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5. Epinephrine inhibits PI3Kα via the Hippo kinases

Author

Lin, Ting-Yu, Ramsamooj, Shakti, Perrier, Tiffany, Liberatore, Katarina, Lantier, Louise, Vasan, Neil, Karukurichi, Kannan, Hwang, Seo-Kyoung, Kesicki, Edward A., Kastenhuber, Edward R., Wiederhold, Thorsten, Yaron, Tomer M., Huntsman, Emily M., Zhu, Mengmeng, Ma, Yilun, Paddock, Marcia N., Zhang, Guoan, Hopkins, Benjamin D., McGuinness, Owen, Schwartz, Robert E., Ersoy, Baran A., Cantley, Lewis C., Johnson, Jared L., and Goncalves, Marcus D.

Published
2023
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6. Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential

Author

Wu, Kenneth, Huynh, Khoi Q, Lu, Iris, Moustakim, Moses, Miao, Haibin, Yu, Clinton, Haeusgen, Matthew J, Hopkins, Benjamin D, Huang, Lan, Zheng, Ning, Sanchez, Roberto, DeVita, Robert J, and Pan, Zhen-Qiang

Subjects
Cancer, Animals, Antineoplastic Agents, Apoptosis, Biomarkers, Tumor, Cell Proliferation, Enzyme Inhibitors, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Leukemia, Myeloid, Acute, Mice, Mice, Inbred BALB C, Mice, Nude, Tumor Cells, Cultured, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, Xenograft Model Antitumor Assays, protein degradation, E3 CRL4, cullin4, small-molecule inhibitors, tumor inhibition
Abstract

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.

Published
2021

7. An atlas of substrate specificities for the human serine/threonine kinome

Author

Johnson, Jared L., Yaron, Tomer M., Huntsman, Emily M., Kerelsky, Alexander, Song, Junho, Regev, Amit, Lin, Ting-Yu, Liberatore, Katarina, Cizin, Daniel M., Cohen, Benjamin M., Vasan, Neil, Ma, Yilun, Krismer, Konstantin, Robles, Jaylissa Torres, van de Kooij, Bert, van Vlimmeren, Anne E., Andrée-Busch, Nicole, Käufer, Norbert F., Dorovkov, Maxim V., Ryazanov, Alexey G., Takagi, Yuichiro, Kastenhuber, Edward R., Goncalves, Marcus D., Hopkins, Benjamin D., Elemento, Olivier, Taatjes, Dylan J., Maucuer, Alexandre, Yamashita, Akio, Degterev, Alexei, Uduman, Mohamed, Lu, Jingyi, Landry, Sean D., Zhang, Bin, Cossentino, Ian, Linding, Rune, Blenis, John, Hornbeck, Peter V., Turk, Benjamin E., Yaffe, Michael B., and Cantley, Lewis C.

Published
2023
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8. Patient-Derived In Vitro and In Vivo Models of Cancer

Author

Claridge, Sally E., Cavallo, Julie-Ann, Hopkins, Benjamin D., Crusio, Wim E., Series Editor, Dong, Haidong, Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Steinlein, Ortrud, Series Editor, Xiao, Junjie, Series Editor, and Laganà, Alessandro, editor

Published
2022
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9. PI3K drives the de novo synthesis of coenzyme A from vitamin B5

Author

Dibble, Christian C., Barritt, Samuel A., Perry, Grace E., Lien, Evan C., Geck, Renee C., DuBois-Coyne, Sarah E., Bartee, David, Zengeya, Thomas T., Cohen, Emily B., Yuan, Min, Hopkins, Benjamin D., Meier, Jordan L., Clohessy, John G., Asara, John M., Cantley, Lewis C., and Toker, Alex

Published
2022
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10. The PI3K Pathway in Human Disease

Author

Fruman, David A, Chiu, Honyin, Hopkins, Benjamin D, Bagrodia, Shubha, Cantley, Lewis C, and Abraham, Robert T

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Animals, Cell Physiological Phenomena, Humans, Immune System, Neoplasms, Phosphatidylinositol 3-Kinases, Signal Transduction, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Phosphoinositide 3-kinase (PI3K) activity is stimulated by diverse oncogenes and growth factor receptors, and elevated PI3K signaling is considered a hallmark of cancer. Many PI3K pathway-targeted therapies have been tested in oncology trials, resulting in regulatory approval of one isoform-selective inhibitor (idelalisib) for treatment of certain blood cancers and a variety of other agents at different stages of development. In parallel to PI3K research by cancer biologists, investigations in other fields have uncovered exciting and often unpredicted roles for PI3K catalytic and regulatory subunits in normal cell function and in disease. Many of these functions impinge upon oncology by influencing the efficacy and toxicity of PI3K-targeted therapies. Here we provide a perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions, two topics closely intertwined with cancer biology. We also discuss recent progress developing PI3K-targeted therapies for treatment of cancer and other diseases.

Published
2017

17. Data from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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18. Supplementary Table 7 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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19. Supplementary Figures 1 - 6 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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20. Supplementary Table 1 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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21. Supplementary Table 3 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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22. Supplementary Table Legends from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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23. Supplementary Table 2 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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24. Supplementary Table 6 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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25. Supplementary Table 4 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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26. Supplementary Table 5 from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine

Author

Pauli, Chantal, primary, Hopkins, Benjamin D., primary, Prandi, Davide, primary, Shaw, Reid, primary, Fedrizzi, Tarcisio, primary, Sboner, Andrea, primary, Sailer, Verena, primary, Augello, Michael, primary, Puca, Loredana, primary, Rosati, Rachele, primary, McNary, Terra J., primary, Churakova, Yelena, primary, Cheung, Cynthia, primary, Triscott, Joanna, primary, Pisapia, David, primary, Rao, Rema, primary, Mosquera, Juan Miguel, primary, Robinson, Brian, primary, Faltas, Bishoy M., primary, Emerling, Brooke E., primary, Gadi, Vijayakrishna K., primary, Bernard, Brady, primary, Elemento, Olivier, primary, Beltran, Himisha, primary, Demichelis, Francesca, primary, Kemp, Christopher J., primary, Grandori, Carla, primary, Cantley, Lewis C., primary, and Rubin, Mark A., primary

Published
2023
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27. Data from 3-Phosphoinositide–Dependent Kinase 1 Potentiates Upstream Lesions on the Phosphatidylinositol 3-Kinase Pathway in Breast Carcinoma

Author

Maurer, Matthew, primary, Su, Tao, primary, Saal, Lao H., primary, Koujak, Susan, primary, Hopkins, Benjamin D., primary, Barkley, Christina R., primary, Wu, Jiaping, primary, Nandula, Subhadra, primary, Dutta, Bhaskar, primary, Xie, Yuli, primary, Chin, Y. Rebecca, primary, Kim, Da-In, primary, Ferris, Jennifer S., primary, Gruvberger-Saal, Sofia K., primary, Laakso, Mervi, primary, Wang, Xiaomei, primary, Memeo, Lorenzo, primary, Rojtman, Albert, primary, Matos, Tulio, primary, Yu, Jennifer S., primary, Cordon-Cardo, Carlos, primary, Isola, Jorma, primary, Terry, Mary Beth, primary, Toker, Alex, primary, Mills, Gordon B., primary, Zhao, Jean J., primary, Murty, Vundavalli V.V.S., primary, Hibshoosh, Hanina, primary, and Parsons, Ramon, primary

Published
2023
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28. Supplementary Information, Methods, Table 1, Figures 1-7 from 3-Phosphoinositide–Dependent Kinase 1 Potentiates Upstream Lesions on the Phosphatidylinositol 3-Kinase Pathway in Breast Carcinoma

Author

Maurer, Matthew, primary, Su, Tao, primary, Saal, Lao H., primary, Koujak, Susan, primary, Hopkins, Benjamin D., primary, Barkley, Christina R., primary, Wu, Jiaping, primary, Nandula, Subhadra, primary, Dutta, Bhaskar, primary, Xie, Yuli, primary, Chin, Y. Rebecca, primary, Kim, Da-In, primary, Ferris, Jennifer S., primary, Gruvberger-Saal, Sofia K., primary, Laakso, Mervi, primary, Wang, Xiaomei, primary, Memeo, Lorenzo, primary, Rojtman, Albert, primary, Matos, Tulio, primary, Yu, Jennifer S., primary, Cordon-Cardo, Carlos, primary, Isola, Jorma, primary, Terry, Mary Beth, primary, Toker, Alex, primary, Mills, Gordon B., primary, Zhao, Jean J., primary, Murty, Vundavalli V.V.S., primary, Hibshoosh, Hanina, primary, and Parsons, Ramon, primary

Published
2023
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30. Characteristics, Treatment, and Outcomes of Primary Urethral Cancer: A Multicenter Review Over Two Decades

Author

Hopkins, Benjamin D., Qian, David C., Xu, Karen M., McCook-Veal, Ashley, Switchenko, Jeffrey, Hartsell, Lindsey M., Cimmino, Cara B., Joshi, Shreyas S., Narayan, Vikram, Master, Viraj A., Nazha, Bassel, Carthon, Bradley C., Bilen, Mehmet A., Kucuk, Omer, Shelton, Joseph W., Patel, Pretesh R., Jani, Ashesh B., Remick, Jill S., and Eng, Tony Y.

Published
2025
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32. Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2

Author

Bhardwaj, Priya, primary, Iyengar, Neil M., additional, Zahid, Heba, additional, Carter, Katharine M., additional, Byun, Dong Jun, additional, Choi, Man Ho, additional, Sun, Qi, additional, Savenkov, Oleksandr, additional, Louka, Charalambia, additional, Liu, Catherine, additional, Piloco, Phoebe, additional, Acosta, Monica, additional, Bareja, Rohan, additional, Elemento, Olivier, additional, Foronda, Miguel, additional, Dow, Lukas E., additional, Oshchepkova, Sofya, additional, Giri, Dilip D., additional, Pollak, Michael, additional, Zhou, Xi Kathy, additional, Hopkins, Benjamin D., additional, Laughney, Ashley M., additional, Frey, Melissa K., additional, Ellenson, Lora Hedrick, additional, Morrow, Monica, additional, Spector, Jason A., additional, Cantley, Lewis C., additional, and Brown, Kristy A., additional

Published
2023
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35. A Secreted PTEN Phosphatase That Enters Cells to Alter Signaling and Survival

Author

Hopkins, Benjamin D., Fine, Barry, Steinbach, Nicole, Dendy, Meaghan, Rapp, Zachary, Shaw, Jacquelyn, Pappas, Kyrie, Yu, Jennifer S., Hodakoski, Cindy, Mense, Sarah, Klein, Joshua, Pegno, Sarah, Sulis, Maria-Luisa, Goldstein, Hannah, Amendolara, Benjamin, Lei, Liang, Maurer, Matthew, Bruce, Jeffrey, Canoll, Peter, Hibshoosh, Hanina, and Parsons, Ramon

Published
2013
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36. Obesity promotes breast epithelium DNA damage in BRCA mutation carriers

Author

Bhardwaj, Priya, primary, Iyengar, Neil M., additional, Zahid, Heba, additional, Carter, Katharine M., additional, Byun, Dong Jun, additional, Choi, Man Ho, additional, Sun, Qi, additional, Savenkov, Oleksandr, additional, Louka, Charalambia, additional, Liu, Catherine, additional, Piloco, Phoebe, additional, Acosta, Monica, additional, Bareja, Rohan, additional, Elemento, Olivier, additional, Foronda, Miguel, additional, Dow, Lukas E., additional, Oshchepkova, Sofya, additional, Giri, Dilip D., additional, Pollak, Michael, additional, Zhou, Xi Kathy, additional, Hopkins, Benjamin D., additional, Laughney, Ashley M., additional, Frey, Melissa K., additional, Ellenson, Lora Hedrick, additional, Morrow, Monica, additional, Spector, Jason A., additional, Cantley, Lewis C., additional, and Brown, Kristy A., additional

Published
2022
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37. Epinephrine inhibits PI3K alpha via the Hippo kinases

Author

Lin, Ting-Yu, primary, Ramsamooj, Shakti, additional, Liberatore, Katarina, additional, Lantier, Louise, additional, Vasan, Neil, additional, Karukurichi, Kannan, additional, Hwang, Seo-Kyoung, additional, Kesicki, Edward A., additional, Kastenhuber, Edward R., additional, Wiederhold, Thorsten, additional, Yaron, Tomer M., additional, Zhu, Mengmeng, additional, Ma, Yilun, additional, Paddock, Marcia N., additional, Zhang, Guoan, additional, Hopkins, Benjamin D., additional, McGuinness, Owen, additional, Schwartz, Robert E., additional, Cantley, Lewis C., additional, Johnson, Jared L., additional, and Goncalves, Marcus D., additional

Published
2022
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39. A Functional Precision Oncology Approach to Identify Treatment Strategies for Myxofibrosarcoma Patients

Author

Pauli, Chantal, De Boni, Lamberto, Pauwels, Jonathan E, Chen, Yanjiang; https://orcid.org/0000-0002-2355-7878, Planas-Paz, Lara, Shaw, Reid, Emerling, Brooke M; https://orcid.org/0000-0002-2168-4582, Grandori, Carla, Hopkins, Benjamin D, Rubin, Mark A; https://orcid.org/0000-0002-8321-9950, Pauli, Chantal, De Boni, Lamberto, Pauwels, Jonathan E, Chen, Yanjiang; https://orcid.org/0000-0002-2355-7878, Planas-Paz, Lara, Shaw, Reid, Emerling, Brooke M; https://orcid.org/0000-0002-2168-4582, Grandori, Carla, Hopkins, Benjamin D, and Rubin, Mark A; https://orcid.org/0000-0002-8321-9950

Abstract

In this era of precision medicine, numerous workflows for the targeting of high-recurrent mutations in common tumor types have been developed, leaving patients with rare diseases with few options. Here, we implement a functional precision oncology approach utilizing comprehensive genomic profiling in combination with high-throughput drug screening, to identify tumor-specific drug sensitivities for patients with rare tumor types such as myxofibrosarcoma. From a patient with a high-grade myxofibrosarcoma, who was enrolled in the Englander Institute for Precision Medicine (EIPM) program, we established patient-derived 3D sarco-spheres and xenograft models for functional testing. In the absence of a large cohort of clinically similar cases, high-throughput drug screening was performed on the patient-derived cells, and compared with two other myxofibrosarcoma lines and a benign fibroblast line to functionally identify tumor-specific drug sensitivities. The addition of functional drug sensitivity testing to complement genomic profiling identified multiple therapeutic options that were further validated in patient derived xenograft models. Genomic analyses detected the frequently known codeletion of the tumor suppressors CDKN2A/B together with the methylthioadenosine phosphorylase (MTAP) and a TP53 E286fs*50 mutation. High-throughput drug screening demonstrated tumor-specific sensitivity to compounds targeting the cell cycle. Based on genomic analysis and high-throughput drug screening, we show that targeting the cell cycle in these tumors is a powerful approach. IMPLICATIONS: This study demonstrates the potential of functional testing to aid clinical decision making for patients with rare or molecularly complex malignancies when combined with comprehensive genomic profiling.

Published
2022

43. Gab2-Mediated Signaling Promotes Melanoma Metastasis

Author

Horst, Basil, Gruvberger-Saal, Sofia K., Hopkins, Benjamin D., Bordone, Lindsey, Yang, Ying, Chernoff, Karen A., Uzoma, Ijeoma, Schwipper, Volker, Liebau, Jutta, Nowak, Norma J., Brunner, Georg, Owens, David, Rimm, David L., Parsons, Ramon, and Celebi, Julide Tok

Published
2009
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46. Thrombospondin-1 modulates VEGF-a-mediated Akt signaling and capillary survival in the developing retina

Author

Sun, Jingfang, Hopkins, Benjamin D., Tsujikawa, Kaoru, Perruzzi, Carole, Adini, Irit, Swerlick, Robert, Bornstein, Paul, Lawler, Jack, and Benjamin, Laura E.

Subjects
Phosphorylation -- Research, Retina -- Physiological aspects, Retina -- Research, Vascular endothelial growth factor -- Physiological aspects, Vascular endothelial growth factor -- Genetic aspects, Vascular endothelial growth factor -- Research, Biological sciences
Abstract

Microvascular development is often perceived to result from a balance of positive and negative factors that impact signaling for proliferation and survival. The survival signaling that results from hypoxia-induced VEGF-A has been well established, but the factors that antagonize this signaling have been poorly studied. As endogenous inhibitors of angiogenesis, thrombospondins (TSPs) are likely candidates to affect survival signaling. Here we report that TSP1 antagonized microvascular survival to retinal hyperoxia, and Akt signaling in both the retina and in cultured endothelial cells. TSP1 expression is correlated with the association of the CD36 receptor with Src versus Fyn. In the presence of TSPI, CD36 is coprecipitated with Fyn as previously shown by others. However, in the absence of TSP1, there is a preferential association with Src. We now demonstrate that these Src family kinases play an important role in modulating microvascular survival in response to TSPI by crossing [tsp1.sup.-/-] mice to the [src.sup.-/-] and [fyn.sup.-/-] mice and testing the survival of retinal blood vessels in hyperoxia. We find that [tsp1.sup.-/-], [fyn.sup.-/-] , and double-mutant [tsp1.sup.-/-]/[fyn.sup.-/-] mice have a similar enhancement of capillary survival in oxygen, whereas in a [tsp.sup.-/-] background, the loss of only one allele of src restores the balance in survival and apoptosis to that of wild-type mice. Taken together, we hypothesize that TSP1 antagonizes VEGF-driven Akt survival signaling in part through the recruitment of Fyn to membrane domains containing CD36, but when TSP1 is absent, an opposing Src recruitment contributes to VEGF-driven Akt phosphorylation and capillary survival. vascular endothelial growth factor

Published
2009

50. Extracellular Matrix Remodelling: Obesity‐Associated Adipose Stromal Cells Promote Breast Cancer Invasion through Direct Cell Contact and ECM Remodeling (Adv. Funct. Mater. 48/2020)

Author

Ling, Lu, primary, Mulligan, Jeffrey A., additional, Ouyang, Yunxin, additional, Shimpi, Adrian A., additional, Williams, Rebecca M., additional, Beeghly, Garrett F., additional, Hopkins, Benjamin D., additional, Spector, Jason A., additional, Adie, Steven G., additional, and Fischbach, Claudia, additional

Published
2020
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