المؤلفون: Schäffer, Alejandro A., Chung, Youngmin, Kammula, Ashwin V., Ruppin, Eytan, Lee, Joo Sang

المساهمون: National Institutes of Health, Institute for Information and Communications Technology Promotion, National Cancer Institute, Samsung Science & Technology Foundation, Samsung, Sungkyunkwan University, Kwanjeong Educational Foundation, Ministry of Science, ICT and Future Planning

المصدر: Med ; volume 5, issue 1, page 73-89.e9 ; ISSN 2666-6340

مصطلحات موضوعية: General Medicine

الإتاحة: https://doi.org/10.1016/j.medj.2023.12.009Test
https://api.elsevier.com/content/article/PII:S2666634023004075?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2666634023004075?httpAccept=text/plainTest

المؤلفون: Ebrahimi-Nik, Hakimeh, Baumgartner, Christina K, Iracheta-Vellve, Arvin, Hamel, Keith M, Olander, Kira, Davis, Thomas GR, McGuire, Kathleen A, Halvorsen, Geoff T, Avila, Omar I, Patel, Chirag, Kim, Sarah, Kammula, Ashwin V, Muscato, Audrey J, Halliwill, Kyle, Geda, Prasanthi, Klinge, Kelly, Xiong, Zhaoming, Duggan, Ryan, Mu, Liang, Yeary, Mitchell D, Patti, James C, Balon, Tyler M, Mathew, Rebecca, Backus, Carey, Kennedy, Domenick, Chen, Angeline, Longenecker, Kenton, Klahn, Joseph, Hrusch, Cara, Krishnan, Navasona, Hutchins, Charles W, Aguado, Jacqueline, Bulic, Marinka, Tiwari, Payal, Colvin, Kayla J, Chuong, Cun Lan, Kohnle, Ian C, Rees, Matthew G, Boghossian, Andrew, Ronan, Melissa, Roth, Jennifer A, Wu, Meng-Ju, Sen, Debattama R, Griffin, Gabriel K, El-Bardeesy, Nabeel, Trusk, Patricia, Sun, Meng, Liu, Yue, Decker, Joshua H, Yang, Yi

المصدر: Regular Abstracts – Part 2

الإتاحة: https://doi.org/10.1136/jitc-2023-sitc2023.1403-aTest

المؤلفون: Baumgartner, Christina K., Ebrahimi-Nik, Hakimeh, Iracheta-Vellve, Arvin, Hamel, Keith M., Olander, Kira E., Davis, Thomas G. R., McGuire, Kathleen A., Halvorsen, Geoff T., Avila, Omar I., Patel, Chirag H., Kim, Sarah Y., Kammula, Ashwin V., Muscato, Audrey J., Halliwill, Kyle, Geda, Prasanthi, Klinge, Kelly L., Xiong, Zhaoming, Duggan, Ryan, Mu, Liang, Yeary, Mitchell D., Patti, James C., Balon, Tyler M., Mathew, Rebecca, Backus, Carey, Kennedy, Domenick E., Chen, Angeline, Longenecker, Kenton, Klahn, Joseph T., Hrusch, Cara L., Krishnan, Navasona, Hutchins, Charles W., Dunning, Jax P., Bulic, Marinka, Tiwari, Payal, Colvin, Kayla J., Chuong, Cun Lan, Kohnle, Ian C., Rees, Matthew G., Boghossian, Andrew, Ronan, Melissa, Roth, Jennifer A., Wu, Meng-Ju, Suermondt, Juliette S. M. T., Knudsen, Nelson H., Cheruiyot, Collins K., Sen, Debattama R., Griffin, Gabriel K., Golub, Todd R., El-Bardeesy, Nabeel, Decker, Joshua H.

المصدر: Nature ; volume 622, issue 7984, page 850-862 ; ISSN 0028-0836 1476-4687

مصطلحات موضوعية: Multidisciplinary

الوصف: Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance 1,2 . The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity 3–6 . However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8 + T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994 ). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

الإتاحة: https://doi.org/10.1038/s41586-023-06575-7Test
https://www.nature.com/articles/s41586-023-06575-7.pdfTest
https://www.nature.com/articles/s41586-023-06575-7Test

المؤلفون: Sinha, Sanju, Vegesna, Rahulsimham, Mukherjee, Sumit, Kammula, Ashwin V, Dhruba, Saugato Rahman, Wu, Wei, Kerr, D Lucas, Nair, Nishanth Ulhas, Jones, Matthew G, Yosef, Nir, Stroganov, Oleg V, Grishagin, Ivan, Aldape, Kenneth D, Blakely, Collin M, Jiang, Peng, Thomas, Craig J, Benes, Cyril H, Bivona, Trever G, Schäffer, Alejandro A, Ruppin, Eytan

المصدر: Nat Cancer ; ISSN:2662-1347 ; Volume:5 ; Issue:6

الوصف: Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients' sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTIONTest . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics.

العلاقة: https://doi.org/10.1038/s43018-024-00756-7Test; https://pubmed.ncbi.nlm.nih.gov/38637658Test

الإتاحة: https://doi.org/10.1038/s43018-024-00756-7Test
https://pubmed.ncbi.nlm.nih.gov/38637658Test

المؤلفون: Kammula, Ashwin V., Schäffer, Alejandro A., Rajagopal, Padma Sheila, Kurzrock, Razelle, Ruppin, Eytan

المصدر: Nature Communications; 3/23/2024, Vol. 15 Issue 1, p1-13, 13p

مصطلحات موضوعية: SEX factors in disease, CLINICAL trials, NON-Hodgkin's lymphoma, ONCOLOGY

الشركة/الكيان: NATIONAL Institutes of Health (U.S.)

مستخلص: Identifying sex differences in outcomes and toxicity between males and females in oncology clinical trials is important and has also been mandated by National Institutes of Health policies. Here we analyze the Trialtrove database, finding that, strikingly, only 472/89,221 oncology clinical trials (0.5%) had curated post-treatment sex comparisons. Among 288 trials with comparisons of survival, outcome, or response, 16% report males having statistically significant better survival outcome or response, while 42% reported significantly better survival outcome or response for females. The strongest differences are in trials of EGFR inhibitors in lung cancer and rituximab in non-Hodgkin's lymphoma (both favoring females). Among 44 trials with side effect comparisons, more trials report significantly lesser side effects in males (N = 22) than in females (N = 13). Thus, while statistical comparisons between sexes in oncology trials are rarely reported, important differences in outcome and toxicity exist. These considerable outcome and toxicity differences highlight the need for reporting sex differences more thoroughly going forward. The role of sex differences in response to cancer therapy remains unclear but this could be improved by reporting sex comparisons of outcomes in clinical trials. Here, the authors characterise the sex outcome comparisons in 89,221 interventional trials, finding that while comparisons were rare, important insights could be obtained. [ABSTRACT FROM AUTHOR]

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المؤلفون: Kammula, Ashwin V., Schäffer, Alejandro A., Rajagopal, Padma Sheila

المصدر: JAMA Netw Open

مصطلحات موضوعية: Original Investigation, psy, socio

الوصف: IMPORTANCE: The recent successes of poly-ADP ribose polymerase (PARP) inhibitors and belzutifan support germline genetic data as an exciting, accessible source for biomarkers in cancer treatment. This study hypothesizes, however, that most oncology clinical trials using germline data largely prioritize BRCA1/2 as biomarkers and PARP inhibitors as therapy. OBJECTIVE: To characterize past and ongoing oncology trials that use germline data. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study of oncology trials used the Informa Trialtrove database to evaluate trial attributes. Trials using germline information (including the terms germline, hereditary, or inherited in the title, treatment plan, interventions, end points, objectives, results, or notes) and conducted globally between December 1, 1990, and April 4, 2022 (data freeze date), were included. MAIN OUTCOMES AND MEASURES: Trials by cancer type, phase, participants, sponsor type, end points, outcomes, and locations were described. Associated biomarkers and mechanisms of action for studied therapeutic interventions were counted. How germline data in trial inclusion and exclusion criteria are associated with end points, outcomes, and enrollment were also examined. RESULTS: A total of 887 of 84 297 (1.1%) oncology clinical trials in the Trialtrove database that use germline data were identified. Most trials were conducted in cancer types where PARP inhibitors are already approved. A total of 74.8% (672) of trials were performed in the phase 2 setting or above. Trials were primarily sponsored by industry (523 trials [59.0%]), academia (382 trials [43.1%]), and the government (274 trials [30.9%]), where trials may have multiple sponsor types. Among 343 trials using germline data with outcomes in Trialtrove, 180 (52.5%) reported meeting primary end points. Although BRCA1/2 are the most frequent biomarkers seen (BRCA1, 224 trials [25.3%]; BRCA2, 228 trials [25.7%]), trials also examine pharmacogenomic variants and germline mediators of somatic ...

العلاقة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669814Test/

الإتاحة: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9669814Test/

المؤلفون: Kammula, Ashwin V., Schaffer, Alejandro A., Rajagopal, Padma Sheila, Kurzrock, Razelle, Ruppin, Eytan

المصدر: Journal of Clinical Oncology; 2023 Supplement 16, Vol. 41, pe18808-e18808, 1p