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Article: Emerging target discovery and drug repurposing opportunities in chordoma.

Freed, Daniel M / Sommer, Josh / Punturi, Nindo

2022 Volume 12, Page(s) 1009193

Abstract: The development of effective and personalized treatment options for patients with rare cancers like chordoma is hampered by numerous challenges. Biomarker-guided repurposing of therapies approved in other indications remains the fastest path to ... ...

Abstract	The development of effective and personalized treatment options for patients with rare cancers like chordoma is hampered by numerous challenges. Biomarker-guided repurposing of therapies approved in other indications remains the fastest path to redefining the treatment paradigm, but chordoma's low mutation burden limits the impact of genomics in target discovery and precision oncology efforts. As our knowledge of oncogenic mechanisms across various malignancies has matured, it's become increasingly clear that numerous properties of tumors transcend their genomes - leading to new and uncharted frontiers of therapeutic opportunity. In this review, we discuss how the implementation of cutting-edge tools and approaches is opening new windows into chordoma's vulnerabilities. We also note how a convergence of emerging observations in chordoma and other cancers is leading to the identification and evaluation of new therapeutic hypotheses for this rare cancer.
Language	English
Publishing date	2022-10-27
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.1009193
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Article ; Online: Painless vision loss.

Freed, Daniel M / Chu, Terence

American family physician

2014 Volume 90, Issue 11, Page(s) 791–792

MeSH term(s)	Adult ; Diagnosis, Differential ; Eye Diseases/diagnosis ; Female ; Humans ; Retinal Vein Occlusion/complications ; Retinal Vein Occlusion/diagnosis ; Retinal Vein Occlusion/therapy ; Vision Disorders/diagnosis ; Vision Disorders/etiology ; Vision Disorders/therapy
Language	English
Publishing date	2014-12-01
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	412694-4
ISSN	1532-0650 ; 0002-838X ; 0572-3612
ISSN (online)	1532-0650
ISSN	0002-838X ; 0572-3612
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Article ; Online: Activity of pemetrexed in pre-clinical chordoma models and humans.

Kesari, Santosh / Wang, Feng / Juarez, Tiffany / Ashili, Shashaanka / Patro, C Pawan K / Carrillo, Jose / Nguyen, Minhdan / Truong, Judy / Levy, Joan / Sommer, Josh / Freed, Daniel M / Xiu, Joanne / Takasumi, Yuki / Bouffet, Eric / Gill, Jaya M

Scientific reports

2023 Volume 13, Issue 1, Page(s) 7317

Abstract: Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular ... ...

Abstract	Chordomas are rare slow growing tumors, arising from embryonic remnants of notochord with a close predilection for the axial skeleton. Recurrence is common and no effective standard medical therapy exists. Thymidylate synthase (TS), an intracellular enzyme, is a key rate-limiting enzyme of DNA biosynthesis and repair which is primarily active in proliferating and metabolically active cells. Eighty-four percent of chordoma samples had loss of TS expression which may predict response to anti-folates. Pemetrexed suppresses tumor growth by inhibiting enzymes involved in folate metabolism, resulting in decreased availability of thymidine which is necessary for DNA synthesis. Pemetrexed inhibited growth in a preclinical mouse xenograft model of human chordoma. We report three cases of metastatic chordoma that had been heavily treated previously with a variety of standard therapies with poor response. In two cases, pemetrexed was added and objective responses were observed on imaging with one patient on continuous treatment for > 2 years with continued shrinkage. One case demonstrated tumor growth after treatment with pemetrexed. The two cases which had a favorable response had a loss of TS expression, whereas the one case with progressive disease had TS present. These results demonstrate the activity of pemetrexed in recurrent chordoma and warrant a prospective clinical trial which is ongoing (NCT03955042).
MeSH term(s)	Humans ; Animals ; Mice ; Pemetrexed/pharmacology ; Pemetrexed/therapeutic use ; Chordoma/drug therapy ; Prospective Studies ; Guanine/pharmacology ; Guanine/therapeutic use ; Glutamates/therapeutic use ; Glutamates/pharmacology ; Neoplasm Recurrence, Local/drug therapy ; DNA ; Thymidylate Synthase/genetics ; Thymidylate Synthase/metabolism
Chemical Substances	Pemetrexed (04Q9AIZ7NO) ; Guanine (5Z93L87A1R) ; Glutamates ; DNA (9007-49-2) ; Thymidylate Synthase (EC 2.1.1.45)
Language	English
Publishing date	2023-05-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-34404-4
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Article ; Online: Mapping the landscape of genetic dependencies in chordoma.

Sharifnia, Tanaz / Wawer, Mathias J / Goodale, Amy / Lee, Yenarae / Kazachkova, Mariya / Dempster, Joshua M / Muller, Sandrine / Levy, Joan / Freed, Daniel M / Sommer, Josh / Kalfon, Jérémie / Vazquez, Francisca / Hahn, William C / Root, David E / Clemons, Paul A / Schreiber, Stuart L

Nature communications

2023 Volume 14, Issue 1, Page(s) 1933

Abstract: Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map ... ...

Abstract	Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets. This approach confirms a known chordoma dependency, TBXT (T; brachyury), and identifies a range of additional dependencies, including PTPN11, ADAR, PRKRA, LUC7L2, SRRM2, SLC2A1, SLC7A5, FANCM, and THAP1. CDK6, SOX9, and EGFR, genes previously implicated in chordoma biology, are also recovered. We find genomic and transcriptomic features that predict specific dependencies, including interferon-stimulated gene expression, which correlates with ADAR dependence and is elevated in chordoma. Validating the therapeutic relevance of dependencies, small-molecule inhibitors of SHP2, encoded by PTPN11, have potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.
MeSH term(s)	Humans ; Chordoma/genetics ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Genes, Essential ; Gene Expression Profiling ; Transcriptome ; Cell Line, Tumor ; DNA-Binding Proteins/metabolism ; Apoptosis Regulatory Proteins/genetics ; DNA Helicases/metabolism
Chemical Substances	THAP1 protein, human ; DNA-Binding Proteins ; Apoptosis Regulatory Proteins ; FANCM protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2023-04-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37593-8
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Article ; Online: Ligand regulation of a constitutively dimeric EGF receptor.

Freed, Daniel M / Alvarado, Diego / Lemmon, Mark A

Nature communications

2015 Volume 6, Page(s) 7380

Abstract: Ligand-induced receptor dimerization has traditionally been viewed as the key event in transmembrane signalling by epidermal growth factor receptors (EGFRs). Here we show that the Caenorhabditis elegans EGFR orthologue LET-23 is constitutively dimeric, ... ...

Abstract	Ligand-induced receptor dimerization has traditionally been viewed as the key event in transmembrane signalling by epidermal growth factor receptors (EGFRs). Here we show that the Caenorhabditis elegans EGFR orthologue LET-23 is constitutively dimeric, yet responds to its ligand LIN-3 without changing oligomerization state. SAXS and mutational analyses further reveal that the preformed dimer of the LET-23 extracellular region is mediated by its domain II dimerization arm and resembles other EGFR extracellular dimers seen in structural studies. Binding of LIN-3 induces only minor structural rearrangements in the LET-23 dimer to promote signalling. Our results therefore argue that EGFR can be regulated by allosteric changes within an existing receptor dimer--resembling signalling by insulin receptor family members, which share similar extracellular domain compositions but form covalent dimers.
MeSH term(s)	Animals ; Caenorhabditis elegans/metabolism ; Cell Line ; Dimerization ; Drosophila melanogaster ; ErbB Receptors/chemistry ; ErbB Receptors/metabolism ; Ligands
Chemical Substances	Ligands ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2015-06-10
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms8380
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Article ; Online: Deletion Mutations Keep Kinase Inhibitors in the Loop.

Freed, Daniel M / Park, Jin H / Radhakrishnan, Ravi / Lemmon, Mark A

Cancer cell

2016 Volume 29, Issue 4, Page(s) 423–425

Abstract: Effective clinical application of conformationally selective kinase inhibitors requires tailoring drug choice to the tumor's activating mutation(s). In this issue of Cancer Cell, Foster et al. (2016) describe how activating deletions in BRAF, EGFR, and ... ...

Abstract	Effective clinical application of conformationally selective kinase inhibitors requires tailoring drug choice to the tumor's activating mutation(s). In this issue of Cancer Cell, Foster et al. (2016) describe how activating deletions in BRAF, EGFR, and HER2 cause primary resistance to common inhibitors, suggesting strategies for improved inhibitor selection.
MeSH term(s)	Carcinoma, Non-Small-Cell Lung/drug therapy ; Drug Resistance, Neoplasm/genetics ; Humans ; Lung Neoplasms/genetics ; Mutation ; Neoplasms/genetics ; Protein Kinase Inhibitors/pharmacology ; Receptor, Epidermal Growth Factor/genetics ; Sequence Deletion
Chemical Substances	Protein Kinase Inhibitors ; Receptor, Epidermal Growth Factor (EC 2.7.10.1)
Language	English
Publishing date	2016-04-11
Publishing country	United States
Document type	Comment ; Journal Article
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2016.03.017
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Article ; Online: The Dark Side of Cell Signaling: Positive Roles for Negative Regulators.

Lemmon, Mark A / Freed, Daniel M / Schlessinger, Joseph / Kiyatkin, Anatoly

Cell

2016 Volume 164, Issue 6, Page(s) 1172–1184

Abstract: Cell signaling is dominated by analyzing positive responses to stimuli. Signal activation is balanced by negative regulators that are generally considered to terminate signaling. Rather than exerting only negative effects, however, many such regulators ... ...

Abstract	Cell signaling is dominated by analyzing positive responses to stimuli. Signal activation is balanced by negative regulators that are generally considered to terminate signaling. Rather than exerting only negative effects, however, many such regulators play important roles in enhancing cell-signaling control. Considering responses downstream of selected cell-surface receptors, we discuss how receptor internalization affects signaling specificity and how rapid kinase/phosphatase and GTP/GDP cycles increase responsiveness and allow kinetic proofreading in receptor signaling. We highlight the blurring of distinctions between positive and negative signals, recasting signal termination as the response to a switch-like transition into a new cellular state.
MeSH term(s)	Animals ; Feedback, Physiological ; Humans ; Phosphorylation ; Receptor Protein-Tyrosine Kinases/metabolism ; Receptors, G-Protein-Coupled/metabolism ; Signal Transduction
Chemical Substances	Receptors, G-Protein-Coupled ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2016-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2016.02.047
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Article ; Online: Putting together structures of epidermal growth factor receptors.

Bessman, Nicholas J / Freed, Daniel M / Lemmon, Mark A

Current opinion in structural biology

2014 Volume 29, Page(s) 95–101

Abstract: Numerous crystal structures have been reported for the isolated extracellular region and tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and its relatives, in different states of activation and bound to a variety of inhibitors used ... ...

Abstract	Numerous crystal structures have been reported for the isolated extracellular region and tyrosine kinase domain of the epidermal growth factor receptor (EGFR) and its relatives, in different states of activation and bound to a variety of inhibitors used in cancer therapy. The next challenge is to put these structures together accurately in functional models of the intact receptor in its membrane environment. The intact EGFR has been studied using electron microscopy, chemical biology methods, biochemically, and computationally. The distinct approaches yield different impressions about the structural modes of communication between extracellular and intracellular regions. They highlight possible differences between ligands, and also underline the need to understand how the receptor interacts with the membrane itself.
MeSH term(s)	Epidermal Growth Factor/chemistry ; ErbB Receptors/chemistry ; Humans ; Ligands ; Microscopy, Electron ; Protein Multimerization
Chemical Substances	Ligands ; Epidermal Growth Factor (62229-50-9) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2014-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2014.10.002
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Article ; Online: Regulation of Kinase Activity in the Caenorhabditis elegans EGF Receptor, LET-23.

Liu, Lijun / Thaker, Tarjani M / Freed, Daniel M / Frazier, Nicole / Malhotra, Ketan / Lemmon, Mark A / Jura, Natalia

Structure (London, England : 1993)

2018 Volume 26, Issue 2, Page(s) 270–281.e4

Abstract: In the active HER receptor dimers, kinases play distinct roles; one is the catalytically active kinase and the other is its allosteric activator. This specialization enables signaling by the catalytically inactive HER3, which functions exclusively as an ... ...

Abstract	In the active HER receptor dimers, kinases play distinct roles; one is the catalytically active kinase and the other is its allosteric activator. This specialization enables signaling by the catalytically inactive HER3, which functions exclusively as an allosteric activator upon heterodimerization with other HER receptors. It is unclear whether the allosteric activation mechanism evolved before HER receptors functionally specialized. We determined the crystal structure of the kinase domain of the only EGF receptor in Caenorhabditis elegans, LET-23. Our structure of a non-human EGFR kinase reveals autoinhibitory features conserved in the human counterpart. Strikingly, mutations within the putative allosteric dimer interface abrogate activity of the isolated LET-23 kinase and of the full-length receptor despite these regions being only partially conserved with human EGFR. Our results indicate that ancestral EGFRs have built-in features that poise them for allosteric activation that could facilitate emergence of the catalytically dead, yet functional, orthologs.
MeSH term(s)	Animals ; Caenorhabditis elegans ; Caenorhabditis elegans Proteins/metabolism ; Dimerization ; ErbB Receptors/metabolism ; Phosphorylation ; Phosphotransferases/metabolism ; Signal Transduction/physiology
Chemical Substances	Caenorhabditis elegans Proteins ; Phosphotransferases (EC 2.7.-) ; ErbB Receptors (EC 2.7.10.1) ; let-23 protein, C elegans (EC 2.7.10.1)
Language	English
Publishing date	2018-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1213087-4
ISSN	1878-4186 ; 0969-2126
ISSN (online)	1878-4186
ISSN	0969-2126
DOI	10.1016/j.str.2017.12.012
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Article ; Online: Lipid and membrane mimetic environments modulate spin label side chain configuration in the outer membrane protein A.

Jiménez, Ricardo H Flores / Freed, Daniel M / Cafiso, David S

The journal of physical chemistry. B

2011 Volume 115, Issue 49, Page(s) 14822–14830

Abstract: In the present work, the factors that determine EPR line shapes from spin labels at the protein-hydrocarbon interface of a β-barrel membrane protein are examined. The EPR spectra from hydrocarbon facing sites in the outer membrane protein A (OmpA) are ... ...

Abstract	In the present work, the factors that determine EPR line shapes from spin labels at the protein-hydrocarbon interface of a β-barrel membrane protein are examined. The EPR spectra from hydrocarbon facing sites in the outer membrane protein A (OmpA) are highly dependent upon the detergent or lipid into which OmpA is reconstituted. In general, line shapes at these sites are correlated with the solvent accessibility in the supporting amphiphile. A notable exception is CHAPS, which yields rigid limit EPR line shapes for labels at every position along a transmembrane β-strand in OmpA. EPR line shapes from the surface of OmpA are not strongly influenced by steric interference with neighboring side chains, but are modulated by solutes that should interact with hydrophobic surfaces. These results suggest that differences in EPR spectra in different supporting environments are not the result of differences in protein dynamics but are a result of different configurations or rotameric states that are assumed by the label. This conclusion is supported by distance measurements across the OmpA β-barrel, which indicate that labels yielding more motionally restricted line shapes interact more closely with the protein surface. These results have implications for the use of spin-label-derived distance constraints in protein structure determination and demonstrate that spin labels on membrane proteins provide a highly sensitive probe for the environment surrounding a membrane protein.
MeSH term(s)	Bacterial Outer Membrane Proteins/chemistry ; Cholic Acids/chemistry ; Detergents/chemistry ; Electron Spin Resonance Spectroscopy ; Escherichia coli/metabolism ; Hydrogen Bonding ; Lipid Bilayers/chemistry ; Micelles ; Phosphorylcholine/analogs & derivatives ; Phosphorylcholine/chemistry ; Spin Labels
Chemical Substances	Bacterial Outer Membrane Proteins ; Cholic Acids ; Detergents ; Lipid Bilayers ; Micelles ; Spin Labels ; Phosphorylcholine (107-73-3) ; OMPA outer membrane proteins (149024-69-1) ; dodecylphosphocholine (53949-18-1) ; 3-((3-cholamidopropyl)dimethylammonium)-1-propanesulfonate (QBP25342AG)
Language	English
Publishing date	2011-11-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1520-5207
ISSN (online)	1520-5207
DOI	10.1021/jp207420d
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