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  • 1
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    Online Resource
    Inhibiting Translation Elongation with SVC112 Suppresses Cancer Stem Cells and Inhibits Growth in Head and Neck Squamous Carcinoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 5 ( 2020-03-01), p. 1183-1198
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 5 ( 2020-03-01), p. 1183-1198
    Abstract: Cancer stem cells (CSC) drive growth, therapy resistance, and recurrence in head and neck squamous cell carcinoma (HNSCC). Regulation of protein translation is crucial for normal stem cells and CSCs; its inhibition could disrupt stemness properties, but translation inhibitors are limited clinically due to toxicity. SVC112 is a synthetic derivative of bouvardin, a plant-derived translation elongation inhibitor. SVC112 had greater antiproliferative effects on HNSCC cells compared with the FDA-approved translation inhibitor omacetaxine mepesuccinate (HHT). SVC112 preferentially inhibited cancer cells compared with patient-matched cancer-associated fibroblasts, whereas HHT was equally toxic to both. SVC112 reduced sphere formation by cell lines and CSCs. SVC112 alone inhibited the growth of patient-derived xenografts (PDX), and SVC112 combined with radiation resulted in tumor regression in HPV-positive and HPV-negative HNSCC PDXs. Notably, CSC depletion after SVC112 correlated with tumor response. SVC112 preferentially impeded ribosomal processing of mRNAs critical for stress response and decreased CSC-related proteins including Myc and Sox2. SVC112 increased cell-cycle progression delay and slowed DNA repair following radiation, enhancing colony and sphere formation radiation effects. In summary, these data demonstrate that SVC112 suppresses CSC-related proteins, enhances the effects of radiation, and blocks growth of HNSCC PDXs by inhibiting CSCs. Significance: Inhibiting protein elongation with SVC112 reduces tumor growth in head and neck squamous cell carcinoma and increases the effects of radiation by targeting the cancer stem cell pool.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-3232
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
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    Abstract 5050: Biomarkers for sensitivity to gamma secretase inhibitors in mouse models of pancreatic adenocarcinoma
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5050-5050
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5050-5050
    Abstract: Background: The Notch pathway is important in carcinogenesis and maintenance of pancreatic adenocarcinoma through its effects on cancer stem cells, cell differentiation and neoangiogenesis. RO4929097 is a novel oral inhibitor of the Notch pathway through its effects on γ-secretase, a key enzyme in this pathway. Several clinical trials are currently in progress with RO4929097 including a CTEP sponsored phase II trial in gemcitabine resistant metastatic pancreas cancer by our group. However, there are no biomarkers of sensitivity available currently for therapy with RO4929097 or other γ-secretase inhibitors (GSIs). Methods: We intend to treat 12 human pancreas cancer cell line mouse xenografts and 6 human primary pancreas tumor explants with RO4929097 (alone or in combination with gemcitabine) to identify sensitive (defined as tumors with ≥ 50% relative tumor growth inhibition with treatment) and resistant tumors. Subsequently, we propose to identify differences in gene expression by RT-PCR (Notch pathway), gene array or gene copy number by FISH between the resistant and sensitive tumors as potential biomarkers. Results: Of the eight pancreas cell line xenografts treated so far, four are sensitive to RO4929097. Comparison between sensitive and resistant tumors by gene array suggests that the sensitive cell lines exhibit higher levels of mesenchymal markers. In addition, two of the four human primary pancreatic explants treated thus far show intermediate sensitivity. RO4929097 in combination with gemcitabine in the four explants reveals a significant decrease in tumor growth inhibition for the combination compared to RO4929097 alone but the additive effect appears to be entirely due to gemcitabine. Similar effects were observed on tumor regrowth, upon observation after an initial period of treatment with either agents alone or in combination. In addition, future experiments to identify stem cell and/or angiogenesis specific biomarkers are also planned. Updated results will be presented at the meeting. Acknowledgements: This work was supported by Roche Pharmaceuticals Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5050. doi:10.1158/1538-7445.AM2011-5050
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5050
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 3
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    Homeoprotein Six2 Promotes Breast Cancer Metastasis via Transcriptional and Epigenetic Control of E-Cadherin Expression
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 24 ( 2014-12-15), p. 7357-7370
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 24 ( 2014-12-15), p. 7357-7370
    Abstract: Misexpression of developmental transcription factors occurs often in human cancers, where embryonic programs may be reinstated in a context that promotes or sustains malignant development. In this study, we report the involvement of the kidney development transcription factor Six2 in the metastatic progression of human breast cancer. We found that Six2 promoted breast cancer metastasis by a novel mechanism involving both transcriptional and epigenetic regulation of E-cadherin. Downregulation of E-cadherin by Six2 was necessary for its ability to increase soft agar growth and in vivo metastasis in an immunocompetent mouse model of breast cancer. Mechanistic investigations showed that Six2 represses E-cadherin expression by upregulating Zeb2, in part, through a microRNA-mediated mechanism and by stimulating promoter methylation of the E-cadherin gene (Cdh1). Clinically, SIX2 expression correlated inversely with CDH1 expression in human breast cancer specimens, corroborating the disease relevance of their interaction. Our findings establish Six2 as a regulator of metastasis in human breast cancers and demonstrate an epigenetic function for SIX family transcription factors in metastatic progression through the regulation of E-cadherin. Cancer Res; 74(24); 7357–70. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-0666
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
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    Kinome RNAi Screens Reveal Synergistic Targeting of MTOR and FGFR1 Pathways for Treatment of Lung Cancer and HNSCC
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 20 ( 2015-10-15), p. 4398-4406
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 20 ( 2015-10-15), p. 4398-4406
    Abstract: The FGFR1 is a therapeutic target under investigation in multiple solid tumors and clinical trials of selective tyrosine kinase inhibitors (TKI) are underway. Treatment with a single TKI represents a logical step toward personalized cancer therapy, but intrinsic and acquired resistance mechanisms limit their long-term benefit. In this study, we deployed RNAi-based functional genomic screens to identify protein kinases controlling the intrinsic sensitivity of FGFR1-dependent lung cancer and head and neck squamous cell cancer (HNSCC) cells to ponatinib, a multikinase FGFR-active inhibitor. We identified and validated a synthetic lethal interaction between MTOR and ponatinib in non–small cell lung carcinoma cells. In addition, treatment with MTOR-targeting shRNAs and pharmacologic inhibitors revealed that MTOR is an essential protein kinase in other FGFR1-expressing cancer cells. The combination of FGFR inhibitors and MTOR or AKT inhibitors resulted in synergistic growth suppression in vitro. Notably, tumor xenografts generated from FGFR1-dependent lung cancer cells exhibited only modest sensitivity to monotherapy with the FGFR-specific TKI, AZD4547, but when combined with the MTOR inhibitor, AZD2014, significantly attenuated tumor growth and prolonged survival. Our findings support the existence of a signaling network wherein FGFR1-driven ERK and activated MTOR/AKT represent distinct arms required to induce full transformation. Furthermore, they suggest that clinical efficacy of treatments for FGFR1-driven lung cancers and HNSCC may be achieved by combining MTOR inhibitors and FGFR-specific TKIs. Cancer Res; 75(20); 4398–406. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-0509
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Tankyrase and the Canonical Wnt Pathway Protect Lung Cancer Cells from EGFR Inhibition
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 16 ( 2012-08-15), p. 4154-4164
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 16 ( 2012-08-15), p. 4154-4164
    Abstract: Lung cancer is the leading cause of death worldwide. Adenocarcinomas, the most common histologic subtype of non-small cell lung cancer (NSCLC), are frequently associated with activating mutations in the epidermal growth factor receptor (EGFR) gene. Although these patients often respond clinically to the EGFR tyrosine kinase inhibitors erlotinib and gefitinib, relapse inevitably occurs, suggesting the development of escape mechanisms that promote cell survival. Using a loss-of-function, whole genome short hairpin RNA (shRNA) screen, we identified that the canonical Wnt pathway contributes to the maintenance of NSCLC cells during EGFR inhibition, particularly the poly-ADP-ribosylating enzymes tankyrase 1 and 2 that positively regulate canonical Wnt signaling. Inhibition of tankyrase and various other components of the Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo. Our findings therefore reveal a critical role for tankyrase and the canonical Wnt pathway in maintaining lung cancer cells during EGFR inhibition. Targeting the Wnt-tankyrase-β-catenin pathway together with EGFR inhibition may improve clinical outcome in patients with NSCLC. Cancer Res; 72(16); 4154–64. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-11-2848
    RVK:
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    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 6
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    Abstract 2705: Novel functions of the homeoprotein SIX2 in mediating anchorage independence and metastasis in breast cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2705-2705
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2705-2705
    Abstract: Homeobox genes encode for transcription factors that are master regulators of embryogenesis, and their misexpression has been implicated in multiple cancers. The role of the homeoprotein Six2 in developing kidney has been well demonstrated; however, its role in cancer progression is largely unknown. Here, we demonstrate, for the first time, that Six2 is causally involved in mammary tumor progression. When Six2 is knocked down (KD) in the 66cl4 mammary carcinoma cells, lung metastasis is significantly decreased compared to control KD; however, Six2 KD conferred no significant effect on growth of the primary tumor or on tumor-associated angiogenesis/lymphangiogenesis, in contrast to its closely related family member, Six1, which has been implicated in all the aforementioned properties; suggesting that Six2 may participate in later stages of the metastatic cascade. Expression of Six2 in the 4TO7 mammary carcinoma cell line (a cell line that is syngeneic with 66cl4, but expresses very low levels of endogenous Six2) led to changes in cell morphology, increased growth in soft agar, increased resistance to anoikis, and significantly enhanced lung metastasis in Balb/c mice. To determine the mechanism by which Six2 mediates metastasis, microarray analysis was performed on 4TO7-control and Six2 expressing cells. Interestingly, genes which have been implicated in lung metastasis (MMP, ANGPTL4, VCAM1) are significantly up-regulated in Six2 overexpressing 4TO7 cells; while the epithelial marker, E-Cadherin, is dramatically decreased. Finally, analysis of SIX2 expression from public microarray datasets indicates that SIX2 is increased in breast cancers compared to normal breast tissue. In addition, high expression of SIX2 correlates with poor prognosis (distant metastasis free survival, overall survival and relapse free survival) in 1881 human breast tumors examined using the GOBO (Gene Expression-Based Outcome for Breast Cancer Online) database, and upon further investigation we found that SIX2 expression is particularly associated with poor prognosis in luminal A, normal-like and ER-positive breast tumors. Together, our studies define a novel role of Six2 in breast cancer metastasis. Citation Format: Chu-An Wang, Paul Jedlicka, Vadym Zaberezhnyy, Aik-Choon Tan, Heide Ford. Novel functions of the homeoprotein SIX2 in mediating anchorage independence and metastasis in breast cancer. [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 2705. doi:10.1158/1538-7445.AM2013-2705
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2705
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 7
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    TWIST1-Induced miR-424 Reversibly Drives Mesenchymal Programming while Inhibiting Tumor Initiation
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9 ( 2015-05-01), p. 1908-1921
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9 ( 2015-05-01), p. 1908-1921
    Abstract: Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT–MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK–ERK signaling is critical for miR-424–mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT–MET axis. Cancer Res; 75(9); 1908–21. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-2394
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 8
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    Abstract 4550: Correlations between tumor mutation burden, inflammatory profile and histological characteristics of tumor microenvironment in early-stage squamous cell lung carcinoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4550-4550
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4550-4550
    Abstract: Background: Anti-PD1/PD-L1 immunotherapy has demonstrated success in the treatment of advanced non-small cell lung cancer (NSCLC). Clinical data have shown that both the expression of PD-L1 in patient tumors and high tumor mutation burden (TMB) predicts the likelihood of a positive response to anti-PD-1/PD-L1 immunotherapy. Also, tumor microenvironment (TME) is the constitutive element in cancer immunity, in which analysis of characteristics reflects the potential existing immune reaction. Method: Histologic sections from 150 squamous cell lung carcinoma (SqCLC) were evaluated by two pathologists independently for percentage and character of intratumoral inflammatory cells and percentage and character of para-tumoral infiltrate. The ratios of infiltrating inflammatory cells to tumor cells were estimated in 10% increments by microscopic inspection. The proportions of immune cell populations were deconvulated using the CIBERSORT method based on Affymetrix gene expression profiles. PD-L1 protein expression by IHC was evaluated using the Dako PD-L1 22C3 pharmDx kit and scoring was determined according to the Dako tumor proportion score (TPS). Tumor Mutation Burden (TMB) was calculated based on data from targeted genome sequencing. CD4 and CD8 mRNA levels were determined from Affymetrix gene expression data from frozen specimens. Results: The infiltrates could be divided into intratumoral and paratumoral patterns according to their location in relation to microscopic tumor cell nests. Using the CIBERSORT assay, we confirmed our histological findings by microscopic examination that the SqCLC cohort can be subtyped into plasma cell dominant (74.8%) or other immune infiltrates dominant (such as macrophages), based on the proportions of immune cell populations. We found by regression analysis that TMB had a negative correlation with the percentage of intratumoral inflammatory cells (P=0.014), but did not significantly correlate with paratumoral infiltrates. The TMB demonstrated a significant negative correlation with CD4 mRNA level (P=0.017), but not with CD8 mRNA level. No correlation was determined for TMB and the immune cells dominant subgroup. Interestingly, we didn’t find any association for PD-L1 protein expression with the percentage of intra- or para-tumoral infiltrates, plasma cells dominant group and CD4 and CD8 mRNA levels. Conclusions: TMB was negatively correlated with the percentage of intratumoral inflammatory cells and CD4 mRNA level, which indicate that high TMB may promote an immune suppression environment. In addition, we did not find any association of PD-L1 expression with characteristics of TME in this early-stage SqCLC cohort. Further studies are needed to verify these interesting results. Citation Format: Hui Yu, Daniel T. Merrick, Ming-Sound Tsao, William G. Richards, Lucian R. Chirieac, Mark A. Watson, Christopher J. Rivard, David H. Harpole, Raphael Bueno, Adrie van Bokhoven, Aik-Choon Tan, Fred R. Hirsch, Wilbur A. Franklin. Correlations between tumor mutation burden, inflammatory profile and histological characteristics of tumor microenvironment in early-stage squamous cell lung carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4550.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4550
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
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    Abstract 5594: ALK-driven lung cancer: Potential therapeutic strategies for treatment and prevention of drug resistance
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5594-5594
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 5594-5594
    Abstract: The identification of oncogenic molecular drivers in non-small cell lung cancer (NSCLC) has allowed biologically targeted therapies to improve clinical outcomes in the treatment of NSCLC. ALK gene rearrangements are observed in a sub-set of NSCLC patients who demonstrate high response rates to treatment with the oral kinase inhibitor, crizotinib. Unfortunately, disease progression is inevitable, either through intrinsic or acquired resistance. A recently completed series of crizotinib-resistant, ALK+ NSCLC patients by our group demonstrates two broad categories of resistance: (1) continued reliance on ALK signaling (via secondary mutations in the ALK kinase domain or ALK gene fusion copy number gain) or (2) loss of reliance on ALK signaling (e.g. via reliance on alternate oncogene signaling). Here we investigate potential therapeutic strategies when ALK signaling is retained. In an effort to minimize drug resistance to crizotinib in ALK+ NSCLC, we performed a genome-wide shRNA synthetic lethal screen to identify genes whose depletion synergizes with crizotinib in ALK+ NSCLC lines. We identified several genes involved in nucleotide synthesis and DNA metabolism, including dihydrofolate reductase (DHFR) and the trifunctional enzyme encoded by GART, which are substrates for inhibition with pemetrexed. Indeed, ALK+ NSCLC cell lines show increased sensitivity to pemetrexed in vitro. Identification of this cellular process as critical for ALK+ NSCLC is also consistent with clinical data demonstrating that patients with ALK+ NSCLC exhibit an increased clinical benefit on pemetrexed compared to other molecular subgroups of NSCLC. We also identified genes involved in chaperone function in our synthetic lethal screen. As such, we investigated whether proper folding and prevention of degradation was essential for continued reliance on ALK signaling. Both non-mutated EML4-ALK wild-type and EML4-ALK containing kinase domain mutations (including a novel mutation, G1269A) are sensitive to HSP inhibition with 17AAG. By identifying critical cellular processes in ALK+ lung cancer and employing therapies that target these pathways, improved treatment strategies can be derived to treat and prevent resistance in this molecular subtype of NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5594. doi:1538-7445.AM2012-5594
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2012-5594
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 10
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    Abstract PO-023: Spatial genomics coupled with machine learning to identify p53-driven molecular signatures that are predictive of lung adenocarcinoma progression
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 21_Supplement ( 2020-11-01), p. PO-023-PO-023
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 21_Supplement ( 2020-11-01), p. PO-023-PO-023
    Abstract: P53 is frequently mutated in a wide variety of tumors; yet, the regulation and expression of downstream targets during tumor progression and response to therapy is unknown. Here, we use Kras/p53-driven lung adenocarcinoma in the mouse as a model system to identify p53-driven molecular signatures that predict lung adenocarcinoma progression. Using these tumors, we have developed a digital pathology tool using machine learning to grade lung adenocarcinomas. To do this, we analyzed hematoxylin and eosin (H & E) from mouse models of lung adenocarcinoma with Kras (KrasG12D/+) and in combination with p53 mutations (KrasG12D/+; p53R172H/+ and KrasG12D/+; p53R270H/+) and loss of TAp73 (KrasG12D/+; TAp73Δtd/Δtd). After grading, slides were divided into approximately 100,000 patches with dimensions of 224 × 224 pixels (113 × 113 µm). A convolutional neural network (CNN) model based on ResNet18 was trained to classify normal lung tissue, normal airways, and the different grades (1–4) of lung adenocarcinoma using 16,000 patches of each class. The resulting classification maps were used for analyses of tumor burden and progression. Adjacent tissue sections used for immunohistochemistry were co-registered to mapped H & E sections to investigate correlation between protein expression and tumor grade. Our CNN demonstrated a strong correspondence with human pathologists on our holdout dataset (81% agreement). Because our CNN can assign different grades to different regions within an image patch, we also uncovered a high degree of intratumor heterogeneity that was missed by human pathologists who assigned grades to entire tumors in a homogeneous manner. Both the pathologists and the CNN reported a significant increase in the tumor burden of compound mutant mice (KrasG12D/+; p53R172H/+, KrasG12D/+; p53R270H/+, and KrasG12D/+; TAp73Δtd/Δtd) compared to KrasG12D/+ mice. In addition, compound mutant mice were noted to have a greater proportion of high-grade (3-4) tumors by both approaches. In conclusion, our CNN demonstrates a high degree of agreement with human pathologists. Furthermore, this computational approach drastically increases the resolution of tumor grading in our mouse models and can detect regions of different grades within a single tumor. We are currently using single cell transcriptome analysis to define p53-molecular signatures that predict lung adenocarcinoma progression and grade. Future work will expand this tool into a multidimensional digital pathology pipeline that can accelerate current investigations and reveal new therapeutic targets and prognostic markers. Citation Format: John H. Lockhart, Kyubum Lee, Hayley D. Ackerman, Mahmoud Abdulah, Andrew Davis, Nicole Montey, Theresa Boyle, James Saller, Aysenur Keske, Kay Hanggi, Olya Stringfield, Aik Choon Tan, Elsa R. Flores. Spatial genomics coupled with machine learning to identify p53-driven molecular signatures that are predictive of lung adenocarcinoma progression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-023.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMHET2020-PO-023
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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