GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Abstract 991: Brain metastasis depends on tumor cell initiated coagulation
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 991-991
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 991-991
    Abstract: Background: The incidence of brain metastasis exceeds that of primary brain tumors tenfold and is most frequently associated with lung cancer, breast cancer and melanoma. Despite a prognosis of only 6-9 months for patients with brain metastases, mechanisms of tumor cell brain colonization from the blood stream are unknown. Understanding this step could enable effective therapeutic strategies to prevent the development of incurable metastatic brain disease. We found that blood borne metastatic cancer cells reside within the cerebral microvasculature for several days and associate with platelets while crossing the blood brain barrier. Intravascular tumor cell survival and extravasation during this time may critically limit the success of brain metastasis. Activation of coagulation, platelets and fibrin formation contribute to tumor progression, cancer-associated thrombosis and metastatic spread to peripheral organs. However the function of coagulation in the seeding of brain metastases is unknown. Aims: We evaluated whether tumor cell-expressed tissue factor, a key activator of coagulation, promotes tumor cell seeding of brain metastases by initiating critical tumor cell-vascular interactions. Methods: We developed models of experimental brain metastasis to study how intravascular tumor cells cooperate with the coagulation system during early stages of brain colonization to survive and cross the blood brain barrier. Human breast cancer cells, injected into the left cardiac ventricle of immune deficient mice, are tracked during the initial phase of brain metastasis and progressive metastatic brain disease by detailed and quantitative histological analyses. We address how coagulation contributes to brain metastasis by targeting human tissue factor with specific inhibitory antibodies. We use ex-vivo bioluminescence imaging and immunohistochemical analyses at later stages of brain metastasis to determine the extent to which an early, transient treatment will result in long-term inhibition of brain metastatic disease. Results: We demonstrate that inhibition of tissue factor expressed by tumor cells reduces brain colonization. Targeting of tissue factor inhibits development of breast cancer brain metastasis and extends animal survival. We find that tissue factor properties which initiate coagulation or promote cytoprotective signaling pathways differentially contribute to brain metastasis development. Blockade of tissue factor-initiated coagulation inhibits intravascular tumor cell survival and prevents brain metastases in vivo. Our findings indicate that the inhibition of coagulation can prevent the seeding of breast cancer cells into the brain. Conclusions: Our studies provide mechanistic insights into the process of tumor cell brain colonization and identify targets for development of therapeutics to prevent cancer metastasis to the brain and enhance patient survival. Citation Format: Laurie J. Gay, John Day, Sarah LeBoeuf, Melissa Ritland, Zaverio Ruggeri, Wolfram Ruf, Brunhilde H. Felding. Brain metastasis depends on tumor cell initiated coagulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 991. doi:10.1158/1538-7445.AM2014-991
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-991
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract B19: Brain metastasis depends on tumor cell initiated coagulation
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 1_Supplement ( 2015-01-01), p. B19-B19
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 1_Supplement ( 2015-01-01), p. B19-B19
    Abstract: Background: The incidence of brain metastasis exceeds that of primary brain tumors tenfold and is most frequently associated with lung cancer, breast cancer and melanoma. Despite a prognosis of only 6-9 months for patients with brain metastases, mechanisms of tumor cell brain colonization from the blood stream are unknown. Understanding this step could enable effective therapeutic strategies to prevent the development of incurable metastatic brain disease. We found that blood borne metastatic cancer cells reside within the cerebral microvasculature for several days and associate with platelets while crossing the blood brain barrier. Intravascular tumor cell survival and extravasation during this time may critically limit the success of brain metastasis. Activation of coagulation, platelets and fibrin formation contribute to tumor progression, cancer-associated thrombosis and metastatic spread to peripheral organs. However the function of coagulation in the seeding of brain metastases is unknown. Aims: We evaluated whether tumor cell-expressed tissue factor, a key activator of coagulation, promotes tumor cell seeding of brain metastases by initiating critical tumor cell-vascular interactions. Methods: We developed models of experimental brain metastasis to study how intravascular tumor cells cooperate with the coagulation system during early stages of brain colonization to survive and cross the blood brain barrier. Human breast cancer cells, injected into the left cardiac ventricle of immune deficient mice, are tracked during the initial phase of brain metastasis and progressive metastatic brain disease by detailed and quantitative histological analyses. We address how coagulation contributes to brain metastasis by targeting human tissue factor with specific inhibitory antibodies. We use ex-vivo bioluminescence imaging and immunohistochemical analyses at later stages of brain metastasis to determine the extent to which an early, transient treatment will result in long-term inhibition of brain metastatic disease. Results: We demonstrate that inhibition of tissue factor expressed by tumor cells reduces brain colonization. Targeting of tissue factor inhibits development of breast cancer brain metastasis and extends animal survival. We find that tissue factor properties which initiate coagulation or promote cytoprotective signaling pathways differentially contribute to brain metastasis development. Our findings indicate that the inhibition of coagulation can prevent the seeding of breast cancer cells into the brain. Conclusions: Our studies provide mechanistic insights into the process of tumor cell brain colonization and identify targets for development of therapeutics to prevent cancer metastasis to the brain and enhance patient survival. Citation Format: Laurie J. Gay, John Day, Sarah LeBoeuf, Melissa Ritland, Zaverio M. Ruggeri, Wolfram Ruf, Brunhilde H. Felding. Brain metastasis depends on tumor cell initiated coagulation. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B19. doi:10.1158/1538-7445.CHTME14-B19
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.CHTME14-B19
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    The Occupational Military Neuromusculoskeletal Injury Matrix
    Oxford University Press (OUP) ; 2022
    In:  Military Medicine Vol. 187, No. 7-8 ( 2022-07-01), p. e889-e897
    Details
    In: Military Medicine, Oxford University Press (OUP), Vol. 187, No. 7-8 ( 2022-07-01), p. e889-e897
    Abstract: Neuromusculoskeletal injuries (NMSKIs) are the primary cause of ambulatory visits, lost duty days, and disability discharges in the U.S. Military. Methods for accurately grouping injury diagnoses are required to allow for surveillance and research identifying risk factors and prevention strategies. The CDC method of grouping these diagnoses includes only the S and T codes (Injury, poisoning, and certain other consequences of external causes) from the ICD-10-CM. However, this does not include the majority of the NMSKI depleting soldier readiness; the M (Disease of the musculoskeletal system and connective tissue) and G (Diseases of the nervous system) codes should be included as these also contain injuries. The goal was to develop a new matrix that would comprehensively capture all NMSKIs experienced by military personnel. This paper details the development of the Occupational Military Neuromusculoskeletal Injury (OMNI) Matrix and characterizes the number and rates of active duty U.S. Army injuries as measured by the OMNI compared to other matrices. Materials and Methods A team of researchers including physical therapists, physician assistants, occupational therapists, physicians, and epidemiologists developed the OMNI. The OMNI utilizes the commonly accepted injury definition inclusive of any anatomical complaint resulting in pain or dysfunction and categorizes injuries from the G, M, S, and T codes. The OMNI follows the CDC’s matrix structure with three body region levels, each becoming more specific, and adds two levels called Description of the Injury. Additionally, the OMNI categorizes injuries as Injury Type (Acute, Overuse, Either, or Not Applicable), NMSKI-Type (NMSKI, NMSKI that could be caused by occupational/training tasks, and not an NMSKI), and a miscellaneous category that demarks injuries as Superficial, Blood Vessels, and/or Internal Organs. The different grouping methods in the OMNI provide standardization for many possible injury case definitions. The OMNI allows these injury categories to be included/excluded in a standardized fashion to meet the researchers’ scientific questions. To enumerate the number of NMSKI that would be captured by the available matrices, the OMNI, the CDC’s matrix, and the U.S. Army Public Health Center’s (APHC) Taxonomy of Injuries were applied to active duty Army outpatient population data and all incident NMSKI diagnostic codes entered in electronic medical provider encounters for calendar years 2017 and 2018. Results Using the OMNI resulted in the capture of over 800,000 more injuries than the CDC’s matrix and over 200,000 more than the APHC Taxonomy. The NMSKI rate utilizing the OMNI was 193 per 100 soldier-years in 2017 (892,780 NMSKI) compared to 23 per 100 soldier-years for the CDC’s matrix, and 141 per 100 soldier-years for the APHC Taxonomy. Conclusion The OMNI provides an updated standardized method of assessing injuries, particularly in occupational military injury research, that can be utilized for Military Performance Division of injury across many countries and still allow for replication of methods and comparison of results. Additionally, the OMNI has the capacity to capture a greater burden of injury beyond what is captured by other available matrices.
    Type of Medium: Online Resource
    ISSN: 0026-4075 , 1930-613X
    URL: Article
    DOI: 10.1093/milmed/usab300
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2130577-8
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Response to Letter to the Editor on Concerning the Occupational Military Neuromusculoskeletal Injury Matrix
    Oxford University Press (OUP) ; 2022
    In:  Military Medicine Vol. 187, No. 5-6 ( 2022-05-03), p. 163-163
    Details
    In: Military Medicine, Oxford University Press (OUP), Vol. 187, No. 5-6 ( 2022-05-03), p. 163-163
    Type of Medium: Online Resource
    ISSN: 0026-4075 , 1930-613X
    URL: Article
    DOI: 10.1093/milmed/usac068
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2130577-8
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Synthesis of site-specific antibody-drug conjugates using unnatural amino acids
    Proceedings of the National Academy of Sciences ; 2012
    In:  Proceedings of the National Academy of Sciences Vol. 109, No. 40 ( 2012-10-02), p. 16101-16106
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 109, No. 40 ( 2012-10-02), p. 16101-16106
    Abstract: Antibody-drug conjugates (ADCs) allow selective targeting of cytotoxic drugs to cancer cells presenting tumor-associated surface markers, thereby minimizing systemic toxicity. Traditionally, the drug is conjugated nonselectively to cysteine or lysine residues in the antibody. However, these strategies often lead to heterogeneous products, which make optimization of the biological, physical, and pharmacological properties of an ADC challenging. Here we demonstrate the use of genetically encoded unnatural amino acids with orthogonal chemical reactivity to synthesize homogeneous ADCs with precise control of conjugation site and stoichiometry. p -Acetylphenylalanine was site-specifically incorporated into an anti-Her2 antibody Fab fragment and full-length IgG in Escherichia coli and mammalian cells, respectively. The mutant protein was selectively and efficiently conjugated to an auristatin derivative through a stable oxime linkage. The resulting conjugates demonstrated excellent pharmacokinetics, potent in vitro cytotoxic activity against Her2 + cancer cells, and complete tumor regression in rodent xenograft treatment models. The synthesis and characterization of homogeneous ADCs with medicinal chemistry-like control over macromolecular structure should facilitate the optimization of ADCs for a host of therapeutic uses.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1211023109
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2012
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Nicotinamide phosphoribosyltransferase can affect metastatic activity and cell adhesive functions by regulating integrins in breast cancer
    Elsevier BV ; 2014
    In:  DNA Repair Vol. 23 ( 2014-11), p. 79-87
    Details
    In: DNA Repair, Elsevier BV, Vol. 23 ( 2014-11), p. 79-87
    Type of Medium: Online Resource
    ISSN: 1568-7864
    URL: Article
    DOI: 10.1016/j.dnarep.2014.08.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
    detail.hit.zdb_id: 2082770-2
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids
    Springer Science and Business Media LLC ; 2017
    In:  Cancer & Metabolism Vol. 5, No. 1 ( 2017-12)
    Details
    In: Cancer & Metabolism, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2017-12)
    Type of Medium: Online Resource
    ISSN: 2049-3002
    URL: Article
    DOI: 10.1186/s40170-017-0171-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2017
    detail.hit.zdb_id: 2700141-6
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Abstract 2392: A multiplex histone H3 PTM assay for epigenetic biomarker discovery in tissue biopsy and archived clinical samples
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2392-2392
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2392-2392
    Abstract: Dysregulation of epigenetic mechanisms is known to play an important role in the development and progression of cancer. One such mechanism is manifested as altered levels of histone modifications involved in regulating gene transcription. N-terminal histone tails can have a variety of modifications, such as phosphorylation, methylation and acetylation at specific amino acid residues which are conserved throughout eukaryotes and function by altering chromatin structure and creating binding sites for chromatin readers, writers or erasers. Numerous studies have reported aberrant global levels of several histone H3 and H4 post-translational modifications (PTMs) in a wide range of solid tumor types. These changes have been shown to be predictive of clinical outcome, raising the possibility that histone modifications have potential as epigenetic biomarkers. Clinical samples have immense potential for biomarker identification since they are often accompanied with valuable information pertaining to patient history, treatment courses and disease outcome. The preferred method for clinical sample preservation is formalin-fixation followed by paraffin embedding (FFPE). While extraction and downstream analysis of DNA and RNA from FFPE samples is now routine, proteomic studies of FFPE samples is hampered by extensive protein cross-linking generated by formalin fixation. Analysis of histone PTMs in patient archival samples is limited to low-throughput immunohistochemical staining, and is not an ideal approach for mining large sample cohorts for biomarker identification. Western blot or ELISA methods, which have large sample requirements, are simply not an option for FFPE samples. We have developed a multiplex bead-based ELISA assay which enables simultaneous interrogation of thirteen histone H3 PTMs. The assay is performed in 96-well plates and is ideally suited for profiling histone modification levels in limiting or small samples. We will present the application of this technology in a variety of sample types including frozen tissue, formaldehyde-cross linked cells and tissues, and in small molecule inhibitor screens with as few as 2,000 cells per well. The ability to simultaneous detect up to thirteen histone H3 PTMs provides a unique feature that enables determination of for on-target and off-target effects within the same sample. Citation Format: Mary Anne Jelinek, Melissa Ritland, AJ Westergren. A multiplex histone H3 PTM assay for epigenetic biomarker discovery in tissue biopsy and archived clinical samples [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 2392. doi:10.1158/1538-7445.AM2017-2392
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-2392
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Abstract IA3: Normalizing tumor cell metabolism in breast cancer metastasis: A novel therapeutic approach
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 3_Supplement ( 2013-02-01), p. IA3-IA3
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 3_Supplement ( 2013-02-01), p. IA3-IA3
    Abstract: Despite advances in clinical therapy, metastasis is still the leading cause of death in breast cancer patients. A better understanding of mechanisms that drive metastasis is a prerequisite for new approaches to effectively prevent and inhibit this most dangerous advancement of the disease. While alterations in the nuclear genome are pivotal in oncogenesis, a role of mitochondria in cancer progression has remained largely unexplored. Mutations in mitochondrial DNA are found in breast tumors and other cancers, however their involvement in driving the disease is unclear. Our study identifies mitochondrial complex I as critical for defining an aggressive phenotype in breast cancer cells. Complex I is the gate-keeper of the respiratory chain and catalyzes the first step of NADH oxidation. It elevates the cellular NAD+/NADH ratio and translocates protons across the inner mitochondrial membrane, which ultimately leads to energy production. We used a unique approach to define contributions of mitochondrial complex I activity to breast cancer progression, based on expression of yeast NADH dehydrogenase Ndi1. Ndi1 encodes a single protein that translocates to mitochondrial, faces the inner mitochondrial matrix and oxidizes NADH from the Krebs cycle. Specific enhancement of mitochondrial complex I activity by Ndi1 expression inhibited tumor growth and metastasis through regulation of the tumor cell NAD+/NADH redox balance, mTORC1 activity, and autophagy. Conversely, non-lethal reduction of NAD+ levels by interfering with nicotinamide phosphoribosyltransferase expression to disturb the NAD+ synthesis and recycling pathway, rendered tumor cells more aggressive and increased metastasis. Thus, the results indicate a cause-and-effect relationship between reduced NAD+/NADH ratios and metastatic activity. Having established that enhancement of NAD+/NADH levels by augmenting breast cancer cell complex I activity inhibits tumorigenicity and metastasis, we used this new concept therapeutically and hypothesized that supplementing tumor cell nutrients with NAD+ precursors, such as nicotinic acid (NIC) or nicotinamide (NAM), could interfere with breast cancer progression. We demonstrate that enhancing NAD+ levels through NAD+ precursor treatment effectively inhibits experimental metastasis of human breast cancer cells in xenograft models. Importantly, this treatment also inhibited spontaneous metastasis, and increased animal survival when the therapy was started after surgical removal of primary tumors. Furthermore, NAD+ precursor treatment strongly interferes with oncogene driven breast cancer development and progression in transgenic MMTV-PyMT mice. Thus, aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells while therapeutic normalization of the NAD+/NADH balance can inhibit metastasis and prevent disease progression. Our study demonstrates that mitochondrial complex I regulation of tumor cell NAD+/NADH levels impacts breast cancer growth and metastasis, and translates into a new therapeutic approach for preventing breast cancer progression. This is highly relevant as current standard of care for cancer patients relies primarily on chemo- and radiation therapies aimed at killing the tumor cells. Evolutionary models predict that selective pressure imposed by these approaches causes survival of resistant clones that eventually re-activate the disease. Based on the central involvement of metabolic tumor cell alterations in cancer, therapeutic normalization of tumor cell metabolism might interfere with the expansion of residual and break-through clones. Thus, a combination of standard therapy with NAD+ precursor treatment may halt breast cancer progression and prevent relapse. Citation Format: Antonio F. Santidrian, Akemi Matsuno-Yagi, Melissa Ritland, Byoung B. Seo1,2, Sarah E. LeBoeuf, Laurie J. Gay, Takao Yagi, Brunhilde Felding-Habermann. Normalizing tumor cell metabolism in breast cancer metastasis: A novel therapeutic approach. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA3.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TIM2013-IA3
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Abstract 1626: Tumors driven by oncogene amplified extrachromosomal DNA (ecDNA) demonstrate enhanced sensitivity to cell cycle checkpoint kinase 1 (CHK1) inhibition
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1626-1626
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1626-1626
    Abstract: Patients whose tumors harbor oncogene amplification on extrachromosomal DNA (ecDNA) fail to respond to targeted or immune therapy and have poor prognosis. ecDNA are cancer-specific circular fragments of genomic DNA engendered with unique properties, including open chromatin architecture associated with hyper transcription and a predilection for structural variation. In addition, ecDNA+ tumors have tremendous copy number heterogeneity mediated through acentric, non-Mendelian segregation. These properties afford ecDNA+ tumors with unparalleled genomic plasticity permitting circumvention of therapeutic pressure. However, these features also confer heightened levels of DNA replication stress (RS), and we have found that ecDNA amplified tumor cells are hyper-reliant on CHK1, a master regulator of the cellular RS response. We identified CHK1 as an ecDNA essential target in a CRISPR genetic screen using a methotrexate-induced ecDNA amplification model in HeLa cancer cells. ecDNA-dependent cell fitness assessment of CHK1 was confirmed using a flow cytometry-based CRISPR competition assay. The target was further validated using a CHK1 inhibitor (CHK1i) tool compound in MYC-amplified COLO320 isogenic cell lines that demonstrated a 10-fold enhanced cytotoxicity in the ecDNA amplified setting.Based on these results, we developed a highly potent, selective, and orally bioavailable CHK1i optimized as an ecDNA-directed therapeutic (ecDTx). An advanced lead, BBI-cmpd1, robustly induced RS biomarkers (e.g., pRPA) in ecDNA+ COLO320 tumor cells as compared to matched chromosomally-amplified (ecDNA-) COLO320 cells, consistent with the increased reliance on CHK1 to manage elevated RS in the ecDNA amplified setting. BBI-cmpd1 demonstrated potent anti-proliferative activity against a panel of ecDNA+ oncogene amplified tumor lines as compared to non-amplified lines demonstrating oncogene and indication agnostic efficacy in ecDNA-based tumors. Oral administration of BBI-cmpd1 resulted in on-target activity against CHK1 and anti-tumor activity in an ecDNA oncogene amplified tumor model in vivo. These findings support the clinical utility of potent, selective, and oral CHK1i to address the significant unmet need driven by ecDNA oncogene amplified cancers. Citation Format: Sudhir Chowdhry, Snezana Milutinovic, Edison Tse, Salvador Garcia, Dean Perusse, Melissa Ritland, Juyeon Ko, Deepti Wilkinson, Kristen Turner, Auzon Steffy, Joshua Plum, Ben Norman, AnnMarie Pferdekamper, Todd Meyer, Debbie Liao, Rachelle Elsdon, Joshua Lange, Anthony Pinkerton, Ryan Hansen, Christian Hassig, Shailaja Kasibhatla. Tumors driven by oncogene amplified extrachromosomal DNA (ecDNA) demonstrate enhanced sensitivity to cell cycle checkpoint kinase 1 (CHK1) inhibition [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 1626.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1626
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...