المؤلفون: Kathrin Böpple, Yaara Oren, Whitney S. Henry, Meng Dong, Sandra Weller, Julia Thiel, Markus Kleih, Andrea Gaißler, Damaris Zipperer, Hans-Georg Kopp, Yael Aylon, Moshe Oren, Frank Essmann, Chunguang Liang, Walter E. Aulitzky

المصدر: Cell Death and Disease, Vol 15, Iss 4, Pp 1-12 (2024)

مصطلحات موضوعية: Cytology, QH573-671

الوصف: Abstract High-grade serous ovarian cancer (HGSOC) represents the most common and lethal subtype of ovarian cancer. Despite initial response to platinum-based standard therapy, patients commonly suffer from relapse that likely originates from drug-tolerant persister (DTP) cells. We generated isogenic clones of treatment-naïve and cisplatin-tolerant persister HGSOC cells. In addition, single-cell RNA sequencing of barcoded cells was performed in a xenograft model with HGSOC cell lines after platinum-based therapy. Published single-cell RNA-sequencing data from neo-adjuvant and non-treated HGSOC patients and patient data from TCGA were analyzed. DTP-derived cells exhibited morphological alterations and upregulation of epithelial-mesenchymal transition (EMT) markers. An aggressive subpopulation of DTP-derived cells showed high expression of the stress marker ATF3. Knockdown of ATF3 enhanced the sensitivity of aggressive DTP-derived cells to cisplatin-induced cell death, implying a role for ATF3 stress response in promoting a drug tolerant persister cell state. Furthermore, single cell lineage tracing to detect transcriptional changes in a HGSOC cell line-derived xenograft relapse model showed that cells derived from relapsed solid tumors express increased levels of EMT and multiple endoplasmic reticulum (ER) stress markers, including ATF3. Single cell RNA sequencing of epithelial cells from four HGSOC patients also identified a small cell population resembling DTP cells in all samples. Moreover, analysis of TCGA data from 259 HGSOC patients revealed a significant progression-free survival advantage for patients with low expression of the ATF3-associated partial EMT genes. These findings suggest that increased ATF3 expression together with partial EMT promote the development of aggressive DTP, and thereby relapse in HGSOC patients.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-4889Test

الوصول الحر: https://doaj.org/article/9769580423ef4dceb07a43d24e176132Test

المؤلفون: Petros Christopoulos, Franziska Herster, Petra Hoffknecht, Markus Falk, Markus Tiemann, Hans-Georg Kopp, Andre Althoff, Anja Stammberger, Eckart Laack

المصدر: Frontiers in Oncology, Vol 14 (2024)

مصطلحات موضوعية: EGFR, non-small cell lung cancer (NSCLC), afatinib, uncommon mutation, tyrosine kinase inhibitor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, 10–20% of patients with EGFRm+ NSCLC have uncommon EGFR variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon EGFR mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon EGFR mutations are lacking. Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon EGFR mutations. We present a series of seven case reports describing clinical outcomes in afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. EGFR alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a case with NSCLC harboring a novel EGFR::CCDC6 gene fusion. Overall, the patients responded well to afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon EGFR mutations, with or without co-mutations, may be sensitive to afatinib.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fonc.2024.1347742/fullTest; https://doaj.org/toc/2234-943XTest

الوصول الحر: https://doaj.org/article/d9d647cfc3ce49f18e8635c29acf8bc3Test

المؤلفون: Andriani Charpidou, Grigorios Gerotziafas, Sanjay Popat, Antonio Araujo, Arnaud Scherpereel, Hans-Georg Kopp, Paolo Bironzo, Gilbert Massard, David Jiménez, Anna Falanga, Anastasios Kollias, Konstantinos Syrigos

المصدر: Cancers, Vol 16, Iss 2, p 450 (2024)

مصطلحات موضوعية: anticoagulation, cancer-associated thrombosis, immune checkpoint inhibitor, lung cancer, venous thromboembolism, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Cancer-associated thrombosis (CAT) is a common complication in lung cancer patients. Lung cancer confers an increased risk of thrombosis compared to other solid malignancies across all stages of the disease. Newer treatment agents, including checkpoint immunotherapy and targeted agents, may further increase the risk of CAT. Different risk-assessment models, such as the Khorana Risk Score, and newer approaches that incorporate genetic risk factors have been used in lung cancer patients to evaluate the risk of thrombosis. The management of CAT is based on the results of large prospective trials, which show similar benefits to low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in ambulatory patients. The anticoagulation agent and duration of therapy should be personalized according to lung cancer stage and histology, the presence of driver mutations and use of antineoplastic therapy, including recent curative lung surgery, chemotherapy or immunotherapy. Treatment options should be evaluated in the context of the COVID-19 pandemic, which has been shown to impact the thrombotic risk in cancer patients. This review focuses on the epidemiology, pathophysiology, risk factors, novel predictive scores and management of CAT in patients with active lung cancer, with a focus on immune checkpoint inhibitors.

العلاقة: https://www.mdpi.com/2072-6694/16/2/450Test; https://doaj.org/toc/2072-6694Test; https://doaj.org/article/c582da94b43145b4bb939c5d3b7d0af0Test

الإتاحة: https://doi.org/10.3390/cancers16020450Test
https://doaj.org/article/c582da94b43145b4bb939c5d3b7d0af0Test

المؤلفون: Sandra Weller, Astrid Toennießen, Benjamin Schaefer, Tobias Beigl, Alina Muenchow, Kathrin Böpple, Ute Hofmann, Bernhard F. Gillissen, Walter E. Aulitzky, Hans-Georg Kopp, Frank Essmann

المصدر: Cell Death Discovery, Vol 8, Iss 1, Pp 1-12 (2022)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282, Cytology, QH573-671

الوصف: Abstract Enhanced expression of anti-apoptotic B-cell lymphoma 2 (BCL-2) protein is frequent in cancer. Targeting of BCL-2 with the specific inhibitor ABT-199 (Venetoclax) has significant clinical activity in malignant diseases such as chronic lymphocytic leukemia and multiple myeloma. The small molecule drug ABT-199 mimics the pro-apoptotic BCL-2 homology domain 3 of BH3-only proteins and blocks the hydrophobic BC-groove in BCL-2. We have previously shown that ABT-199 synergizes with the proteasome inhibitor (PI) bortezomib in soft tissue sarcoma derived cells and cell lines to induce apoptosis. Synergistic apoptosis induction relies on the pore-forming effector BAX and expression of the pro-apoptotic BH3-only protein NOXA. Bortezomib augments expression of NOXA by blocking its proteasomal degradation. Interestingly, shown here for the first time, expression of NOXA is strongly enhanced by ABT-199 induced integrated stress response (ISR). ISR transcription factors ATF3 & ATF4 mediate transactivation of the BH3-only protein NOXA which specifically inhibits the anti-apoptotic MCL-1. Thus, NOXA potentiates the efficacy of the BCL-2 inhibitor ABT-199 by simultaneous inhibition of MCL-1. Hence, ABT-199 has a double impact by directly blocking anti-apoptotic BCL-2 and inhibiting MCL-1 via transactivated NOXA. By preventing degradation of NOXA PIs synergize with ABT-199. Synergism of ABT-199 and PIs therefore occurs on several, previously unexpected levels. This finding should prompt clinical evaluation of combinatorial regimens in further malignancies.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2058-7716Test

الوصول الحر: https://doaj.org/article/25b403ed7a8d4d12935b61caf6d80df9Test

المؤلفون: Thomas Fischer, Oliver Hartmann, Michaela Reissland, Cristian Prieto-Garcia, Kevin Klann, Nikolett Pahor, Christina Schülein-Völk, Apoorva Baluapuri, Bülent Polat, Arya Abazari, Elena Gerhard-Hartmann, Hans-Georg Kopp, Frank Essmann, Mathias Rosenfeldt, Christian Münch, Michael Flentje, Markus E. Diefenbacher

المصدر: Cell & Bioscience, Vol 12, Iss 1, Pp 1-22 (2022)

مصطلحات موضوعية: PTEN, ATM, IR, NSCLC, Radiotherapy, Cancer, Biotechnology, TP248.13-248.65, Biology (General), QH301-705.5, Biochemistry, QD415-436

الوصف: Abstract Background Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Results We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2045-3701Test

الوصول الحر: https://doaj.org/article/6e2b77747e884b2d9b01fa05018ce46eTest

المؤلفون: Clemens Hinterleitner, Jasmin Strähle, Elke Malenke, Martina Hinterleitner, Melanie Henning, Marco Seehawer, Tatjana Bilich, Jonas Heitmann, Martina Lutz, Sven Mattern, Sophia Scheuermann, Marius Horger, Stefanie Maurer, Juliane Walz, Falko Fend, Rupert Handgretinger, Christian Seitz, Bettina Weigelin, Stephan Singer, Helmut Salih, Oliver Borst, Hans-Georg Kopp, Lars Zender

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021)

مصطلحات موضوعية: Science

الوصف: The definition of biomarkers to predict therapy responses to immune-checkpoint inhibitors represent an unmet clinical need. Here the authors provide evidences that platelet-derived PD-L1 could serve as a prognostic and predictive biomarker in patients with non-small cell lung cancer.

وصف الملف: electronic resource

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

الوصول الحر: https://doaj.org/article/667bac11196140cc814118dc5b22f2f3Test

المؤلفون: Petros Christopoulos, Franziska Herster, Petra Hoffknecht, Markus Falk, Markus Tiemann, Hans-Georg Kopp, Andre Althoff, Anja Stammberger, Eckart Laack

مصطلحات موضوعية: Cancer, Cancer Cell Biology, Cancer Diagnosis, Cancer Genetics, Cancer Therapy (excl. Chemotherapy and Radiation Therapy), Chemotherapy, Haematological Tumours, Molecular Targets, Radiation Therapy, Solid Tumours, Oncology and Carcinogenesis not elsewhere classified, EGFR, non-small cell lung cancer (NSCLC), afatinib, uncommon mutation, tyrosine kinase inhibitor

الوصف: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent first-line standard of care in unresectable EGFR mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC). However, 10–20% of patients with EGFRm+ NSCLC have uncommon EGFR variants, defined as mutations other than L858R substitutions or exon 19 deletions. NSCLC harboring uncommon EGFR mutations may demonstrate lower sensitivity to targeted agents than NSCLC with L858R or exon 19 deletion mutations. Prospective clinical trial data in patients with NSCLC uncommon EGFR mutations are lacking. Afatinib is a second-generation TKI and the only Food and Drug Administration-approved drug for some of the more prevalent uncommon EGFR mutations. We present a series of seven case reports describing clinical outcomes in afatinib-treated patients with NSCLC harboring a diverse range of extremely rare mutations with or without co-mutations affecting other genes. EGFR alterations included compound mutations, P-loop αC-helix compressing mutations, and novel substitution mutations. We also present a case with NSCLC harboring a novel EGFR::CCDC6 gene fusion. Overall, the patients responded well to afatinib, including radiologic partial responses in six patients during treatment. Responses were durable for three patients. The cases presented are in line with a growing body of clinical and preclinical evidence that indicating that NSCLC with various uncommon EGFR mutations, with or without co-mutations, may be sensitive to afatinib.

العلاقة: https://figshare.com/articles/dataset/DataSheet_1_Activity_of_afatinib_in_patients_with_NSCLC_harboring_novel_uncommon_EGFR_mutations_with_or_without_co-mutations_a_case_report_docx/25756509Test

الإتاحة: https://doi.org/10.3389/fonc.2024.1347742.s001Test
https://figshare.com/articles/dataset/DataSheet_1_Activity_of_afatinib_in_patients_with_NSCLC_harboring_novel_uncommon_EGFR_mutations_with_or_without_co-mutations_a_case_report_docx/25756509Test

المؤلفون: Rainer Hamacher, Xiaofei Liu, Markus K. Schuler, Leopold Hentschel, Patrick Schöffski, Hans-Georg Kopp, Sebastian Bauer, Bernd Kasper, Lars Lindner, Jens-Markus Chemnitz, Martina Crysandt, Alexander Stein, Björn Steffen, Stephan Richter, Gerlinde Egerer, Philipp Ivanyi, Annegret Kunitz, Viktor Grünwald

المصدر: European Journal of Cancer. 181:145-154

مصطلحات موضوعية: Cancer Research, Oncology, Medizin

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5b391f2b982c9ad31a10fc2d24ca0737Test
https://doi.org/10.1016/j.ejca.2022.12.012Test

المؤلفون: Ilona Hagelstein, Martina S. Lutz, Moritz Schmidt, Jonas S. Heitmann, Elke Malenke, Yanjun Zhou, Kim L. Clar, Hans-Georg Kopp, Gundram Jung, Helmut R. Salih, Melanie Märklin, Clemens Hinterleitner

المصدر: Frontiers in Immunology, Vol 12 (2021)

مصطلحات موضوعية: sarcoma, NKG2DL, CD3, CD16, fusion protein, mAb, Immunologic diseases. Allergy, RC581-607

الوصف: Soft tissue sarcoma (STS) constitutes a rare group of heterogeneous malignancies. Effective treatment options for most subtypes of STS are still limited. As a result, especially in metastatic disease, prognosis is still dismal. The ligands for the activating immunoreceptor NKG2D (NKG2DL) are commonly expressed in STS, but generally absent in healthy tissues. This provides the rationale for utilization of NKG2DL as targets for immunotherapeutic approaches. We here report on the preclinical characterization of bispecific fusion proteins (BFP) consisting of the extracellular domain of the NKG2D receptor fused to Fab-fragments directed against CD3 (NKG2D-CD3) or CD16 (NKG2D-CD16) for treatment of STS. After characterization of NKG2DL expression patterns on various STS cell lines, we demonstrated that both NKG2D-CD16 and NKG2D-CD3 induce profound T and NK cell reactivity as revealed by analysis of activation, degranulation and secretion of IFNγ as well as granule associated proteins, resulting in potent target cell lysis. In addition, the stimulatory capacity of the constructs to induce T and NK cell activation was analyzed in heavily pretreated STS patients and found to be comparable to healthy donors. Our results emphasize the potential of NKG2D-CD3 and NKG2D-CD16 BFP to target STS even in an advanced disease.

وصف الملف: electronic resource

العلاقة: https://www.frontiersin.org/articles/10.3389/fimmu.2021.653081/fullTest; https://doaj.org/toc/1664-3224Test

الوصول الحر: https://doaj.org/article/c983352f25e8461eb8b95d844f20a749Test

المؤلفون: Martin Metzenmacher, Hans-Georg Kopp, Frank Griesinger, Niels Reinmuth, Martin Sebastian, Monika Serke, Cornelius Florian Waller, Michael Thomas, Jochen Eggert, Gerald Schmid-Bindert, Mathias Hoiczyk, Daniel Christian Christoph, Martin Kimmich, Burkhard Deuß, Stephanie Seifert, Swantje Held, Martin Schuler, Thomas Herold, Frank Breitenbuecher, Wilfried Ernst Erich Eberhardt

المصدر: Therapeutic Advances in Medical Oncology, Vol 13 (2021)

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

الوصف: Background: Pemetrexed and cisplatin is a first-line standard in non-squamous non-small-cell lung cancer without targetable mutations. It became the backbone of checkpoint-inhibitor–chemotherapy combinations. Single high doses of cisplatin pose toxicity risks and require hyperhydration, potentially prolonging outpatient application. The aim of this study was to compare efficacy, safety and tolerability of split-dose cisplatin with the standard schedule. Methods: Patients with metastatic non-squamous non-small-cell lung cancer were randomly assigned to up to six 21-day cycles of pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 on day 1 (arm A), or pemetrexed 500 mg/m 2 (day 1) and cisplatin 40 mg/m 2 (day 1 + 8, arm B), followed by pemetrexed maintenance. Primary endpoint was objective response rate. Secondary objectives were overall survival, progression-free survival, time to progression, treatment compliance, toxicity profile, and quality of life. Results: We enrolled 130 patients (129 evaluable). Median cycle numbers in A and B were six (1–6) and five (1–6). Dose intensities were comparable between arms. More patients in A received pemetrexed maintenance (24.2% versus 11.1%). With 16 (24.2%) in A and 19 (30.2%) patients in B achieving objective responses [odds ratio 0.74 (0.34–1.62), p = 0.55] the primary endpoint was met. Overall survival was not different between arms (median 14.4 versus 14.9 months); [HR = 1.07; (0.68–1.68), p = 0.78]. Median progression-free survival was 7.0 months in A and 6.2 months in B [HR = 1.63; (1.17–2.38); p = 0.01]. Adverse events of CTCAE grade ⩾3, particularly hematological, were more frequent in B. No difference in grade 4 and 5 infections between arms was noted. Treatment-related asthenia and nausea/vomiting of any grade were more frequent in A. Global health status, fatigue and constipation measured on day 1 of cycle 4 demonstrated superior scores in B. Conclusion: Pemetrexed and split-dose cisplatin is safe and effective. Advantages of split-dose cisplatin with regard to specific toxicities allow personalization of this important chemotherapy backbone. Trial Registration: European Clinical Trials Database (EudraCT) number 2011-001963-37.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1758-8359Test

الوصول الحر: https://doaj.org/article/d242cd41cb214934942f7de020430e08Test