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Stanley  Lipkowitz, M.D., Ph.D.

Stanley Lipkowitz, M.D., Ph.D.

  • Center for Cancer Research
  • National Cancer Institute

RESEARCH SUMMARY

My laboratory has two main areas of interest. 1) We study Cbl proteins, a family of ubiquitin ligases that negatively regulate signaling by receptor tyrosine kinases. 2) We investigate induction of apoptosis in breast cancer cells by TRAIL receptor agonists. I am an attending physician in the Women’s Malignancies clinic at NCI and in the Breast Cancer clinic at Walter Reed National Military Medical Center. As Chief, I oversee the laboratory and clinical research in the WMB. Our goal is to integrate laboratory and clinical research findings into mechanism-based, hypothesis-driven clinical trials on patients with breast and gynecological malignancies.

Areas of Expertise

1) Cbl proteins, 2) ubiquitin ligases, 3) receptor tyrosine kinases, 4) TRAIL, 5) apoptosis,
6) breast cancer

Information for Patients

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Publications

Selected Key Publications

In Vitro Ubiquitination Platform Identifies Methyl Ellipticiniums as Ubiquitin Ligase Inhibitors

Wilson BAP, Voeller D, Smith EA, Wamiru A, Goncharova EI, Liu G, Lipkowitz S, O'Keefe BR.
SLAS Discov. 26(7): 870-884, 2021.
Full-Text Article
[ Journal Article ]

ONC201 kills breast cancer cells in vitro by targeting mitochondria.

Greer YE, Porat-Shliom N, Nagashima K, Stuelten C, Crooks D, Koparde VN, Gilbert SF, Islam C, Ubaldini A, Ji Y, Gattinoni L, Soheilian F, Wang X, Hafner M, Shetty J, Tran B, Jailwala P, Cam M, Lang M, Voeller D, Reinhold WC, Rajapakse V, Pommier Y, Weigert R, Linehan WM, Lipkowitz S.
Oncotarget. 9(26): 18454-18479, 2018.
Full-Text Article
[ Journal Article ]

Analysis of breast cancer in young women in the Department of Defense (DOD) database

Zimmer AS, Zhu K, Steeg PS, Wu A, Gatti-Mays ME, Soltani S, Perkins JG, Shao S, Brown D, Georg M, Hu H, Shriver CD, Lipkowitz S.
Breast Cancer Res.. 168(2): 501-511, 2018.
Full-Text Article

Job Vacancies

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Team

Patient Care Coordinator (Contr.)
Mireya Gomez
Branch Secretary
Josselyn White
Postdoctoral Fellow (Visiting)
Manjari Kundu Sil, Ph.D.
Research Nurse
Ann McCoy, R.N.
Nurse Practitioner
Britanny Brooke Solarz , R.N., B.S.N.
Research Nurse (Contr.)
Erin Villanueva, R.N.
Research Chemist
Donna M. Voeller
Postdoctoral Fellow (CRTA)
David Wisnewski, Ph.D.
PostBaccalaureate Fellow (CRTA)
Sarah Weltz
Graduate Student
Yonit Addissie, M.A.
Patient Care Coordinator
Jessica Presentacion-Blanco

Covers

Oncotarget Cover - April 6, 2018

ONC201 kills breast cancer cells in vitro by targeting mitochondria

Published Date

About the Cover
The cover for issue 26 of Oncotarget features Figure 8, "Proposed mechanism of action of ONC201" from Greer, et al.

Abstract

We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA-encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201.

Citation

ONC201 kills breast cancer cells in vitro by targeting mitochondria.  Greer YE, Porat-Shliom N, Nagashima K, Stuelten C, Crooks D, Koparde VN, Gilbert SF, Islam C, Ubaldini A, Ji Y, Gattinoni L, Soheilian F, Wang X, Hafner M, Shetty J, Tran B, Jailwala P, Cam M, Lang M, Voeller D, Reinhold WC, Rajapakse V, Pommier Y, Weigert R, Linehan WM, and Lipkowitz S. Oncotarget 9(26):18454-18479, 2018.

About Oncotarget
Oncotarget is a weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com or connect with @Oncotarget
Oncotarget is published by Impact Journals, LLC. Please visit https://www.ImpactJournals.com or connect with @ImpactJrnls
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