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Article ; Online: Chemoenzymatic Synthesis of Novel Cytotoxic Epoxyketones Using the Eponemycin Biosynthetic Enzyme EpnF.

Corless, Broderick C / Geißen, Raphael / Prescott, Nicholas A / David, Yael / Scheinberg, David A / Tan, Derek S

ACS chemical biology

2023 Volume 18, Issue 6, Page(s) 1360–1367

Abstract: Eponemycin is an α,β-epoxyketone natural product that inhibits the ... ...

Abstract	Eponemycin is an α,β-epoxyketone natural product that inhibits the proteasome
MeSH term(s)	Proteasome Inhibitors/metabolism ; Antineoplastic Agents/pharmacology ; Amides/chemistry ; Serine/chemistry
Chemical Substances	eponemycin (126509-46-4) ; Proteasome Inhibitors ; Antineoplastic Agents ; Amides ; Serine (452VLY9402)
Language	English
Publishing date	2023-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.3c00080
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Article ; Online: Development of a

Lee, J Peter / Corless, Broderick C / Gardner, Thomas J / Scheinberg, David A / Tan, Derek S

Organic letters

2023 Volume 25, Issue 34, Page(s) 6295–6299

Abstract: Directed enzyme-prodrug therapies used for targeted drug delivery require prodrugs that are chemically stable and processed efficiently by the activating enzyme. We recently reported the development of AMS-6-Glu ( ...

Abstract	Directed enzyme-prodrug therapies used for targeted drug delivery require prodrugs that are chemically stable and processed efficiently by the activating enzyme. We recently reported the development of AMS-6-Glu (
MeSH term(s)	Prodrugs/pharmacology ; gamma-Glutamyl Hydrolase ; Glutamic Acid ; Antineoplastic Agents ; Drug Delivery Systems
Chemical Substances	Prodrugs ; gamma-Glutamyl Hydrolase (EC 3.4.19.9) ; Glutamic Acid (3KX376GY7L) ; Antineoplastic Agents
Language	English
Publishing date	2023-08-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1523-7052
ISSN (online)	1523-7052
DOI	10.1021/acs.orglett.3c02130
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Article: Host-cell Interactions of Engineered T cell Micropharmacies.

Bourne, Christopher M / Wallisch, Patrick / Dacek, Megan / Gardner, Thomas / Pierre, Stephanie / Vogt, Kristen / Corless, Broderick C / Bah, Mamadou A / Romero Pichardo, Jesus / Charles, Angel / Kurtz, Keifer G / Tan, Derek S / Scheinberg, David A

bioRxiv : the preprint server for biology

2023

Abstract: Genetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, ... ...

Abstract	Genetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with an orthogonal killing mechanism to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Here, we also expand the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with TCR-engineered T cells. We demonstrate that SEAKER cells localize specifically to tumors, and activate bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells are efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
Language	English
Publishing date	2023-05-01
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.05.535717
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Article ; Online: Host Interactions with Engineered T-cell Micropharmacies.

Bourne, Christopher M / Wallisch, Patrick / Dacek, Megan M / Gardner, Thomas J / Pierre, Stephanie / Vogt, Kristen / Corless, Broderick C / Bah, Mamadou A / Romero-Pichardo, Jesus E / Charles, Angel / Kurtz, Keifer G / Tan, Derek S / Scheinberg, David A

Cancer immunology research

2023 Volume 11, Issue 9, Page(s) 1253–1265

Abstract: Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More ... ...

Abstract	Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
MeSH term(s)	Mice ; Animals ; Humans ; Immunotherapy, Adoptive ; T-Lymphocytes, Cytotoxic ; Genetic Engineering ; Melanoma ; Receptors, Antigen, T-Cell/genetics
Chemical Substances	Receptors, Antigen, T-Cell
Language	English
Publishing date	2023-07-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-22-0879
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Zs.A 7022: Show issues

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Article ; Online: Development of Novel Mutation-Specific Droplet Digital PCR Assays Detecting TERT Promoter Mutations in Tumor and Plasma Samples.

Corless, Broderick C / Chang, Gregory A / Cooper, Samantha / Syeda, Mahrukh M / Shao, Yongzhao / Osman, Iman / Karlin-Neumann, George / Polsky, David

The Journal of molecular diagnostics : JMD

2018 Volume 21, Issue 2, Page(s) 274–285

Abstract: Detecting mutations in the plasma of patients with solid tumors is becoming a valuable method of diagnosing and monitoring cancer. The TERT promoter is mutated at high frequencies in multiple cancer types, most commonly at positions -124 and -146 ( ... ...

Abstract	Detecting mutations in the plasma of patients with solid tumors is becoming a valuable method of diagnosing and monitoring cancer. The TERT promoter is mutated at high frequencies in multiple cancer types, most commonly at positions -124 and -146 (designated C228T and C250T, respectively). Detection of these mutations has been challenging because of the high GC content of this region (approximately 80%). We describe development of novel probe-based droplet digital PCR assays that specifically detect and quantify these two mutations, along with the less common 242-243 CC>TT mutation, and demonstrate their application using human tumor and plasma samples from melanoma patients. Assay designs and running conditions were optimized using cancer cell line genomic DNAs with the C228T or C250T mutations. The limits of detection were 0.062% and 0.051% mutant allele fraction for the C228T and C250T assays, respectively. Concordance of 100% was observed between droplet digital PCR and sequencing-based orthogonal methods in the detection of TERT mutant DNA in 32 formalin-fixed, paraffin-embedded melanoma tumors. TERT
MeSH term(s)	Humans ; Mutation/genetics ; Polymerase Chain Reaction/methods ; Promoter Regions, Genetic/genetics ; Telomerase/genetics
Chemical Substances	TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2018-10-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2000060-1
ISSN	1943-7811 ; 1525-1578
ISSN (online)	1943-7811
ISSN	1525-1578
DOI	10.1016/j.jmoldx.2018.09.003
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Zs.A 5146: Show issues

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Article ; Online: Engineering CAR-T cells to activate small-molecule drugs in situ.

Gardner, Thomas J / Lee, J Peter / Bourne, Christopher M / Wijewarnasuriya, Dinali / Kinarivala, Nihar / Kurtz, Keifer G / Corless, Broderick C / Dacek, Megan M / Chang, Aaron Y / Mo, George / Nguyen, Kha M / Brentjens, Renier J / Tan, Derek S / Scheinberg, David A

Nature chemical biology

2021 Volume 18, Issue 2, Page(s) 216–225

Abstract: Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell ... ...

Abstract	Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient's own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/therapeutic use ; Drug Delivery Systems ; Female ; HEK293 Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasms/therapy ; Neoplasms, Experimental ; Prodrugs ; Receptors, Chimeric Antigen ; T-Lymphocytes ; Tumor Microenvironment ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents ; Prodrugs ; Receptors, Chimeric Antigen
Language	English
Publishing date	2021-12-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2202962-X
ISSN	1552-4469 ; 1552-4450
ISSN (online)	1552-4469
ISSN	1552-4450
DOI	10.1038/s41589-021-00932-1
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Zs.A 6251: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 90: Show issues

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Article ; Online: Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.

Syeda, Mahrukh M / Wiggins, Jennifer M / Corless, Broderick C / Long, Georgina V / Flaherty, Keith T / Schadendorf, Dirk / Nathan, Paul D / Robert, Caroline / Ribas, Antoni / Davies, Michael A / Grob, Jean Jacques / Gasal, Eduard / Squires, Matthew / Marker, Mahtab / Garrett, James / Brase, Jan C / Polsky, David

The Lancet. Oncology

2021 Volume 22, Issue 3, Page(s) 370–380

Abstract: Background: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large ... ...

Abstract	Background: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes. Methods: In this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAF Findings: In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAF Interpretation: Pretreatment and on-treatment BRAF Funding: Novartis.
MeSH term(s)	Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/secondary ; Circulating Tumor DNA/analysis ; Circulating Tumor DNA/genetics ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Imidazoles/administration & dosage ; Male ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Middle Aged ; Oximes/administration & dosage ; Prognosis ; Pyridones/administration & dosage ; Pyrimidinones/administration & dosage ; Survival Rate
Chemical Substances	Circulating Tumor DNA ; Imidazoles ; Oximes ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; dabrafenib (QGP4HA4G1B)
Language	English
Publishing date	2021-02-12
Publishing country	England
Document type	Clinical Trial, Phase II ; Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't ; Validation Study
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(20)30726-9
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Zs.A 5696: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: TERT, BRAF, and NRAS Mutational Heterogeneity between Paired Primary and Metastatic Melanoma Tumors.

Chang, Gregory A / Wiggins, Jennifer M / Corless, Broderick C / Syeda, Mahrukh M / Tadepalli, Jyothirmayee S / Blake, Shria / Fleming, Nathaniel / Darvishian, Farbod / Pavlick, Anna / Berman, Russell / Shapiro, Richard / Shao, Yongzhao / Karlin-Neumann, George / Spittle, Cindy / Osman, Iman / Polsky, David

The Journal of investigative dermatology

2020 Volume 140, Issue 8, Page(s) 1609–1618.e7

Abstract: Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with ... ...

Abstract	Mutational heterogeneity can contribute to therapeutic resistance in solid cancers. In melanoma, the frequencies of intertumoral and intratumoral heterogeneity are controversial. We examined mutational heterogeneity within individual patients with melanoma using multiplatform analysis of commonly mutated driver and nonpassenger genes. We analyzed paired primary and metastatic tumors from 60 patients and multiple metastatic tumors from 39 patients whose primary tumors were unavailable (n = 271 tumors). We used a combination of multiplex SNaPshot assays, Sanger sequencing, mutation-specific PCR, or droplet digital PCR to determine the presence of BRAF
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Female ; GTP Phosphohydrolases/genetics ; Genetic Heterogeneity ; Humans ; Longitudinal Studies ; Male ; Melanoma/genetics ; Melanoma/mortality ; Melanoma/secondary ; Membrane Proteins/genetics ; Middle Aged ; Mutation ; Neoplasms, Second Primary/drug therapy ; Neoplasms, Second Primary/genetics ; Neoplasms, Second Primary/mortality ; Neoplasms, Second Primary/pathology ; Prospective Studies ; Proto-Oncogene Proteins B-raf/genetics ; Skin/pathology ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/mortality ; Skin Neoplasms/pathology ; Telomerase/genetics
Chemical Substances	Antineoplastic Agents ; Membrane Proteins ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; TERT protein, human (EC 2.7.7.49) ; Telomerase (EC 2.7.7.49) ; GTP Phosphohydrolases (EC 3.6.1.-) ; NRAS protein, human (EC 3.6.1.-)
Language	English
Publishing date	2020-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2020.01.027
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