BMI-1 Targeting Interferes with Patient-Derived Tumor-Initiating Cell Survival and Tumor Growth in Prostate Cancer.
OBJECTIVE
Current prostate cancer management calls for identifying novel and more effective therapies. Self-renewing tumor-initiating cells (TICs) hold intrinsic therapy resistance and account for tumor relapse and progression. As BMI-1 regulates stem cell self-renewal, impairing BMI-1 function for TIC-tailored therapies appears to be a promising approach.


METHODS
We have previously developed a combined immunophenotypic and time-of-adherence assay to identify CD49bhiCD29hiCD44hicells as human prostate TICs. We utilized this assay with patient-derived prostate cancer cells and xenograft models to characterize the effects of pharmacologic inhibitors of BMI-1.


RESULTS
We demonstrate that in cell lines and patient-derived TICs, BMI-1 expression is upregulated and associated with stem cell-like traits. From a screened library, we identified a number of post-transcriptional small molecules that target BMI-1 in prostate TICs. Pharmacologic inhibition of BMI-1 in patient-derived cells significantly decreased colony formation in vitro and attenuated tumor initiation in vivo, thereby functionally diminishing the frequency of TICs, particularly in cells resistant to proliferation- and androgen receptor-directed therapies, without toxic effects on normal tissues.


CONCLUSIONS
Our data offer a paradigm for targeting TICs and support the development of BMI-1-targeting therapy for a more effective prostate cancer treatment. Clin Cancer Res; 22(24); 6176-91. ©2016 AACR.
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.
Nitu
N
Bansal
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.
Monica
M
Bartucci
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.
Shamila
S
Yusuff
Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, New Brunswick, NJ 08901.
Stephani
S
Davis
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.
Kathleen
K
Flaherty
Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, New Brunswick, NJ 08901.
Eric
E
Huselid
Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, New Brunswick, NJ 08901.
Michele
M
Patrizii
Graduate Program in Cell and Developmental Biology, RBHS-Robert Wood Johnson Medical School, Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, NJ 08901.
Daniel
D
Jones
PTC Therapeutics, Inc., 100 Corporate CT, South Plainfield, NJ 07080.
Liangxian
L
Cao
PTC Therapeutics, Inc., 100 Corporate CT, South Plainfield, NJ 07080.
Nadiya
N
Sydorenko
PTC Therapeutics, Inc., 100 Corporate CT, South Plainfield, NJ 07080.
Young-Choon
YC
Moon
Department of Pathology and Laboratory Medicine, Rutgers University, New Brunswick, NJ 08901.
Hua
H
Zhong
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.|Department of Medicine, Rutgers University, New Brunswick, NJ 08901.
Daniel J
DJ
Medina
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.
John
J
Kerrigan
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.|Department of Medicine, Rutgers University, New Brunswick, NJ 08901.
Mark N
MN
Stein
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.|Department of Surgery, RBHS-Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901.
Isaac Y
IY
Kim
PTC Therapeutics, Inc., 100 Corporate CT, South Plainfield, NJ 07080.
Thomas W
TW
Davis
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.|Department of Medicine, Rutgers University, New Brunswick, NJ 08901.
Robert S
RS
DiPaola
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.|Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, New Brunswick, NJ 08901.|Department of Medicine, Rutgers University, New Brunswick, NJ 08901.
Joseph R
JR
Bertino
Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901.|Graduate Program in Cellular and Molecular Pharmacology, Rutgers University, New Brunswick, NJ 08901.|Graduate Program in Cell and Developmental Biology, RBHS-Robert Wood Johnson Medical School, Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, NJ 08901.|Department of Medicine, Rutgers University, New Brunswick, NJ 08901.
Hatem E
HE
Sabaawy
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D011944:Receptors, Androgen; D063150:Polycomb Repressive Complex 1