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1. BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance

Author

Nesic, Ksenija, Krais, John J., Wang, Yifan, Vandenberg, Cassandra J., Patel, Pooja, Cai, Kathy Q., Kwan, Tanya, Lieschke, Elizabeth, Ho, Gwo-Yaw, Barker, Holly E., Bedo, Justin, Casadei, Silvia, Farrell, Andrew, Radke, Marc, Shield-Artin, Kristy, Penington, Jocelyn S., Geissler, Franziska, Kyran, Elizabeth, Betsch, Robert, Xu, Lijun, Zhang, Fan, Dobrovic, Alexander, Olesen, Inger, Kristeleit, Rebecca, Oza, Amit, McNeish, Iain, Ratnayake, Gayanie, Traficante, Nadia, DeFazio, Anna, Bowtell, David D. L., Harding, Thomas C., Lin, Kevin, Swisher, Elizabeth M., Kondrashova, Olga, Scott, Clare L., Johnson, Neil, and Wakefield, Matthew J.

Published
2024
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2. Necroptosis blockade prevents lung injury in severe influenza

Author

Gautam, Avishekh, Boyd, David F., Nikhar, Sameer, Zhang, Ting, Siokas, Ioannis, Van de Velde, Lee-Ann, Gaevert, Jessica, Meliopoulos, Victoria, Thapa, Bikash, Rodriguez, Diego A., Cai, Kathy Q., Yin, Chaoran, Schnepf, Daniel, Beer, Julius, DeAntoneo, Carly, Williams, Riley M., Shubina, Maria, Livingston, Brandi, Zhang, Dingqiang, Andrake, Mark D., Lee, Seungheon, Boda, Raghavender, Duddupudi, Anantha L., Crawford, Jeremy Chase, Vogel, Peter, Loch, Christian, Schwemmle, Martin, Fritz, Lawrence C., Schultz-Cherry, Stacey, Green, Douglas R., Cuny, Gregory D., Thomas, Paul G., Degterev, Alexei, and Balachandran, Siddharth

Published
2024
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6. Autophagy Contributes to Homeostasis in Esophageal Epithelium Where High Autophagic Vesicle Level Marks Basal Cells With Limited Proliferation and Enhanced Self-Renewal Potential

Author

Klochkova, Alena, Karami, Adam L., Fuller, Annie D., Parham, Louis R., Panchani, Surali R., Natarajan, Shruthi, Jackson, Jazmyne L., Mu, Anbin, Tan, Yinfei, Cai, Kathy Q., Klein-Szanto, Andres J., Muir, Amanda B., Tétreault, Marie-Pier, Graña, Xavier, Hamilton, Kathryn E., and Whelan, Kelly A.

Published
2024
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9. TET1 and TDG Suppress Inflammatory Response in Intestinal Tumorigenesis: Implications for Colorectal Tumors With the CpG Island Methylator Phenotype

Author

Tricarico, Rossella, Madzo, Jozef, Scher, Gabrielle, Cohen, Maya, Jelinek, Jaroslav, Maegawa, Shinji, Nagarathinam, Rajeswari, Scher, Carly, Chang, Wen-Chi, Nicolas, Emmanuelle, Slifker, Michael, Zhou, Yan, Devarajan, Karthik, Cai, Kathy Q., Kwok, Tim, Nakajima, Pamela, Xu, Jinfei, Mancuso, Pietro, Doneddu, Valentina, Bagella, Luigi, Williams, Riley, Balachandran, Siddharth, Maskalenko, Nicholas, Campbell, Kerry, Ma, Xueying, Cañadas, Israel, Viana-Errasti, Julen, Moreno, Victor, Valle, Laura, Grivennikov, Sergei, Peshkova, Iuliia, Kurilenko, Natalia, Mazitova, Aleksandra, Koltsova, Ekaterina, Lee, Hayan, Walsh, Martin, Duttweiler, Reuben, Whetstine, Johnathan R., Yen, Timothy J., Issa, Jean-Pierre, and Bellacosa, Alfonso

Published
2023
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12. HRS phosphorylation drives immunosuppressive exosome secretion and restricts CD8+ T-cell infiltration into tumors

Author

Guan, Lei, Wu, Bin, Li, Ting, Beer, Lynn A., Sharma, Gaurav, Li, Mingyue, Lee, Chin Nien, Liu, Shujing, Yang, Changsong, Huang, Lili, Frederick, Dennie T., Boland, Genevieve M., Shao, Guangcan, Svitkina, Tatyana M., Cai, Kathy Q., Chen, Fangping, Dong, Meng-Qiu, Mills, Gordon B., Schuchter, Lynn M., Karakousis, Giorgos C., Mitchell, Tara C., Flaherty, Keith T., Speicher, David W., Chen, Youhai H., Herlyn, Meenhard, Amaravadi, Ravi K., Xu, Xiaowei, and Guo, Wei

Published
2022
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13. Suppression of Ca2+ signaling enhances melanoma progression

Author

Gross, Scott, Hooper, Robert, Tomar, Dhanendra, Armstead, Alexander P, Shanas, No'ad, Mallu, Pranava, Joshi, Hinal, Ray, Suravi, Chong, Parkson Lee‐Gau, Astsaturov, Igor, Farma, Jeffrey M, Cai, Kathy Q, Chitrala, Kumaraswamy Naidu, Elrod, John W, Zaidi, M Raza, and Soboloff, Jonathan

Published
2022
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15. Supplementary Figure S7 from Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer

Author

Murayama, Takahiko, primary, Nakayama, Jun, primary, Jiang, Xinpei, primary, Miyata, Kenichi, primary, Morris, Alexander D., primary, Cai, Kathy Q., primary, Prasad, Rahul M., primary, Ma, Xueying, primary, Efimov, Andrey, primary, Belani, Neel, primary, Gerstein, Emily R., primary, Tan, Yinfei, primary, Zhou, Yan, primary, Kim, William, primary, Maruyama, Reo, primary, Campbell, Kerry S., primary, Chen, Lu, primary, Yang, Yibin, primary, Balachandran, Siddharth, primary, and Cañadas, Israel, primary

Published
2024
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16. Supplementary Table S3 from Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer

Author

Murayama, Takahiko, primary, Nakayama, Jun, primary, Jiang, Xinpei, primary, Miyata, Kenichi, primary, Morris, Alexander D., primary, Cai, Kathy Q., primary, Prasad, Rahul M., primary, Ma, Xueying, primary, Efimov, Andrey, primary, Belani, Neel, primary, Gerstein, Emily R., primary, Tan, Yinfei, primary, Zhou, Yan, primary, Kim, William, primary, Maruyama, Reo, primary, Campbell, Kerry S., primary, Chen, Lu, primary, Yang, Yibin, primary, Balachandran, Siddharth, primary, and Cañadas, Israel, primary

Published
2024
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17. Data from Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer

Author

Murayama, Takahiko, primary, Nakayama, Jun, primary, Jiang, Xinpei, primary, Miyata, Kenichi, primary, Morris, Alexander D., primary, Cai, Kathy Q., primary, Prasad, Rahul M., primary, Ma, Xueying, primary, Efimov, Andrey, primary, Belani, Neel, primary, Gerstein, Emily R., primary, Tan, Yinfei, primary, Zhou, Yan, primary, Kim, William, primary, Maruyama, Reo, primary, Campbell, Kerry S., primary, Chen, Lu, primary, Yang, Yibin, primary, Balachandran, Siddharth, primary, and Cañadas, Israel, primary

Published
2024
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19. Thyroid Hormone Suppresses Medulloblastoma Progression Through Promoting Terminal Differentiation of Tumor Cells

Author

Yang, Yijun, primary, Valdés-Rives, Silvia Anahi, additional, Liu, Qing, additional, Li, Yuzhe, additional, Tan, Jun, additional, Tan, Yinfei, additional, Koch, Christian A, additional, Rong, Yuan, additional, Houser, Steven R., additional, Wei, Shuanzeng, additional, Cai, Kathy Q, additional, Cheng, Sheue-yann, additional, Curran, Tom, additional, Wechsler-Reya, Robert, additional, and Yang, Zeng-jie, additional

Published
2024
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20. Supplementary Figure S1 from SAR-096: Phase II Clinical Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS)

Author

Movva, Sujana, primary, Matloob, Sahar, primary, Handorf, Elizabeth A., primary, Choy, Edwin, primary, Merriam, Priscilla, primary, Flieder, Douglas B., primary, Cai, Kathy Q., primary, Zhou, Yan, primary, Tetzlaff, Eric D., primary, Pagan, Cheyenne, primary, Barker, Emma, primary, Veggeberg, Rosanna, primary, Zumpano, Delia, primary, Rink, Lori, primary, von Mehren, Margaret, primary, and George, Suzanne, primary

Published
2024
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21. Supplementary Table S2 from SAR-096: Phase II Clinical Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS)

Author

Movva, Sujana, primary, Matloob, Sahar, primary, Handorf, Elizabeth A., primary, Choy, Edwin, primary, Merriam, Priscilla, primary, Flieder, Douglas B., primary, Cai, Kathy Q., primary, Zhou, Yan, primary, Tetzlaff, Eric D., primary, Pagan, Cheyenne, primary, Barker, Emma, primary, Veggeberg, Rosanna, primary, Zumpano, Delia, primary, Rink, Lori, primary, von Mehren, Margaret, primary, and George, Suzanne, primary

Published
2024
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22. Data from SAR-096: Phase II Clinical Trial of Ribociclib in Combination with Everolimus in Advanced Dedifferentiated Liposarcoma (DDL) and Leiomyosarcoma (LMS)

Author

Movva, Sujana, primary, Matloob, Sahar, primary, Handorf, Elizabeth A., primary, Choy, Edwin, primary, Merriam, Priscilla, primary, Flieder, Douglas B., primary, Cai, Kathy Q., primary, Zhou, Yan, primary, Tetzlaff, Eric D., primary, Pagan, Cheyenne, primary, Barker, Emma, primary, Veggeberg, Rosanna, primary, Zumpano, Delia, primary, Rink, Lori, primary, von Mehren, Margaret, primary, and George, Suzanne, primary

Published
2024
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23. Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer

Author

Murayama, Takahiko, primary, Nakayama, Jun, additional, Jiang, Xinpei, additional, Miyata, Kenichi, additional, Morris, Alexander D., additional, Cai, Kathy Q., additional, Prasad, Rahul M., additional, Ma, Xueying, additional, Efimov, Andrey, additional, Belani, Neel, additional, Gerstein, Emily R., additional, Tan, Yinfei, additional, Zhou, Yan, additional, Kim, William, additional, Maruyama, Reo, additional, Campbell, Kerry S., additional, Chen, Lu, additional, Yang, Yibin, additional, Balachandran, Siddharth, additional, and Cañadas, Israel, additional

Published
2024
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24. Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case

Author

Belinsky, Martin G, Rink, Lori, Cai, Kathy Q, Capuzzi, Stephen J, Hoang, Yen, Chien, Jeremy, Godwin, Andrew K, and von Mehren, Margaret

Subjects
Human Genome, Genetics, Neurosciences, Neurofibromatosis, Cancer, Digestive Diseases, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Adult, Aged, Aged, 80 and over, Basic-Leucine Zipper Transcription Factors, Exome, Female, Frameshift Mutation, Gastrointestinal Stromal Tumors, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Neurofibromin 1, Proto-Oncogene Proteins c-kit, Receptor, Platelet-Derived Growth Factor alpha, Succinate Dehydrogenase, Gastrointestinal stromal tumor, Wild type, KIT, PDGFRA, Succinate dehydrogenase, NF1, MAX, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundApproximately 10-15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. An alternate mechanism of oncogenesis through loss of function of the succinate-dehydrogenase (SDH) enzyme complex has been identified for a subset of these "wild type" GISTs.MethodsPaired tumor and normal DNA from an SDH-intact wild-type GIST case was subjected to whole exome sequencing to identify the pathogenic mechanism(s) in this tumor. Selected findings were further investigated in panels of GIST tumors through Sanger DNA sequencing, quantitative real-time PCR, and immunohistochemical approaches.ResultsA hemizygous frameshift mutation (p.His2261Leufs*4), in the neurofibromin 1 (NF1) gene was identified in the patient's GIST; however, no germline NF1 mutation was found. A somatic frameshift mutation (p.Lys54Argfs*31) in the MYC associated factor X (MAX) gene was also identified. Immunohistochemical analysis for MAX on a large panel of GISTs identified loss of MAX expression in the MAX-mutated GIST and in a subset of mainly KIT-mutated tumors.ConclusionThis study suggests that inactivating NF1 mutations outside the context of neurofibromatosis may be the oncogenic mechanism for a subset of sporadic GIST. In addition, loss of function mutation of the MAX gene was identified for the first time in GIST, and a broader role for MAX in GIST progression was suggested.

Published
2015

27. Floxed Il1rl2 Locus with mCherry Reporter Element Reveals Distinct Expression Patterns of the IL-36 Receptor in Barrier Tissues.

Author

Tongmuang, Nopprarat, Cai, Kathy Q., An, Jiahui, Novy, Mariah, and Jensen, Liselotte E.

Subjects
*EPITHELIUM, *EPITHELIAL cells, *TISSUES, *ORAL mucosa, *LUNGS, *LOCUS (Genetics), *KNOCKOUT mice
Abstract

IL-36 cytokines are emerging as beneficial in immunity against pathogens and cancers but can also be detrimental when dysregulated in autoimmune and autoinflammatory conditions. Interest in targeting IL-36 activity for therapeutic purposes is rapidly growing, yet many unknowns about the functions of these cytokines remain. Thus, the availability of robust research tools is essential for both fundamental basic science and pre-clinical studies to fully access outcomes of any manipulation of the system. For this purpose, a floxed Il1rl2, the gene encoding the IL-36 receptor, mouse strain was developed to facilitate the generation of conditional knockout mice. The targeted locus was engineered to contain an inverted mCherry reporter sequence that upon Cre-mediated recombination will be flipped and expressed under the control of the endogenous Il1rl2 promoter. This feature can be used to confirm knockout in individual cells but also as a reporter to determine which cells express the IL-36 receptor IL-1RL2. The locus was confirmed to function as intended and further used to demonstrate the expression of IL-1RL2 in barrier tissues. Il1rl2 expression was detected in leukocytes in all barrier tissues. Interestingly, strong expression was observed in epithelial cells at locations in direct contact with the environment such as the skin, oral mucosa, the esophagus, and the upper airways, but almost absent from epithelial cells at more inward facing sites, including lung alveoli, the small intestine, and the colon. These findings suggest specialized functions of IL-1RL2 in outward facing epithelial tissues and cells. The generated mouse model should prove valuable in defining such functions and may also facilitate basic and translational research. [ABSTRACT FROM AUTHOR]

Published
2024
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28. SAR-096: Phase II clinical trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS)

Author

Movva, Sujana, primary, Matloob, Sahar, additional, Handorf, Elizabeth A., additional, Choy, Edwin, additional, Merriam, Priscilla, additional, Flieder, Douglas B., additional, Cai, Kathy Q., additional, Zhou, Yan, additional, Tetzlaff, Eric D., additional, Pagan, Cheyenne, additional, Barker, Emma, additional, Veggeberg, Rosanna, additional, Zumpano, Delia, additional, Rink, Lori, additional, von Mehren, Margaret, additional, and George, Suzanne, additional

Published
2023
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29. Data from Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Author

Restifo, Diana, primary, McDermott, Joseph R., primary, Cvetkovic, Dusica, primary, Dos Santos, Troy, primary, Ogier, Charline, primary, Surumbayeva, Aizhan, primary, Handorf, Elizabeth A., primary, Schimke, Caleb, primary, Ma, Charlie, primary, Cai, Kathy Q., primary, Olszanski, Anthony J., primary, Kathad, Umesh, primary, Bhatia, Kishor, primary, Sharma, Panna, primary, Kulkarni, Aditya, primary, and Astsaturov, Igor, primary

Published
2023
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30. Supplementary figures and tables legends from Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Author

Restifo, Diana, primary, McDermott, Joseph R., primary, Cvetkovic, Dusica, primary, Dos Santos, Troy, primary, Ogier, Charline, primary, Surumbayeva, Aizhan, primary, Handorf, Elizabeth A., primary, Schimke, Caleb, primary, Ma, Charlie, primary, Cai, Kathy Q., primary, Olszanski, Anthony J., primary, Kathad, Umesh, primary, Bhatia, Kishor, primary, Sharma, Panna, primary, Kulkarni, Aditya, primary, and Astsaturov, Igor, primary

Published
2023
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31. Supplementary Table 1 from Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Author

Restifo, Diana, primary, McDermott, Joseph R., primary, Cvetkovic, Dusica, primary, Dos Santos, Troy, primary, Ogier, Charline, primary, Surumbayeva, Aizhan, primary, Handorf, Elizabeth A., primary, Schimke, Caleb, primary, Ma, Charlie, primary, Cai, Kathy Q., primary, Olszanski, Anthony J., primary, Kathad, Umesh, primary, Bhatia, Kishor, primary, Sharma, Panna, primary, Kulkarni, Aditya, primary, and Astsaturov, Igor, primary

Published
2023
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32. Supplementary Table 2 from Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Author

Restifo, Diana, primary, McDermott, Joseph R., primary, Cvetkovic, Dusica, primary, Dos Santos, Troy, primary, Ogier, Charline, primary, Surumbayeva, Aizhan, primary, Handorf, Elizabeth A., primary, Schimke, Caleb, primary, Ma, Charlie, primary, Cai, Kathy Q., primary, Olszanski, Anthony J., primary, Kathad, Umesh, primary, Bhatia, Kishor, primary, Sharma, Panna, primary, Kulkarni, Aditya, primary, and Astsaturov, Igor, primary

Published
2023
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33. Supplementary Figure 2 from Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Author

Restifo, Diana, primary, McDermott, Joseph R., primary, Cvetkovic, Dusica, primary, Dos Santos, Troy, primary, Ogier, Charline, primary, Surumbayeva, Aizhan, primary, Handorf, Elizabeth A., primary, Schimke, Caleb, primary, Ma, Charlie, primary, Cai, Kathy Q., primary, Olszanski, Anthony J., primary, Kathad, Umesh, primary, Bhatia, Kishor, primary, Sharma, Panna, primary, Kulkarni, Aditya, primary, and Astsaturov, Igor, primary

Published
2023
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34. Supplementary Figure 1 from Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Author

Restifo, Diana, primary, McDermott, Joseph R., primary, Cvetkovic, Dusica, primary, Dos Santos, Troy, primary, Ogier, Charline, primary, Surumbayeva, Aizhan, primary, Handorf, Elizabeth A., primary, Schimke, Caleb, primary, Ma, Charlie, primary, Cai, Kathy Q., primary, Olszanski, Anthony J., primary, Kathad, Umesh, primary, Bhatia, Kishor, primary, Sharma, Panna, primary, Kulkarni, Aditya, primary, and Astsaturov, Igor, primary

Published
2023
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35. Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies

Author

Restifo, Diana, primary, McDermott, Joseph R., additional, Cvetkovic, Dusica, additional, Dos Santos, Troy, additional, Ogier, Charline, additional, Surumbayeva, Aizhan, additional, Handorf, Elizabeth A., additional, Schimke, Caleb, additional, Ma, Charlie, additional, Cai, Kathy Q., additional, Olszanski, Anthony J., additional, Kathad, Umesh, additional, Bhatia, Kishor, additional, Sharma, Panna, additional, Kulkarni, Aditya, additional, and Astsaturov, Igor, additional

Published
2023
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36. Autophagy contributes to homeostasis in esophageal epithelium where high autophagic vesicle content marks basal cells with limited proliferation and enhanced self-renewal potential

Author

Klochkova, Alena, primary, Karami, Adam L., additional, Fuller, Annie D., additional, Parham, Louis R., additional, Panchani, Surali R., additional, Natarajan, Shruthi, additional, Jackson, Jazmyne L., additional, Mu, Anbin, additional, Tan, Yinfei, additional, Cai, Kathy Q., additional, Klein-Szanto, Andres J., additional, Muir, Amanda B., additional, Tétreault, Marie-Pier, additional, Hamilton, Kathryn E., additional, and Whelan, Kelly A., additional

Published
2023
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38. Musashi-2 (MSI2) regulates epidermal growth factor receptor (EGFR) expression and response to EGFR inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC)

Author

Makhov, Petr, Bychkov, Igor, Faezov, Bulat, Deneka, Alexander, Kudinov, Alexander, Nicolas, Emmanuelle, Brebion, Rohan, Avril, Eleanor, Cai, Kathy Q., Kharin, Leonid V., Voloshin, Mark, Frantsiyants, Elena, Karnaukhov, Nikolay, Kit, Oleg I., Topchu, Iuliia, Fazliyeva, Rushaniya, Nikonova, Anna S., Serebriiskii, Ilya G., Borghaei, Hossein, Edelman, Martin, Dulaimi, Essel, Golemis, Erica A., and Boumber, Yanis

Published
2021
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42. Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment

Author

Wagner, Jessica, Kline, C. Leah, Zhou, Lanlan, Campbell, Kerry S., MacFarlane, Alexander W., Olszanski, Anthony J., Cai, Kathy Q., Hensley, Harvey H., Ross, Eric A., Ralff, Marie D., Zloza, Andrew, Chesson, Charles B., Newman, Jenna H., Kaufman, Howard, Bertino, Joseph, Stein, Mark, and El-Deiry, Wafik S.

Subjects
Cancer treatment -- Methods, Killer cells -- Health aspects -- Physiological aspects, Ligands (Biochemistry) -- Health aspects -- Physiological aspects, Antineoplastic agents -- Dosage and administration, Cancer metastasis -- Drug therapy, Health care industry
Abstract

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose--and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated [NK.sup.+] and [CD3.sup.+] cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant [Box.sup.-/-] tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated [GFP.sup.+] NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy., Introduction We previously identified ONC201/TIC10 as a small molecule that upregulates endogenous TNF-related apoptosis-inducing ligand (TRAIL) in tumor and normal cells, and restores autocrine and paracrine antitumor activity within tumor [...]

Published
2018
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