Advances in cancer treatment have been hampered by a limited understanding of the mechanisms blocking apoptosis that is mediated by death receptors such as Fas/CD95/Apo-1. It is surprising that there is little research directed toward restoring Fas receptor, despite its pervasiveness in cancer and possible beneficial role in cancer therapy. Restoring Fas-apoptosis to cancer cells would be a major breakthrough in cancer therapy. We screened non-Hodgkin lymphoma (NHL) cells for inhibitors of Fas and identified CD74 as a candidate. CD74 is a major histocompatibility complex-associated protein that is highly expressed in hematopoietic cancers. We showed that CD74 binds Fas and suppresses Fas-mediated apoptosis. We also showed that human chronic lymphocytic leukemia (CLL) and NHL tumor tissues contain complexes of CD74-Fas. We disrupted the CD74- Fas complex with competing peptides and with an anti-CD74 antibody, which substantially facilitated Fas- mediated apoptosis. In a clinical trial we show anti-CD74 antibody therapy is associated with disruption of CD74-Fas complexes. We therefore hypothesize that CD74-Fas complexes inhibit apoptosis and can be disrupted to enhance apoptosis in vivo. In a clinical trial using anti-CD74 antibody for patients with CLL and NHL, we will correlate CD74 antibody therapy with intercellular mediators of apoptosis and CD74-dependent signaling. We will also analyze plasma before and during chemotherapy for intercellular CD74-Fas-related signaling markers. We will identify the predominant intracellular signaling pathway activated in antitumor responses with CD74-targeted therapy. As an alternative plan, we will analyze CD74-Fas signaling in CLL cells from patients before and during therapy with fludarabine, cyclophosphamide, rituximab, which uses Fas- mediated apoptosis in tumor regression. The long-term goal of this project is to develop a detailed understanding of mechanisms by which inhibitors of Fas can be modulated to enhance cancer cell apoptosis.

Public Health Relevance

Lymphoma and leukemia express Fas but are commonly resistant to Fas-mediated apoptosis. We have identified an inhibitor of Fas, termed CD74, and will treat patients with the anti-CD74 antibody. We will determine if CD74 antibodies sensitize cancer cells to apoptosis in vivo by examining CD74-dependent signaling and apoptosis rates.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA153170-02
Application #
8111086
Study Section
Special Emphasis Panel (ZRG1-OBT-Z (55))
Program Officer
Wali, Anil
Project Start
2010-07-14
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
2
Fiscal Year
2011
Total Cost
$166,671
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Berkova, Zuzana; Wang, Shu; Ao, Xue et al. (2014) CD74 interferes with the expression of fas receptor on the surface of lymphoma cells. J Exp Clin Cancer Res 33:80
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