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  • American Association for Cancer Research (AACR)  (15)
  • 1
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    Abstract 143: Preclinical studies on potential therapeutic combination partners for the potent and selective PI3Kδ inhibitor INCB050465 in DLBCL
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 143-143
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 143-143
    Abstract: The delta isoform of PI3K (PI3Kδ) plays an essential role in B-cell development and function by mediating the signaling of key receptors on B cells. Increased malignant B cell proliferation and survival has also been associated with aberrant activation of PI3Kδ, making selective inhibition of this isoform an attractive therapeutic approach for the treatment of B cell malignancies. INCB050465 is a potent inhibitor of PI3Kδ, with a & gt;20,000 fold selectivity over other PI3K isoforms. Emerging clinical data indicate that INCB050465 monotherapy is well tolerated and results in promising clinical responses in patients with various lymphoma histologies, including those with DLBCL. We therefore sought to explore rational combination strategies for INCB050465 using mouse xenograft models of ABC-subtype (HBL-1), GCB-subtype (Pfeiffer), and GCB/double-hit (WILL-2) human DLBCL, evaluating standard of care agents such as bendamustine and rituximab, as well as with targeted agents. PIM inhibition is a logical addition to PI3Kδ inhibition as a therapeutic approach as both kinases play a critical role in the AKT signaling pathway, having overlapping substrates. Likewise BET inhibition is a rational addition to PI3Kδ inhibition in “double-hit” DLBCL due to de-regulation of MYC transcriptional activity. In vivo studies performed in the Pfeiffer xenograft model demonstrate that INCB050465 combined with the pan-PIM inhibitor INCB053914 yielded complete tumor regressions. This profound decrease in tumor cell survival was due in part to the significant reduction in pBAD levels resulting from dual PIM and PI3Kδ inhibition. Despite modest single agent activity in vivo, the combination of INCB050465 with BET inhibitors, INCB054329 or INCB057643, resulted in significant anti-tumor efficacy in all of the DLBCL models studied, and caused a marked repression in tumor MYC expression. To study the transcriptional effects of combining PI3Kδ and BET inhibitors in this lymphoma model, WILL-2 xenograft tumors from mice treated with single dose INCB050465, INCB054329, the combination, or vehicle control were analyzed by RNAseq. INCB050465 enhanced the ability of INCB054329 to repress a MYC-driven transcriptional program, and the combination also regulated multiple developmental and inflammatory pathways. Together, these data support the clinical evaluation of the PI3Kδ inhibitor INCB050465 as part of a combination regimen with PIM or BET inhibitors for the treatment of DLBCL. Citation Format: Matthew C. Stubbs, Robert Collins, Leslie Hall, Alla Volgina, Holly Koblish, Sang Hyun Lee, Timothy Burn, Phillip C. Liu, Jin Lu, Eddy Yue, Yun-Long Li, Andrew P. Combs, Wenqing Yao, Gregory Hollis, Reid Huber, Bruce Ruggeri, Peggy Scherle. Preclinical studies on potential therapeutic combination partners for the potent and selective PI3Kδ inhibitor INCB050465 in DLBCL [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 143. doi:10.1158/1538-7445.AM2017-143
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-143
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 2
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    Oncolytic Measles Virus Expressing the Sodium Iodide Symporter to Treat Drug-Resistant Ovarian Cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 1 ( 2015-01-01), p. 22-30
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 1 ( 2015-01-01), p. 22-30
    Abstract: Edmonston vaccine strains of measles virus (MV) have significant antitumor activity in mouse xenograft models of ovarian cancer. MV engineered to express the sodium iodide symporter gene (MV-NIS) facilitates localization of viral gene expression and offers a tool for tumor radiovirotherapy. Here, we report results from a clinical evaluation of MV-NIS in patients with taxol- and platinum-resistant ovarian cancer. MV-NIS was given intraperitoneally every 4 weeks for up to 6 cycles. Treatment was well tolerated and associated with promising median overall survival in these patients with heavily pretreated ovarian cancer; no dose-limiting toxicity was observed in 16 patients treated at high-dose levels (108–109 TCID50), and their median overall survival of 26.5 months compared favorably with other contemporary series. MV receptor CD46 and nectin-4 expression was confirmed by immunohistochemistry in patient tumors. Sodium iodide symporter expression in patient tumors after treatment was confirmed in three patients by 123I uptake on SPECT/CTs and was associated with long progression-free survival. Immune monitoring posttreatment showed an increase in effector T cells recognizing the tumor antigens IGFBP2 and FRα, indicating that MV-NIS treatment triggered cellular immunity against the patients' tumor and suggesting that an immune mechanism mediating the observed antitumor effect. Our findings support further clinical evaluation of MV-NIS as an effective immunovirotherapy. Cancer Res; 75(1); 22–30. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-14-2533
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Abstract 5774: Small cell lung cancer subtype plasticity is regulated by KDM6A
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5774-5774
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5774-5774
    Abstract: Small cell lung cancer (SCLC) is a high-grade neuroendocrine cancer that accounts for ~15% of lung cancers. While nearly all SCLCs are genetically driven by near universal loss of function (LOF) mutations in RB1 and TP53; several recent studies show that there are different phenotypic SCLC molecular subtypes characterized by expression of lineage transcription factors. These include the neuroendocrine ASCL1 and NEUROD1 subtypes which together comprise ~70-80% of SCLCs. Initially subtypes were thought to be mutually exclusive, but recent evidence shows intra-tumoral subtype heterogeneity and plasticity between subtypes. A recent study found that 35-40% of human SCLCs express both ASCL1 and NEUROD1, but the mechanisms driving ASCL1 and NEUROD1 intra-tumoral heterogeneity are not well understood. My laboratory previously developed an autochthonous CRISPR-based SCLC genetically-engineered mouse model (GEMM) generated by intratracheally injecting adenoviruses encoding Cre recombinase and sgRNAs targeting Rb1, Trp53, and Rbl2. Cre turns on Cas9 expression and allows for CRISPR/Cas9 editing of Rb1, Trp53, and Rbl2 in somatic cells in the lungs. The unique advantage of this model is that it allows the inclusion of sgRNAs targeting additional genes of interest in the same adenovirus. Using this CRISPR-based autochthonous SCLC GEMM approach, we studied the consequences of inactivating the epigenetic modifier KDM6A during SCLC tumorigenesis. KDM6A functions as an H3K27 histone demethylase and also exists in the COMPASS complex with KMT2C/D to promote H3K4 mono-/di-methylation at enhancers. KDM6A along with its protein binding partner KMT2D are mutated in SCLC and KDM6A has been implicated in controlling differentiation in other lineages. Strikingly, we found that KDM6A inactivation in SCLC GEMMs induced plasticity from ASCL1 to NEUROD1 resulting in SCLC tumors that expressed both ASCL1 and NEUROD1. ATAC-sequencing showed open chromatin at the promoters of NEUROD1 and NEUROD1 target genes in KDM6A inactivated tumors. Interestingly, KDM6A inactivated tumors showed a spectrum of ASCL1 to NEUROD1 heterogeneity where some KDM6A inactivated tumors completely lost ASCL1 and solely expressed NEUROD1, some tumors expressed ASCL1 and NEUROD1 in a mutually exclusive manner, while others primarily expressed ASCL1 with very few NEUROD1 positive cells. Mechanistically, KDM6A binds and maintains ASCL1 target genes in an active chromatin state with its loss increasing H3K27me3 near both promoters and enhancers, and decreasing H3K4me1/2 at enhancers together leading to a cell state primed for ASCL1 to NEUROD1 subtype switching. This work identifies KDM6A as an epigenetic regulator that controls ASCL1 to NEUROD1 subtype plasticity and provides an autochthonous SCLC GEMM to model ASCL1 and NEUROD1 subtype heterogeneity, which is found in 35-40% of human SCLCs. Citation Format: Leslie Duplaquet, Yixiang Li, Matthew A. Booker, Yingtian Xie, Radhika A. Patel, Deli Hong, Thomas Denize, Emily Walton, Yasmin N. Laimon, Roderick Bronson, Jackson Southard, Shuqiang Li, Sabina Signoretti, Michael Y. Tolstorukov, Paloma Cejas, Henry W. Long, Michael C. Haffner, Matthew G. Oser. Small cell lung cancer subtype plasticity is regulated by KDM6A. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5774.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5774
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    The 5-Hydroxymethylcytosine Landscape of Prostate Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 21 ( 2022-11-02), p. 3888-3902
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 21 ( 2022-11-02), p. 3888-3902
    Abstract: Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease. Significance: In prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-22-1123
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    Abstract 5074: Addition of MAPK inhibitors to prime and sensitize poorly differentiated thyroid cancers as a strategy to improve TSHR-CART cell therapy antitumor activity
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5074-5074
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5074-5074
    Abstract: Thyroid cancer is the most common endocrine cancer in the US, and its incidence is rising. Most thyroid cancer deaths are attributed to treatment-refractory, metastatic tumors. Thyroid stimulating hormone receptor (TSRH) expression is largely limited to the thyroid gland and is abundantly expressed on thyroid tumor cells, making TSRH a compelling target for advanced thyroid cancer diagnostics and therapeutics. Therefore, we developed a novel TSHR-targeted chimeric antigen receptor (CAR) T cell therapy to treat aggressive thyroid cancers. TSHR-CAR constructs were cloned into a lentiviral CAR construct containing 4-1BB and CD3ζ. First, we demonstrated potent TSHR-CART antigen-specific anti-tumor activity in vitro. Then, NOD-SCID-γ-/- (NSG) mice were inoculated subcutaneously with TSHR+ tumor cells and randomized by tumor volume to treatment with TSHR-CART cells or control Untransduced T cells (UTD). Treatment with TSHR-CART cells resulted in dose-dependent antitumor activity and prolonged survival. De-differentiated anaplastic thyroid cancers (ATC) downregulate TSHR. Our TSHR immunohistochemistry results corroborated these findings and displayed minimal TSHR protein expression, precluding successful TSHR-CART treatment. We therefore sought to sensitize these tumors with MAPK inhibitors, as a strategy to upregulate TSHR expression in patients with metastatic thyroid cancer. TSHR expression was upregulated in patient-derived xenograft (PDX) ATC models after one week of daily administration of the MAPK inhibitors (p=0.0024). After confirming that MAPK inhibition does not dampen TSHR-CART effector functions, we tested sequential and combination therapy of TSHR-CART with MEK and BRAF inhibition in vivo. NSG mice were engrafted with ATC BRAF-mutant PDX tumors and randomized by tumor volume to daily oral treatment with placebo or trametinib (MEK inhibitor) plus dabrafenib (BRAF inhibitor). One week later, mice received either UTD or TSHR-CART. Mice conditioned with trametinib plus dabrafenib (p=0.0018) and subsequently treated with TSHR-CART showed superior antitumor activity. However, the improved antitumor activity in this setting was transient. We therefore tested the durability of TSHR upregulation following MEK/BRAF inhibition and demonstrated that TSHR upregulation lasts less than 48-72 hours after discontinuation. Finally, we tested the combination of TSHR CART cells with MEK/BRAF inhibitors in ATC BRAF-mutant PDX tumors. Here, combining TSHR-CART cells with MEK/BRAF inhibitors result in durable control of the tumors. Collectively, our findings indicate that MEK/BRAF inhibition of de-differentiated thyroid cancers upregulated TSHR expression and enhanced TSHR-CART antitumor activity. This work represents a viable strategy to improve outcomes of patients with aggressive, metastatic thyroid cancers. Citation Format: Claudia Manriquez Roman, Kendall J. Schick, Justyna J. Gleba, Truc N. Huynh, Elizabeth L. Siegler, James L. Miller, Aylin Alasonyalilar Demirer, Matthew L. Pawlush, Ahmet Biligili, Long K. Mai, Erin Tapper, Leo R. Sakemura, Michelle J. Cox, Carli M. Stewart, Ismail Can, Ekene J. Ogbodo, Gaofeng Cui, Georges Mer, Gloria R. Olivier, Yushi Qiu, Robert C. Smallridge, Zubair C. Abba, Han W. Tun, John A. Copland, Saad S. Kenderian. Addition of MAPK inhibitors to prime and sensitize poorly differentiated thyroid cancers as a strategy to improve TSHR-CART cell therapy antitumor activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5074.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5074
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 6
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    Abstract 2490: Optimizing treatment strategy for NF1-depleted estrogen receptor positive breast cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2490-2490
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2490-2490
    Abstract: Background: Germline mutations in the NF1 gene are responsible for neurofibromatosis type 1, which is the world's most common genetic disorder. NF1 is also a key tumor suppressor gene that is frequently somatically mutated in a wide range of cancers. Approximately 80% of breast cancer is driven by the estrogen receptor α (ER), encoded by the ESR1 gene, and ER-positive (ER+) breast cancer can be treated by endocrine therapy targeting the ER transcriptional pathway. NF1 encodes neurofibromin, which is best known as a GTPase Activating Protein (GAP) for repressing Ras signaling. However, in a recent study we presented evidence supporting the model that NF1 has a GAP-independent activity by also acting as a transcriptional co-repressor for ER. NF1 loss enhanced ER transcription causing resistance to tamoxifen and aromatase inhibition. Approach and Results: In this study, we examined patient data from TCGA cohort and found that low NF1 mRNA levels associated with recurrence in luminal breast cancer, particularly in the luminal B subtype. Using purified components, we showed that full-length NF1 can directly bind ER. The ESR1-pE380Q mutation is a recurrent event in metastatic ER+ breast cancer. Our two-hybrid data showed that NF1 interacted less with the ER-E380Q than wild type ER, which agrees with structural analysis predicting co-repressors binding to be mediated by the ER-E380 residue. To assess how NF1-loss impacts ER-dependent gene expression in ER+ breast cancer cells, our ER ChIP-seq data showed that in the presence of estradiol, NF1-depletion promoted global ER recruitment to estrogen response elements (EREs) on chromatin. Expression of ERE-bound genes showed concordant expression changes by RNA-seq, confirming genome-wide transcriptional dysregulation of ER targeted genes by NF1 loss. ER+ NF1-depleted breast cancer cells responded initially to a selective ER degrader (SERD), such as fulvestrant and an oral SERD AZD9496, but acquired resistance with prolonged treatment. Resistance may be dependent on CDK4/6, a common growth pathway controlled by both Ras and ER. We showed that fulvestrant together with a CDK4/6 inhibitor Palbociclib can efficiently inhibit the growth of ER+ NF1-depleted breast cancer leading to tumor regression in a patient derived xenograft model. Conclusion: The loss of the full length NF1 can stimulate both ER and Ras signaling, and it is possible to efficiently treat ER+ NF1-depleted breast cancer by a SERD, in combination with CDK4/6 inhibitor. Citation Format: Zeyi Zheng, Jonathan T. Lei, Meenakshi Anurag, Long Feng, Purba Singh, Hilda Kennedy, Jin Cao, Xi Chen, Matthew J. Ellis, Eric C. Chang. Optimizing treatment strategy for NF1-depleted estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2490.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2490
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract 5666: A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5666-5666
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 5666-5666
    Abstract: Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICI) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we analyze 211 samples from 99 patients and demonstrate that pre-treatment circulating tumor DNA (ctDNA) and circulating immune profiles are independently associated with DCB. We further show that ctDNA dynamics after a single ICI infusion can identify the majority of patients who will achieve DCB. Integrating these determinants, we describe an entirely noninvasive multi-analyte assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA- On-treatment) that robustly predicted DCB, and that was validated in two independent cohorts (AUC = 0.89-0.93, PPV = 92-100%, HR = 0.04-0.11). Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICI. Citation Format: Barzin Y. Nabet, Mohammad S. Esfahani, Emily G. Hamilton, Jacob J. Chabon, Everett J. Moding, Hira Rizvi, Chloe B. Steen, Aadel A. Chaudhuri, Chih Long Liu, Angela B. Hui, Henning Stehr, Linda Goljenola, Michael C. Jin, Young-Jun Jeon, Diane Tseng, Taha Merghoub, Joel W. Neal, Heather A. Wakelee, Sukhmani K. Padda, Kavitha J. Ramchandran, Millie Das, Rene F. Bonilla, Christopher Yoo, Emily L. Chen, Ryan B. Ko, Aaron M. Newman, Matthew D. Hellmann, Ash A. Alizadeh, Maximilian Diehn. A noninvasive approach for early prediction of therapeutic benefit from immune checkpoint inhibition for lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5666.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-5666
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 8
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    Transcriptional Subtypes Resolve Tumor Heterogeneity and Identify Vulnerabilities to MEK Inhibition in Lung Adenocarcinoma
    American Association for Cancer Research (AACR) ; 2021
    In:  Clinical Cancer Research Vol. 27, No. 4 ( 2021-02-15), p. 1162-1173
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 27, No. 4 ( 2021-02-15), p. 1162-1173
    Abstract: Lung adenocarcinomas comprise the largest fraction of non–small cell lung cancer, which is the leading cause of cancer-related deaths. Seventy-five percent of adenocarcinomas lack targeted therapies because of scarcity of druggable drivers. Here, we classified tumors on the basis of signaling similarities and discovered subgroups within this unmet patient population. Experimental Design: We leveraged transcriptional data from & gt;800 early- and advanced-stage patients. Results: We identified three robust subtypes dubbed mucinous, proliferative, and mesenchymal with respective pathway phenotypes. These transcriptional states lack discrete and causative mutational etiology as evidenced by similarly distributed oncogenic drivers, including KRAS and EGFR. The subtypes capture heterogeneity even among tumors lacking known oncogenic drivers. Paired multi-regional intratumoral biopsies demonstrated unified subtypes despite divergently evolved prooncogenic mutations, indicating subtype stability during selective pressure. Heterogeneity among in vitro and in vivo preclinical models is expounded by the human lung adenocarcinoma subtypes and can be leveraged to discover subtype-specific vulnerabilities. As proof of concept, we identified differential subtype response to MEK pathway inhibition in a chemical library screen of 89 lung cancer cell lines, which reproduces across model systems and a clinical trial. Conclusions: Our findings support forward translational relevance of transcriptional subtypes, where further exploration therein may improve lung adenocarcinoma treatment. See related commentary by Skoulidis, p. 913
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-1835
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 9
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    Circulating Tumor DNA Analysis to Assess Risk of Progression after Long-term Response to PD-(L)1 Blockade in NSCLC
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 12 ( 2020-06-15), p. 2849-2858
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 12 ( 2020-06-15), p. 2849-2858
    Abstract: Treatment with PD-(L)1 blockade can produce remarkably durable responses in patients with non–small cell lung cancer (NSCLC). However, a significant fraction of long-term responders ultimately progress and predictors of late progression are unknown. We hypothesized that circulating tumor DNA (ctDNA) analysis of long-term responders to PD-(L)1 blockade may differentiate those who will achieve ongoing benefit from those at risk of eventual progression. Experimental Design: In patients with advanced NSCLC achieving long-term benefit from PD-(L)1 blockade (progression-free survival ≥ 12 months), plasma was collected at a surveillance timepoint late during/after treatment to interrogate ctDNA by Cancer Personalized Profiling by Deep Sequencing. Tumor tissue was available for 24 patients and was profiled by whole-exome sequencing (n = 18) or by targeted sequencing (n = 6). Results: Thirty-one patients with NSCLC with long-term benefit to PD-(L)1 blockade were identified, and ctDNA was analyzed in surveillance blood samples collected at a median of 26.7 months after initiation of therapy. Nine patients also had baseline plasma samples available, and all had detectable ctDNA prior to therapy initiation. At the surveillance timepoint, 27 patients had undetectable ctDNA and 25 (93%) have remained progression-free; in contrast, all 4 patients with detectable ctDNA eventually progressed [Fisher P & lt; 0.0001; positive predictive value = 1, 95% confidence interval (CI), 0.51–1; negative predictive value = 0.93 (95% CI, 0.80–0.99)]. Conclusions: ctDNA analysis can noninvasively identify minimal residual disease in patients with long-term responses to PD-(L)1 blockade and predict the risk of eventual progression. If validated, ctDNA surveillance may facilitate personalization of the duration of immune checkpoint blockade and enable early intervention in patients at high risk for progression.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-19-3418
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
  • 10
    Online Resource
    Online Resource
    Abstract PO-101: Transcriptional heterogeneity in lung adenocarcinoma reveals distinct therapeutic vulnerabilities
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 21_Supplement ( 2020-11-01), p. PO-101-PO-101
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 21_Supplement ( 2020-11-01), p. PO-101-PO-101
    Abstract: Lung adenocarcinomas comprise the largest fraction of non-small cell lung cancer, which is the leading cause of cancer deaths. 75% of adenocarcinomas lack targeted therapies due to scarcity of druggable drivers. Here we leverage transcriptional data from & gt;800 early-stage and advanced patients to classify tumors based on signaling similarities and discover subgroups within this unmet patient population. We identify three robust subtypes dubbed Mucinous, Proliferative, and Mesenchymal with respective pathway phenotypes. These transcriptional states lack discrete and causative mutational etiology as evidenced by similarly distributed oncogenic drivers including KRAS and EGFR. The subtypes capture heterogeneity even amongst tumors lacking known oncogenic drivers. Paired multi-regional intratumoral biopsies demonstrate unified subtypes despite divergently evolved pro-oncogenic mutations, indicating subtype stability during selective pressure. Heterogeneity amongst in vitro and in vivo preclinical models is expounded by the human lung adenocarcinoma subtypes and can be leveraged to discover subtype-specific vulnerabilities. As proof-of-concept, we identify differential subtype response to MEK pathway inhibition in a chemical library screen of 89 lung cancer cell lines, which reproduces across model systems and a clinical trial, supporting prognostic utility of transcriptional subtyping. Our findings support forward translational relevance of transcriptional subtypes, where further exploration therein may improve lung adenocarcinoma treatment. Citation Format: Anneleen Daemen, Jonathan E. Cooper, Szymon Myrta, Matthew J. Wongchenko, Eva Lin, Jason E. Long, Oded Foreman, Zora Modrusan, Jarrod Tremayne, Cecile C. de la Cruz, Mark Merchant, Scott E. Martin, Yibing Yan, Melissa R. Junttila. Transcriptional heterogeneity in lung adenocarcinoma reveals distinct therapeutic vulnerabilities [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-101.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TUMHET2020-PO-101
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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    BTU Cottbus
    Wissenschaftspark Albert Einstein
    EUV Frankfurt
    TH Wildau
    FH Potsdam
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