المؤلفون: Albert Grinshpun, Douglas Russo, Wen Ma, Ana Verma, Francisco Hermida-Prado, Shira Sherman, Giorgio Gaglia, Sheheryar Kabraji, Gregory Kirkner, Melissa E. Hughes, Nancy U. Lin, Zachary Sandusky, Agostina Nardone, Cristina Guarducci, Quang-De Nguyen, Sandro Santagata, Zsuzsanna Nagy, Rinath Jeselsohn

المصدر: npj Breast Cancer, Vol 10, Iss 1, Pp 1-12 (2024)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract The ESR1 ligand binding domain activating mutations are the most prevalent genetic mechanism of acquired endocrine resistance in metastatic hormone receptor-positive breast cancer. These mutations confer endocrine resistance that remains estrogen receptor (ER) dependent. We hypothesized that in the presence of the ER mutations, continued ER blockade with endocrine therapies that target mutant ER is essential for tumor suppression even with chemotherapy treatment. Here, we conducted comprehensive pre-clinical in vitro and in vivo experiments testing the efficacy of adding fulvestrant to fluorouracil (5FU) and the 5FU pro-drug, capecitabine, in models of wild-type (WT) and mutant ER. Our findings revealed that while this combination had an additive effect in the presence of WT-ER, in the presence of the Y537S ER mutation there was synergy. Notably, these effects were not seen with the combination of 5FU and selective estrogen receptor modulators, such as tamoxifen, or in the absence of intact P53. Likewise, in a patient-derived xenograft (PDX) harboring a Y537S ER mutation the addition of fulvestrant to capecitabine potentiated tumor suppression. Moreover, multiplex immunofluorescence revealed that this effect was due to decreased cell proliferation in all cells expressing ER and was not dependent on the degree of ER expression. Taken together, these results support the clinical investigation of the combination of ER antagonists with capecitabine in patients with metastatic hormone receptor-positive breast cancer who have experienced progression on endocrine therapy and targeted therapies, particularly in the presence of an ESR1 activating mutation.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2374-4677Test

الوصول الحر: https://doaj.org/article/7c7a103652a4404eac1f649798184d56Test

المؤلفون: Yufei Wang, Alicia Buck, Brandon Piel, Luann Zerefa, Nithyassree Murugan, Christian D. Coherd, Andras G. Miklosi, Haraman Johal, Ricardo Nunes Bastos, Kun Huang, Miriam Ficial, Yasmin Nabil Laimon, Sabina Signoretti, Zhou Zhong, Song-My Hoang, Gabriella M. Kastrunes, Marion Grimaud, Atef Fayed, Hsien-Chi Yuan, Quang-De Nguyen, Tran Thai, Elena V. Ivanova, Cloud P. Paweletz, Ming-Ru Wu, Toni K. Choueiri, Jon O. Wee, Gordon J. Freeman, David A. Barbie, Wayne A. Marasco

المصدر: Molecular Cancer, Vol 23, Iss 1, Pp 1-16 (2024)

مصطلحات موضوعية: Chimeric antigen receptor (CAR) T, Affinity/avidity fine-tuned, Clear cell renal cell carcinoma (ccRCC), Carbonic anhydrase IX (CAIX), Direct stochastic optical reconstruction microscopy (dSTORM), On-target off-tumor (OTOT) toxicity, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1476-4598Test

الوصول الحر: https://doaj.org/article/90de263ab4864245afd1b4be5c061876Test

المؤلفون: Yufei Wang, Jae-Won Cho, Gabriella Kastrunes, Alicia Buck, Cecile Razimbaud, Aedin C. Culhane, Jiusong Sun, David A. Braun, Toni K. Choueiri, Catherine J. Wu, Kristen Jones, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Quan Zhu, Sabina Signoretti, Gordon J. Freeman, Martin Hemberg, Wayne A. Marasco

المصدر: iScience, Vol 27, Iss 2, Pp 108879- (2024)

مصطلحات موضوعية: Immunology, Cancer, Transcriptomics, Science

الوصف: Summary: One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2589004224001007Test; https://doaj.org/toc/2589-0042Test

الوصول الحر: https://doaj.org/article/0c2301842fd04b6197a7bca08f019c78Test

المؤلفون: Yufei Wang, Alicia Buck, Marion Grimaud, Aedin C. Culhane, Sreekumar Kodangattil, Cecile Razimbaud, Dennis M. Bonal, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Madison L. O'Donnell, Ying Huang, Sabina Signoretti, Toni K. Choueiri, Gordon J. Freeman, Quan Zhu, Wayne A. Marasco

المصدر: Molecular Therapy: Oncolytics, Vol 24, Iss , Pp 385-399 (2022)

مصطلحات موضوعية: chimeric antigen receptor T, CAR-T, clear cell renal cell carcinoma, ccRCC, carbonic anhydrase IX, CAIX, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Improving CAR-T cell therapy for solid tumors requires a better understanding of CAR design and cellular composition. Here, we compared second-generation (BBζ and 28ζ) with third-generation (28BBζ) carbonic anhydrase IX (CAIX)-targeted CAR constructs and investigated the antitumor effect of CAR-T cells with different CD4/CD8 proportions in vitro and in vivo. The results demonstrated that BBζ exhibited superior efficacy compared with 28ζ and 28BBζ CAR-T cells in a clear-cell renal cell carcinoma (ccRCC) skrc-59 cell bearing NSG-SGM3 mouse model. The mice treated with a single dose of BBζ CD4/CD8 mixture (CAR4/8) showed complete tumor remission and remained tumor-free 72 days after CAR-T cells infusion. In the other CAR-T and control groups, tumor-infiltrating T cells were recovered and profiled. We found that BBζ CAR8 cells upregulated expression of major histocompatibility complex (MHC) class II and cytotoxicity-associated genes, while downregulating inhibitory immune checkpoint receptor genes and diminishing differentiation of regulatory T cells (Treg cells), leading to excellent therapeutic efficacy in vivo. Increased memory phenotype, elevated tumor infiltration, and decreased exhaustion genes were observed in the CD4/8 untransduced T (UNT) cells compared with CD8 alone, indicating that CD4/8 would be the favored cellular composition for CAR-T cell therapy with long-term persistence. In summary, these findings support that BBζ CAR4/8 cells are a highly potent, clinically translatable cell therapy for ccRCC.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2372770521001911Test; https://doaj.org/toc/2372-7705Test

الوصول الحر: https://doaj.org/article/a6fd413e589b4d888e2d0422199d80d7Test

المؤلفون: Lina Ding, Ying Su, Anne Fassl, Kunihiko Hinohara, Xintao Qiu, Nicholas W. Harper, Sung Jin Huh, Noga Bloushtain-Qimron, Bojana Jovanović, Muhammad Ekram, Xiaoyuan Zi, William C. Hines, Maša Alečković, Carlos Gil del Alcazar, Ryan J. Caulfield, Dennis M. Bonal, Quang-De Nguyen, Vanessa F. Merino, Sibgat Choudhury, Gabrielle Ethington, Laura Panos, Michael Grant, William Herlihy, Alfred Au, Gedge D. Rosson, Pedram Argani, Andrea L. Richardson, Deborah Dillon, D. Craig Allred, Kirsten Babski, Elizabeth Min Hui Kim, Charles H. McDonnell, Jon Wagner, Ron Rowberry, Kristie Bobolis, Celina G. Kleer, E. Shelley Hwang, Joanne L. Blum, Simona Cristea, Piotr Sicinski, Rong Fan, Henry W. Long, Saraswati Sukumar, So Yeon Park, Judy E. Garber, Mina Bissell, Jun Yao, Kornelia Polyak

المصدر: Nature Communications, Vol 10, Iss 1, Pp 1-16 (2019)

مصطلحات موضوعية: Science

الوصف: Myoepithelial cells prevent tumour growth and invasion in DCIS. Here, the authors show that p63 and TCF7 cooperate to regulate a transcription factor network for the maintenance of normal myoepithelial function and altered expression of these genes perturb myoepithelial function in DCIS to promote invasive progression.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/784cf49197cf4d50824d3974f6c39d75Test

المؤلفون: Rozanna L Slade, Federica Pisaneschi, Quang-De Nguyen, Graham Smith, Laurence Carroll, Alice Beckley, Maciej A Kaliszczak, Eric O Aboagye

المصدر: PLoS ONE, Vol 11, Iss 8, p e0161427 (2016)

مصطلحات موضوعية: Medicine, Science

الوصف: BackgroundThe epidermal growth factor receptor (EGFR) is overexpressed in many cancers including lung, ovarian, breast, head and neck and brain. Mutation of this receptor has been shown to play a crucial role in the response of non-small cell lung carcinoma (NSCLC) to EGFR-targeted therapies. It is envisaged that imaging of EGFR using positron emission tomography (PET) could aid in selection of patients for treatment with novel inhibitors. We recognised multi-drug resistant phenotype as a threat to development of successful imaging agents. In this report, we describe discovery of a novel cyanoquinoline radiotracer that lacks ABC transporter activity.MethodsCellular retention of the prototype cyanoquinoline [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-({[1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}amino)-but-2-enamide ([18F]FED6) and [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-[({1-[(2R,5S)-3-fluoro-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]-1H-1,2,3-triazol-4-yl}methyl)amino]but-2-enamide ([18F]FED20) were evaluated to establish potential for imaging specificity. The substrate specificity of a number of cyanoquinolines towards ABC transporters was investigated in cell lines proficient or deficient in ABCB1 or ABCG2.ResultsFED6 demonstrated substrate specificity for both ABCG2 and ABCB1, a property that was not observed for all cyanoquinolines tested, suggesting scope for designing novel probes. ABC transporter activity was confirmed by attenuating the activity of transporters with drug inhibitors or siRNA. We synthesized a more hydrophilic compound [18F]FED20 to overcome ABC transporter activity. FED20 lacked substrate specificity for both ABCB1 and ABCG2, and maintained a strong affinity for EGFR. Furthermore, FED20 showed higher inhibitory affinity for active mutant EGFR versus wild-type or resistant mutant EGFR; this property resulted in higher [18F]FED20 cellular retention in active mutant EGFR expressing NSCLC.Conclusion[18F]FED20 binds EGFR but is devoid of ABC transporter activity, thus, has potential for EGFR imaging.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1932-6203Test

الوصول الحر: https://doaj.org/article/90d6ea89b11749b29a6f1bf611af8b27Test

المؤلفون: Martin K. Bakht, Yasutaka Yamada, Sheng-Yu Ku, Varadha Balaji Venkadakrishnan, Joshua A. Korsen, Teja M. Kalidindi, Kei Mizuno, Shin Hye Ahn, Ji-Heui Seo, Maria Mica Garcia, Francesca Khani, Olivier Elemento, Henry W. Long, Alain Chaglassian, Nagavarakishore Pillarsetty, Jason S. Lewis, Matthew Freedman, Anthony P. Belanger, Quang-De Nguyen, Himisha Beltran

المصدر: Nature Cancer. 4:699-715

مصطلحات موضوعية: Cancer Research, Oncology

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::8055913d919d251e89a3a93d03518d65Test
https://doi.org/10.1038/s43018-023-00539-6Test

المؤلفون: Poplawski, Sarah E., Hallett, Robin M., Dornan, Mark H., Novakowski, Kyle E., Shuang Pan, Belanger, Anthony P., Quang-De Nguyen, Wengen Wu, Felten, Albert E., Yuxin Liu, Shin Hye Ahn, Hergott, Valerie S., Jones, Barry, Lai, Jack H., McCann, Joe A. B., Bachovchin, William W.

المصدر: Journal of Nuclear Medicine; Jan2024, Vol. 65 Issue 1, p100-108, 9p

المؤلفون: Eshini Panditharatna, Joana G. Marques, Tingjian Wang, Maria C. Trissal, Ilon Liu, Li Jiang, Alexander Beck, Andrew Groves, Neekesh V. Dharia, Deyao Li, Samantha E. Hoffman, Guillaume Kugener, McKenzie L. Shaw, Hafsa M. Mire, Olivia A. Hack, Joshua M. Dempster, Caleb Lareau, Lingling Dai, Logan H. Sigua, Michael A. Quezada, Ann-Catherine J. Stanton, Meghan Wyatt, Zohra Kalani, Amy Goodale, Francisca Vazquez, Federica Piccioni, John G. Doench, David E. Root, Jamie N. Anastas, Kristen L. Jones, Amy Saur Conway, Sylwia Stopka, Michael S. Regan, Yu Liang, Hyuk-Soo Seo, Kijun Song, Puspalata Bashyal, William P. Jerome, Nathan D. Mathewson, Sirano Dhe-Paganon, Mario L. Suvà, Angel M. Carcaboso, Cinzia Lavarino, Jaume Mora, Quang-De Nguyen, Keith L. Ligon, Yang Shi, Sameer Agnihotri, Nathalie Y.R. Agar, Kimberly Stegmaier, Charles D. Stiles, Michelle Monje, Todd R. Golub, Jun Qi, Mariella G. Filbin

المصدر: Cancer Discovery. :OF1-OF26

مصطلحات موضوعية: Mammals, Epigenome, Oncology, Mutation, Neoplastic Stem Cells, DNA Helicases, Animals, Humans, Nuclear Proteins, Glioma, Transcription Factors

الوصف: Diffuse midline gliomas are uniformly fatal pediatric central nervous system cancers that are refractory to standard-of-care therapeutic modalities. The primary genetic drivers are a set of recurrent amino acid substitutions in genes encoding histone H3 (H3K27M), which are currently undruggable. These H3K27M oncohistones perturb normal chromatin architecture, resulting in an aberrant epigenetic landscape. To interrogate for epigenetic dependencies, we performed a CRISPR screen and show that patient-derived H3K27M-glioma neurospheres are dependent on core components of the mammalian BAF (SWI/SNF) chromatin remodeling complex. The BAF complex maintains glioma stem cells in a cycling, oligodendrocyte precursor cell–like state, in which genetic perturbation of the BAF catalytic subunit SMARCA4 (BRG1), as well as pharmacologic suppression, opposes proliferation, promotes progression of differentiation along the astrocytic lineage, and improves overall survival of patient-derived xenograft models. In summary, we demonstrate that therapeutic inhibition of the BAF complex has translational potential for children with H3K27M gliomas. Significance: Epigenetic dysregulation is at the core of H3K27M-glioma tumorigenesis. Here, we identify the BRG1–BAF complex as a critical regulator of enhancer and transcription factor landscapes, which maintain H3K27M glioma in their progenitor state, precluding glial differentiation, and establish pharmacologic targeting of the BAF complex as a novel treatment strategy for pediatric H3K27M glioma.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::53149d7866fec5060943e9c04bc735cfTest
https://doi.org/10.1158/2159-8290.cd-21-1491Test

المؤلفون: Mariella G. Filbin, Jun Qi, Todd R. Golub, Michelle Monje, Charles D. Stiles, Kimberly Stegmaier, Nathalie Y.R. Agar, Sameer Agnihotri, Yang Shi, Keith L. Ligon, Quang-De Nguyen, Jaume Mora, Cinzia Lavarino, Angel M. Carcaboso, Mario L. Suvà, Sirano Dhe-Paganon, Nathan D. Mathewson, William P. Jerome, Puspalata Bashyal, Kijun Song, Hyuk-Soo Seo, Yu Liang, Michael S. Regan, Sylwia Stopka, Amy Saur Conway, Kristen L. Jones, Jamie N. Anastas, David E. Root, John G. Doench, Federica Piccioni, Francisca Vazquez, Amy Goodale, Zohra Kalani, Meghan Wyatt, Ann-Catherine J. Stanton, Michael A. Quezada, Logan H. Sigua, Lingling Dai, Caleb Lareau, Joshua M. Dempster, Olivia A. Hack, Hafsa M. Mire, McKenzie L. Shaw, Guillaume Kugener, Samantha E. Hoffman, Deyao Li, Neekesh V. Dharia, Andrew Groves, Alexander Beck, Li Jiang, Ilon Liu, Maria C. Trissal, Tingjian Wang, Joana G. Marques, Eshini Panditharatna

الوصف: Supplementary Table from BAF Complex Maintains Glioma Stem Cells in Pediatric H3K27M Glioma

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0d35750181befe4f5da4f650722948e9Test
https://doi.org/10.1158/2159-8290.22541856.v1Test