and exhibits activity in combination with MEK inhibitor PD-325901 and docetaxel in human head and neck squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, and standard treatment with surgery or chemoradiation has significant morbidity, with 5 year survival of <50%. Personalized targeted therapies with small molecule inhibitors have gained interest following identification of genetic drivers from The Cancer Genome Atlas (TCGA). TCGA data shows >60% of head and neck tumors harbor genomic alterations in the RTK-PI3K-mTOR and MAPK pathways important in cell growth and survival. In this study, we determined the effects of the novel PI3K-mTOR inhibitor PF-5212384 (PF-384) on molecular targets and HNSCC growth in preclinical models. PF-384 IC50s of 0.75nM-133nM were found in 12 HNSCC lines by XTT cell density assays and treatment resulted in increased sub-G0 cell death and G0/G1 phase blockade by DNA flow cytometry. PF-384 strongly inhibited direct targets of PI3K-mTOR, aberrant NF-kB transactivation and induced cytokines, but only partially inhibited MEK pathway targets. Transient siRNA knockdown of PIK3CA inhibited NF-kB activity, supporting PI3K-mTOR as an important driver and target for inhibition of NF-kB prosurvival signaling in HNSCC. PF-384 partially inhibited UMSCC1 tumor xenografts in vivo. PF-384 with MEK inhibitor PD-325901 or docetaxel revealed combinatorial activity. Given the high proportion of HNSCC patients with aberrations in the PI3K pathway and combinatorial activity observed, PF-384 with PD-901 or docetaxel merit further investigation in HNSCC. Supported by NIH Medical Research Scholars Program (SM, RVB, DFE) and NIDCD intramural projects ZIA-DC-000016, 73 and 74 (AS, JC, ZC, CVW). Citation Format: Suresh Mohan, Robert J. Vander Broek, Anthony D. Saleh, Matthew L. Pierce, Jamie F. Coupar, Danielle F. Eytan, Zhong Chen, Carter Van Waes. PI3K/mTOR dual inhibitor PF-5212384 inhibits aberrant NF-kB activation and exhibits activity in combination with MEK inhibitor PD-325901 and docetaxel in human head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2623. doi:10.1158/1538-7445.AM2014-2623

Abstract 2282: Rapid identification of targetable CSF3R mutations that define neutrophilic leukemia by combining functional and genomic screens.

Abstract Large scale sequencing efforts are currently being applied to numerous cancers and although significant numbers of mutations are being identified, functional validation to identify driver mutations is lagging. To accelerate progress in the identification of genetic drivers in hematological malignances, we are taking an integrated approach of deep sequencing coupled with functional screens using molecularly targeted drugs and siRNA screening of primary patient leukemia samples. The functional screens allow prioritization of mutations for validation. Using this approach, we identified a CSF3R mutation in a patient with chronic neutrophilic leukemia (CNL). Patients with CNL and the related disorder, atypical chronic myeloid leukemia (aCML), have neoplastic expansion of granulocytic cells with the diagnosis including exclusion of genetic drivers known to occur in other types of World Health Organization-defined myeloproliferative neoplasms (MPN) or myelodysplastic syndrome/MPN overlap disorders. After identifying a CSF3R mutation in our index case, we examined 21 additional cases of CNL and aCML and found that 59% of patients with CNL/aCML harbor CSF3R mutations. Two distinct regions of mutations within the CSF3R gene were identified. Expression of these classes of mutations in a growth factor-dependent myeloid cell line, BaF3, transformed these cells to growth factor independence. Interestingly, these two mutational classes produce preferential downstream kinase signaling (via TNK2/SRC or JAK kinases) and differential sensitivity to kinase inhibitors. Specifically, mutants signaling through TNK2/SRC are sensitive to SRC inhibitors such as dasatinib while mutants signaling thought JAK kinases were sensitive to JAK inhibitors such as ruxolitinib. One patient with CNL carrying a CSF3R mutation that signals through JAK kinases showed a dramatic and durable clinical improvement after treatment with the JAK1/2 kinase inhibitor, ruxolitinib. Mutations in the CSF3R define a large subset of patients with CNL/aCML and testing for these mutations will complement histopathologic diagnosis of CNL and aCML. Patients with CSF3R mutations may benefit from clinical administration of TNK2/SRC inhibitors (such as dasatinib) or JAK inhibitors (such as ruxolitinib). Our studies demonstrate that combining functional screens with genome sequencing can significantly accelerate target validation to define driving mutations that can be matched with therapies. Citation Format: Julia Maxson, Jason Gotlib, Daniel Pollyea, Angela Fleischman, Christopher Eide, Daniel Bottomly, Beth Wilmot, Shannon McWeeney, Cristina Tognon, J. Blake Pond, Robert Collins, Michael Deininger, Bill Chang, Marc Loriaux, Brian Druker, Jeffrey Tyner. Rapid identification of targetable CSF3R mutations that define neutrophilic leukemia by combining functional and genomic screens. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2282. doi:10.1158/1538-7445.AM2013-2282