Combination therapy targeting both tumor-initiating and differentiated cell populations in prostate carcinoma.
OBJECTIVE
The cancer stem cell hypothesis predicts that standard prostate cancer monotherapy eliminates bulk tumor cells but not a tumor-initiating cell population, eventually leading to relapse. Many studies have sought to determine the underlying differences between bulk tumor and cancer stem cells.


METHODS
Our previous data suggest that the PTEN/PI3K/AKT pathway is critical for the in vitro maintenance of CD133(+)/CD44(+) prostate cancer progenitors and, consequently, that targeting PI3K signaling may be beneficial in treatment of prostate cancer.


RESULTS
Here, we show that inhibition of PI3K activity by the dual PI3K/mTOR inhibitor NVP-BEZ235 leads to a decrease in the population of CD133(+)/CD44(+) prostate cancer progenitor cells in vivo. Moreover, the combination of the PI3K/mTOR modulator NVP-BEZ235, which eliminates prostate cancer progenitor populations, and the chemotherapeutic drug Taxotere, which targets the bulk tumor, is significantly more effective in eradicating tumors in a prostate cancer xenograft model than monotherapy.


CONCLUSIONS
This combination treatment ultimately leads to the expansion of cancer progenitors with a PTEN E91D mutation, suggesting that the analysis of PTEN mutations could predict therapeutic response to the dual therapy.
The Scripps Research Institute, La Jolla, California 92037, USA.
Anna
A
Dubrovska
Jimmy
J
Elliott
Richard J
RJ
Salamone
Sungeun
S
Kim
Lindsey J
LJ
Aimone
John R
JR
Walker
James
J
Watson
Maira
M
Sauveur-Michel
Carlos
C
Garcia-Echeverria
Charles Y
CY
Cho
Venkateshwar A
VA
Reddy
Peter G
PG
Schultz
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010455:Peptides / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011804:Quinolines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D007093:Imidazoles; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D011804:Quinolines; D051059:PTEN Phosphohydrolase; C531198:dactolisib