Increased serum insulin-like growth factor-1 levels are associated with prolonged response to dasatinib-based regimens in metastatic prostate cancer.
BACKGROUND
Dasatinib, an inhibitor of Src-family kinases, combined with docetaxel in men with castrate-resistant prostate cancer (CRPC), affects bone turnover markers in a phase I/II clinical trial in metastatic CRPC. Only a subset of men benefit from this therapy, and predictive markers are lacking. We hypothesized a role for insulin-like growth factor-1 (IGF-1) as a predictive marker, since IGF-1 is important in both prostate cancer progression and bone development. Hence, we determined the association of IGF-1 expression to treatment response, and whether this expression resulted from tumor cells, the microenvironment, or their interactions.


METHODS
We measured serum IGF-1 levels in men with CRPC treated with dasatinib plus docetaxel. To investigate the source of IGF-1, we utilized two different mouse models harboring human prostate cancer cells, and used species-specific IGF-1 ELISA kits (mouse vs. human).


RESULTS
In men with CRPC, an increase in IGF-1 levels after one cycle of treatment with dasatinib and docetaxel is associated with a higher response rate and longer duration of treatment. Xenograft experiments with subcutaneous and intratibial injection of prostate cancer cells suggest that direct interaction of prostate cancer cells with bone microenvironment is necessary for IGF-1 induction, is entirely host-derived, and occurs only in mice that respond to dasatinib-based therapy.


CONCLUSIONS
Our results support a role for serum IGF-1 as a potential biomarker for benefit from dasatinib-based combination treatments in CRPC.
UT MD Anderson Cancer Center, Genitourinary Medical Oncology, Houston, Texas 77030, USA.
Farshid
F
Dayyani
Andreas
A
Varkaris
John C
JC
Araujo
Jian H
JH
Song
Tanushree
T
Chatterji
Geralyn C
GC
Trudel
Christopher J
CJ
Logothetis
Gary E
GE
Gallick
D016475:3T3 Cells; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000097:blood; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D000069439:Dasatinib; D000077143:Docetaxel; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy; D010006:Osteoblasts / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood* / Q000188:drug therapy*; D011743:Pyrimidines / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D014408:Biomarkers, Tumor; D011743:Pyrimidines; D043823:Taxoids; D013844:Thiazoles; D000077143:Docetaxel; D007334:Insulin-Like Growth Factor I; D000069439:Dasatinib