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  • American Association for Cancer Research (AACR)  (573)
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  • 1
    Online Resource
    Online Resource
    Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 28, No. 5 ( 2019-05-01), p. 935-942
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 28, No. 5 ( 2019-05-01), p. 935-942
    Abstract: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non–small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15–2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27–7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-18-0356
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Abstract P2-01-16: Comparison of axillary nodal status between different defined clinically node negative breast cancer: Is ACOSOG Z0011 criteria applicable to preoperative cytologically negative axilla?
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 4_Supplement ( 2017-02-15), p. P2-01-16-P2-01-16
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 4_Supplement ( 2017-02-15), p. P2-01-16-P2-01-16
    Abstract: Background Axillary ultrasound (AUS) and US-guided fine-needle aspiration (FNA) are now part of the preoperative axillary assessment. The ACOSOG Z0011 trial demonstrated axillary lymph node dissection (ALND) may be omitted in patients with T1-2 tumor, clinically negative axilla and 1-2 positive sentinel lymph nodes (SLN). But for clinically node negative patients with AUS suspicious but FNA negative axilla, whether they could receive the same surgical procedure and omit ALND referencing to Z0011 criteria as clinically node negative patients identified by AUS has not been illustrated. The purpose of this study was to evaluate potential differences in axillary lymph node (ALN) metastatic status between clinically node negative patients identified by AUS (AUS group) and FNA (FNA group). Methods Patients with T1-2 tumor and clinically negative axilla treated in Shanghai Ruijin Hospital from Jan 2013 to Dec 2015 were enrolled. ALN metastatic status were compared between AUS group and FNA group. Results A total of 1007 patients were included. Preoperative axillary status (AUS negative or FNA negative) did not differ significantly between ALN positive and ALN negative patients (p = 0.170). Similarly, ALN metastatic status (negative, 1-2 positive or ≥3 positive) did not differ significantly between AUS group and FNA group (p = 0.405) table 1. ALN status of patients with different defined clinically node negative breast cancer AUS group N = 886 (%)FNA group N = 121 (%)P valueALN status  0.405Negative740 (83.5)95 (78.5) 1-2 positive125 (14.1)125 (14.1) ≥3 positive21 (2.4)4 (3.3)  Subset analysis of patients fulfilling Z0011 eligibility criteria showed no significant difference in nonsentinel lymph node (NSLN) metastasis rate (p = 0.591) and number of positive lymph nodes (p = 0.777) between AUS group and FNA group. table 2. Nodal status of 1-2 SLN positive patients with different defined clinically node negative breast cancer AUS group N = 138 (%)FNA group N = 24 (%)P valueNSLN  0.591Positive27 (19.6)3 (12.5) Negative111 (80.4)21 (87.5) Number of positive lymph nodes  0.777194 (68.1)13 (9.4) 231 (22.5)4 (16.7) 3 or more13 (9.4)2 (8.3)  Conclusions Patients with clinically node negative axilla identified by FNA were comparable to those identified by AUS in ALN metastatic status. Indicating that patients with preoperative FNA negative axilla could receive the same surgical procedure and may omit ALND referencing to Z0011 criteria as preoperative AUS negative patients. Citation Format: Liang Y, Chen X, Zhu Y, Wu J, Huang O, Zong Y, Zhu S, Gao W, He J, Zhu L, Chen W, Li Y, Shen K. Comparison of axillary nodal status between different defined clinically node negative breast cancer: Is ACOSOG Z0011 criteria applicable to preoperative cytologically negative axilla? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-16.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS16-P2-01-16
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 3
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    Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Discovery Vol. 8, No. 9 ( 2018-09-01), p. 1176-1193
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 9 ( 2018-09-01), p. 1176-1193
    Abstract: Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs. Significance: Nearly 30% of endocrine therapy–resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176–93. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1047
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-17-1229
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 4
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    Abstract A18: Personalized prevention of colorectal cancer trial
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Prevention Research Vol. 8, No. 10_Supplement ( 2015-10-01), p. A18-A18
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 8, No. 10_Supplement ( 2015-10-01), p. A18-A18
    Abstract: Background: High calcium or high magnesium consumption has been linked to reduced risks of colorectal adenoma and cancer. However, results are not consistent. In the Tennessee Colorectal Polyp Study (TCPS), the Calcium Polyp Prevention Study (a large-scale randomized trial), we found that high intake of supplemental calcium or total calcium was related to a reduced risk of colorectal adenoma or adenoma recurrence only among those with calcium/magnesium intake ratio below 2.8 or 2.6. This effect modification by the calcium/magnesium ratio cannot solely be attributed to the dietary intake in calcium or magnesium. Furthermore, we found in the TCPS that calcium/magnesium intake ratio significantly interacted with Thr1482Ile polymorphism (rs8042919, GàA) in the TRPM7 gene, in relation to both adenomas and hyperplastic polyps. The TRPM7 gene is involved in magnesium and calcium re(absorption) and homeostasis. Compared to those with the GG genotype, we found that people who carry A allele(s) were at 60% and 85% increased risks of adenoma and hyperplastic polyp, respectively, if they also consumed diets with calcium/magnesium intake ratio & gt;2.8; and the corresponding risks increased by 345% and 1500% among those with the AA genotype. The risk was not increased among those who carried the A allele(s) if they consumed diets low in calcium/magnesium ratio ( & lt;2.8). Objectives: 1) Test the hypothesis whether reducing the calcium/magnesium through magnesium supplementation affects biomarkers related to colorectal carcinogenesis in rectal tissues; and 2) Test whether the effect differs by TRPM7 genotype. Methods: Personalized Prevention of Colorectal Cancer Trial (PPCCT, R01CA149633) is an ongoing double-blind, randomized trial of 12 week personalized magnesium supplementation. 288 participants with high calcium/magnesium intake ratio and at high risk of colorectal cancer are being recruited. The uniqueness of the trial includes 1) only target participants with a high calcium/magnesium ratio through nutritional screening using multiple 24-hour dietary recalls; 2) personalized doses are based on and used to reduce the current calcium/magnesium intake ratios; and finally, 3) the participants are also randomized by the TRPM7 genotype. Results: As of July 20, 2014, we have enrolled at least 170 participants. We have conducted immunohistochemical assays to measure expressions of carcinogenesis biomarkers, including apoptosis, cell proliferation, COX2 and TRPM7, in normal rectal tissues collected at baseline and the end of the intervention for 40 participants who first completed the trial. We are also assaying lipid profile and other novel biomarkers, including DNA methylation, and microbial markers. We have obtained some very promising preliminary findings. We will report updated findings in the presentation. Conclusions: The results from our study may ultimately help to develop personalized strategies to prevent colorectal cancer. Citation Format: Xiangzhu Zhu Zhu, Chang Yu, Martha J. Shrubsole, Xinqing Deng, Eugene Shubin, Jennifer M. Engle, Wei Zheng, Harvey J. Murff, Douglas L. Seidner, Reid M. Ness, Qi Dai. Personalized prevention of colorectal cancer trial. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A18.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6215.PREV-14-A18
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    KIR3DL3 Is an Inhibitory Receptor for HHLA2 that Mediates an Alternative Immunoinhibitory Pathway to PD1
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Immunology Research Vol. 9, No. 2 ( 2021-02-01), p. 156-169
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 9, No. 2 ( 2021-02-01), p. 156-169
    Abstract: Blockade of the PD1 pathway is a broadly effective cancer therapy, but additional immune-inhibitory pathways contribute to tumor immune evasion. HERV–H LTR-associating 2 (HHLA2; also known as B7H5 and B7H7) is a member of the B7 family of immunoregulatory ligands that mediates costimulatory effects through its interaction with the CD28 family member transmembrane and immunoglobulin domain containing 2 (TMIGD2). However, HHLA2 has also been known to have inhibitory effects on T cells. Here, we report that we have identified killer cell immunoglobulin-like receptor, three immunoglobulin domains and long cytoplasmic tail 3 (KIR3DL3) as an inhibitory receptor for HHLA2 in T cells and natural killer (NK) cells and have generated HHLA2 and KIR3DL3 antibodies that block the immune-inhibitory activity of HHLA2, preserving the costimulatory signal. It is known that HHLA2 is frequently expressed in several tumor types, including clear cell renal cell carcinoma (ccRCC). We found that HHLA2 expression was nonoverlapping with PDL1 expression in ccRCC, suggesting that HHLA2 mediates a mechanism of tumor immune evasion that is independent from PDL1. Blockade of both the PD1 and KIR3DL3 pathways may be a more effective way to reverse tumor immune evasion. See related Spotlight on p. 128
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-20-0315
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract 886: Fine-tuned CAIX targeted CAR-T cells exhibit superior efficacy and mitigate on-target off-tumor side effects
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 886-886
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 886-886
    Abstract: Chimeric Antigen Receptor (CAR) T cell therapy is a new type of “living drug” that has proven to be a powerful immunotherapy for hematologic malignancies. To date, there are six CAR-T products approved by the FDA for hematologic malignancies, four targeting CD19, and two targeting B-cell maturation antigen (BCMA). However, this success has not yet been transferred to solid tumors. A major hurdle is the on-target off-tumor toxicities due to the shared expression of target antigen on normal tissues. Carbonic anhydrase IX (CAIX) is highly expressed in clear cell renal cell carcinoma (ccRCC); however, it is also expressed on bile duct at a lower physiological level leading to off-tumor toxicity of CAIX targeted therapies. The first anti-CAIX CAR-T studies, using the 1st generation G250 CAR-T cells plus IL-2 to treat patients with metastatic ccRCC, caused severe liver enzyme abnormalities in the treated patients after CAR-T cell infusions. To understand CAIX expression on tumor and normal tissues, we quantified CAIX expression on ccRCC patient samples and healthy bile duct tissues using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution. Tet-On inducible CAIX expressing cell lines were established to mimic various CAIX densities on normal tissue and tumor samples. Using biolayer interferometry (BLI) and avidity analyzer, we identified a low-affinity, high-avidity anti-CAIX CAR G9. G9 CAR-T cells only kill CAIX high ccRCC tumor cells but not CAIX low normal cholangiocytes, and exhibited a CAIX density dependent response to Tet-On inducible CAIX expressing cell lines. Compared to high-affinity G250 CAR-T cells, G9 showed a better safety profile and a wider therapeutic window. G9 demonstrated a superior ex vivo efficacy on ccRCC patient derived organotypic tumor spheroids (PDOTS) 3D cultures which recapitulate ccRCC patient tumor microenvironment (TME), as well as low toxicity on cholangiocyte derived organotypic spheroids (CDOS). In summary, affinity/avidity fine-tuned CAIX targeted CAR-T cell therapy holds promise to achieve cures of ccRCC by efficaciously killing tumor cells and mitigating on-target off-tumor toxicity on normal tissues. Citation Format: Yufei Wang, Alicia Buck, Gabriella Kastrunes, Rabia Abbas, Michael Lynch, Zhou Zhong, Song-My Hoang, Andras Miklosi, Kun Huang, Jae-Won Cho, Marion Grimaud, Cecile Razimbaud, Matthew Chang, Atef Fayed, Audrey Apollon, Nithyassree Murugan, Ze-Hua Li, Tran Thai, Luann Zerefa, Brandon Piel, Elena Ivanova, Amy Cameron, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Yasmin Nabil Laimon, Aseman Bagheri Sheshdeh, Sabina Signoretti, David A. Braun, Catherine J. Wu, Toni K. Choueiri, Jon Wee, Cloud P. Paweletz, Martin Hemberg, Aedin C. Culhane, David A. Barbie, Gordon J. Freeman, Wayne A. Marasco. Fine-tuned CAIX targeted CAR-T cells exhibit superior efficacy and mitigate on-target off-tumor side effects [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 886.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-886
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Abstract 445: Integrated proteogenomic characterization across seven histological types of pediatric brain tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 445-445
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 445-445
    Abstract: We performed a comprehensive proteogenomic analysis across seven major types of childhood brain tumors for a deeper understanding of their functional biology. Whole genome seq, RNAseq, quantitative proteomic and phosphoproteomic profiling were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93), ependymoma (32), high grade astrocytoma (26), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid rhabdoid tumor (12). Characterization of the tumor microenvironment through multi-omics based deconvolution analyses revealed 5 distinct tumor clusters associated with different populations of infiltrating immune cells: Cold-medullo, Cold-mixed, Epithelial, Neuronal and Hot. The two cold-tumor clusters have the lowest immune cell infiltration, one characterized by the enrichment of medulloblastoma tumors; while the other is a mixture of ependymoma, ATRT, HGG and medulloblastoma. The Epithelial group, on the other hand, was enriched in craniopharyngioma samples, an epithelium derived tumor. Interestingly, the RNA levels of PD-1 and CTLA4 were significantly upregulated in this Epithelial group, confirming that craniopharingioma could potentially benefit from anti PD-1 and/or CTLA-4 therapies as previously reported. LLG and ganglioglioma were allocated into two groups of Neuronal and Hot, the former characterized by the presence of neuronal cells, and the latter by the presence of macrophages, microglia, and dendritic cells. Adenosine producers (e.g., ENTPD1 and NT5E), which act as inhibitory immune checkpoint molecular, showed up-regulation in the Hot cluster based on both RNAseq and proteome data, suggesting patients in this group might benefit from adenosine reducing treatments. Among LGG tumors, there is a significant difference between microglial and macrophage polarization across BRAF statuses: BRAF-fusion promoted more pro-regenerative (immune suppressive) microglia than pro-inflammatory microglia, while BRAF-V600E promoted more pro-regenerative macrophages than pro-inflammatory macrophages, implying different immunosuppressive mechanisms in the BRAF-V600E and fusion tumors. This study reports the first large-scale deep comprehensive proteogenomic analysis crossing traditional histologic boundaries to uncover foundational pediatric brain tumor biology relating to tumor microenvironment. The incorporation of the proteomic and phosphoproteomic dimension into this large-scale multi-omic study adds functional insight that helps drive translational efforts. Citation Format: Francesca Petralia, Nicole Tignor, Boris Reva, Pichai Raman, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Weiping Ma, Jiayi Ji, Xiaoyu Song, Yuankun Zhu, Jo Lynne Rokita, Antonio Colaprico, Anna Calinawan, Jeffrey R. Whiteaker, Richard G. Ivey, Zeynep Gumus, Selim Kalayci, Gonzalo L. Garcia, Seungyeul Yoo, Lizabeth Katsnelson, Ying Wang, Jacob J. Kennedy, Uliana J. Voytovich, Lei Zhao, Felipe Leprevost, Hui-Yin Chang, Krutika S. Gaonkar, Elizabeth M. Appert, Ximena Cuellar, Jena Lilly, Jun Zhu, Eric E. Schadt, Medhi Mesri, Emily Boja, Tara Hiltka, Henry Rodriguez, Li Ding, Antonio Iavarone, Maciej Wiznerowicz, Alexey I. Nesvizhskii, David Fenyo, Steven Gygi, Amanda Paulovich, Adam C. Resnick, Phillip B. Storm, Brian Rood, Pei Wang, Children's Brain Tumor Tissue Consortium and Clinical Proteomic Tumor Analysis Consortium. Integrated proteogenomic characterization across seven histological types of pediatric brain tumors [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 445.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-445
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 8
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    Abstract GS4-07: The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. GS4-07-GS4-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. GS4-07-GS4-07
    Abstract: Background. DCIS consists of a molecularly heterogeneous group of premalignant lesions, with variable risk of invasive progression. Understanding biomarkers for invasive progression could help individualize treatment recommendations based upon tumor biology. As part of the NCI Human Tumor Atlas Network (HTAN), we conducted comprehensive genomic analyses on two large DCIS case-control cohorts. Methods. We performed smart3-seq and low-pass whole genome sequencing on two independent, retrospective, longitudinally sampled DCIS case-control cohorts. TBCRC 038 was a multicenter cohort diagnosed with DCIS between 1998 and 2016 at one of the Translational Breast Cancer Research sites; the RAHBT (Resource of Archival Human Breast Tissue) cohort included women identified through the St. Louis Breast Tissue Repository, and the Women’s Health Repository diagnosed between 1997 and 2001. We studied the spectrum of molecular changes present and sought genomic predictors of subsequent ipsilateral breast events (iBEs: DCIS recurrence or invasive progression) in both DCIS epithelium and stroma in formalin fixed paraffin embedded tissue. We generated de novo tumor and stroma-centric subtypes for DCIS that represents fundamental transcriptomic organization. Copy number analysis was performed using low-pass DNA sequencing. Non-negative matrix factorization (NMF) was applied to the RNA expression of all coding genes to identify clusters. A negative-binomial regression model was used to identify differentially expressed genes. Results. We analyzed 677 DCIS samples from 481 patients with 7.1 years median follow-up. In TBCRC samples, we identified three clusters via NMF in TBCRC referred to as ER low, quiescent, and ER high. The ER-low cluster had significantly higher levels of ERBB2 and lower levels of ESR1 compared to quiescent and ER-high clusters. Quiescent cluster lesions were less proliferative and less metabolically active than ER high and ER low subtypes. These findings were replicated in the RAHBT cohort. Focusing on the stromal component of DCIS from laser capture microdissection in RAHBT samples, we identified four distinct DCIS-associated stromal clusters. A “normal-like” stromal cluster with ECM organization and PI3K-AKT signaling; a “collagen-rich” stromal cluster; a “desmoplastic” stromal cluster with high fibroblast and total myeloid abundance, mostly associated with macrophages and myeloid dendritic cells (mDC); and an “immune-dense” stromal cluster. Further, we compared differentially expressed genes in patients with or without subsequent iBEs within 5 years of diagnosis. Hypothesizing that the resulting 812 DE genes (DESeq2) represent multiple routes to subsequent iBEs, we leveraged NMF to identify paths to progression. In both TBCRC and RAHBT cohorts, poor outcome groups exhibited increased ER, MYC signaling, and oxidative phosphorylation, supporting that these pathways are important for DCIS recurrence and progression. Conclusion. Comprehensive genomic profiling in two independent DCIS cohorts with longitudinal outcomes shows distinct DCIS stromal expression patterns and immune cell composition. RNA expression profiles reveal underlying tumor biology that is associated with later iBEs in both cohorts. These studies provide new insight into DCIS biology and will guide the design of diagnostic strategies to prevent invasive progression. Citation Format: Siri H Strand, Belén Rivero-Gutiérrez, Kathleen E Houlahan, Jose A Seoane, Lorraine M King, Tyler Risom, Lunden Simpson, Sujay Vennam, Aziz Khan, Timothy Hardman, Bryan E Harmon, Fergus J Couch, Kristalyn Gallagher, Mark Kilgore, Shi Wei, Angela DeMichele, Tari King, Priscilla F McAuliffe, Julie Nangia, Joanna Lee, Jennifer Tseng, Anna Maria Storniolo, Alastair Thompson, Gaorav Gupta, Robyn Burns, Deborah J Veis, Katherine DeSchryver, Chunfang Zhu, Magdalena Matusiak, Jason Wang, Shirley X Zhu, Jen Tappenden, Daisy Yi Ding, Dadong Zhang, Jingqin Luo, Shu Jiang, Sushama Varma, Cody Straub, Sucheta Srivastava, Christina Curtis, Rob Tibshirani, Robert Michael Angelo, Allison Hall, Kouros Owzar, Kornelia Polyak, Carlo Maley, Jeffrey R Marks, Graham A Colditz, E Shelley Hwang, Robert B West. The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS4-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-GS4-07
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Abstract P3-03-08: Not presented
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P3-03-08-P3-03-08
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P3-03-08-P3-03-08
    Abstract: This abstract was not presented at the conference. Citation Format: Liang Y, Chen X, Zhan W, Zhu Y, Wu J, Huang O, He J, Zhu L, Li Y, Chen W, Shen K. Not presented [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-03-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P3-03-08
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
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    Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant Breast Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Molecular Cancer Therapeutics Vol. 21, No. 6 ( 2022-06-01), p. 890-902
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    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 21, No. 6 ( 2022-06-01), p. 890-902
    Abstract: Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both  ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy–resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). Summary: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-21-0378
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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