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1.  Dasatinib inhibits both osteoclast activation and prostate cancer PC-3 cell-induced osteoclast formation 
Cancer biology & therapy  2009;8(22):2153-2159.
Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast function, we hypothesized that dasatinib, a Src family kinase inhibitor, would reduce osteoclast activity and prostate cancer (PC-3) cell-induced osteoclast formation.
Dasatinib inhibited RANKL-induced osteoclast differentiation of bone marrow-derived monocytes with an EC50 of 7.5 nM. PC-3 cells, a human prostate cancer cell line, were able to differentiate RAW 264.7 cells, a murine monocytic cell line, into osteoclasts and dasatinib inhibited this differentiation. In addition, conditioned medium from PC-3 cell cultures was able to differentiate RAW 264.7 cells into osteoclasts and this too, was inhibited by dasatinib. Even the lowest concentration of dasatinib, 1.25 nmol, inhibited osteoclast differentiation by 29%. Moreover, dasatinib inhibited osteoclast activity by 58% as measured by collagen 1 release.
Experimental design
We performed in vitro experiments utilizing the Src family kinase inhibitor dasatinib to target osteoclast activation as a means of inhibiting prostate cancer bone metastases.
Dasatinib inhibits osteoclast differentiation of mouse primary bone marrow-derived monocytes and PC-3 cell-induced osteoclast differentiation. Dasatinib also inhibits osteoclast degradation activity. Inhibiting osteoclast differentiation and activity may be an effective targeted therapy in patients with prostate cancer bone metastases.
PMCID: PMC4073296  PMID: 19855158
osteoclast; Src; prostate cancer; dasatinib; PC-3
2.  Dasatinib Combined With Docetaxel For Castration-Resistant Prostate Cancer: Results From a Phase 1/2 Study 
Cancer  2011;118(1):63-71.
To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (CRPC), we conducted a phase 1/2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.
In phase 1, 16 men received dasatinib 50–120 mg once daily (QD) and docetaxel 60–75 mg/m2 every 21 days (Q21D). In phase 2, 30 additional men received dasatinib 100 mg QD/docetaxel 75 mg/m2 Q21D. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied.
Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3/4 toxicity. Drug–drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26/46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone-marker assessments, 33/38 (87%) and 26/34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib following docetaxel discontinuation and had stabilization of disease for an additional 1–12 months.
The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in CRPC. Parallel declines in levels of PSA and bone markers are consistent with co-targeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study.
PMCID: PMC3898168  PMID: 21976132
Dasatinib; Docetaxel; Prostate Cancer; Metastases; Bone
3.  Long-term use of dasatinib in patients with metastatic castration-resistant prostate cancer after receiving the combination of dasatinib and docetaxel 
Dasatinib is a potent oral tyrosine kinase inhibitor which targets several kinases, including the SRC family kinases. SRC family kinases have been implicated in androgen therapy resistance that often develops in metastatic castration-resistant prostate cancer (mCRPC), which drives the need for non-androgen targeting therapies. This article describes the preclinical rationale for the use of combination dasatinib and docetaxel therapy in mCRPC, and highlights the results of a phase I–II trial in which 46 patients with mCRPC, treated with a regimen of dasatinib and docetaxel, demonstrated improvements in bone scans, high rates of soft tissue responses, and modulation of markers of bone turnover. This brief report discusses in detail follow-up data on two patients who remain alive after >2.5 years on dasatinib single-agent therapy after discontinuing docetaxel treatment.
PMCID: PMC3601649  PMID: 23516140
case study; dasatinib; docetaxel; prostate cancer; targeted therapy
4.  Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer 
Clinical features characteristic of small-cell prostate carcinoma (SCPC), (““anaplastic””) often emerge during the progression of prostate cancer. We sought to determine the efficacy of platinum-based chemotherapy in patients meeting at least one of seven prospectively defined “anaplastic” clinical criteria, including exclusive visceral or predominantly lytic bone metastases, bulky tumor masses, low PSA levels relative to tumor burden or short response to androgen deprivation therapy.
Experimental Design
A 120-patient phase II trial of frontline carboplatin and docetaxel (CD) and second-line etoposide and cisplatin (EP) was designed to provide reliable clinical response estimates under a Bayesian probability model with early stopping rules in place for futility and toxicity.
Seventy-four of 113 (65.4%) and 24 of 71 (33.8%) were progression free after 4 cycles of CD and EP, respectively. Median overall survival (OS) was 16 months (95% CI, 13.6-19.0 months). Of the 7 “anaplastic” criteria, bulky tumor mass was significantly associated with poor outcome. Lactic acid dehydrogenase (LDH) strongly predicted for OS and rapid progression. Serum carcinoembryonic antigen (CEA) concentration strongly predicted OS but not rapid progression. Neuroendocrine markers did not predict outcome or response to therapy.
Our findings support the hypothesis that patients with “anaplastic” prostate cancer are a recognizable subset characterized by a high response rate of short duration to platinum-containing chemotherapies, similar to SCPC. Our results suggest that CEA is useful for selecting therapy in men with CRPC and consolidative therapies to bulky high-grade tumor masses should be considered in this patient population.
PMCID: PMC3699964  PMID: 23649003
Small-cell; neuroendocrine; castration-resistant; prostate carcinoma; platinum chemotherapy
5.  Increased Serum Insulin-like Growth Factor-1 Levels are Associated with Prolonged Response to Dasatinib-based Regimens in Metastatic Prostate Cancer 
The Prostate  2013;73(9):979-985.
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.
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).
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.
Our results support a role for serum IGF-1 as a potential biomarker for benefit from dasatinib-based combination treatments in CRPC.
PMCID: PMC4013833  PMID: 23371521
predictive marker; Src inhibition; bone microenvironment; docetaxel; xenograft
6.  Neuroendocrine Prostate Cancer Xenografts with Large-cell and Small-cell Features Derived from a Single Patient’s Tumor: Morphological, Immunohistochemical and Gene Expression Profiles 
The Prostate  2010;71(8):10.1002/pros.21301.
Small-cell carcinoma (SCC) of the prostate is an AR-negative variant of prostate cancer found at progression in 10–20% of castrate-resistant disease. Its finding predicts a distinct clinical course and a poor prognosis. Large-cell neuroendocrine carcinoma (LCNEC) is a much rarer variant that behaves similarly to SCC. The biological mechanisms that drive these disease variants are poorly understood.
Eight tumor fragments from the salvage pelvic exenteration specimen of a patient with castrate-resistant prostate carcinoma were subcutaneously implanted into 6- to 8-week-old male CB17 SCID mice. Serial tissue sections and tissue microarrays of the resulting MDA PCa 144 xenograft lines were used for histopathologic and immunohistochemical characterization of the xenografts and their tissue of origin. RNA from two representative xenograft sublines was used for gene-expression profiling.
All eight fragments formed tumors: four of the MDA PCa 144 xenograft sublines had morphologic characteristics of SCC and four, of LCNEC. All retained high fidelity to their parent tumor tissue, which remained stable through serial passages. Morphological transitions in the specimen of origin suggested LCNEC represents an intermediate step between adenocarcinoma and SCC. Over 2,500 genes were differentially expressed between the SCC (MDA PCa 144-13) and the LCNEC (MDA PCa 144-4) sublines and enriched in “Nervous System Development” Gene Ontology subtree.
The eight xenograft models described represent the spectrum of neuroendocrine carcinomas in prostate cancer and will be valuable preclinical tools to study the pathogenesis of and therapy targets for this increasingly recognized subset of lethal prostate cancer.
PMCID: PMC3883511  PMID: 21456067
castrate-resistant; cancer; androgen-independent; neural development; array
7.  Phase II trial of Pemetrexed plus Gemcitabine in patients with advanced non-clear cell renal cell carcinoma 
American journal of clinical oncology  2013;36(5):10.1097/COC.0b013e3182546a91.
To determine the clinical activity and toxicity of combination pemetrexed and gemcitabine for locally advance and metastatic non-clear cell renal cell carcinoma.
In this phase II study patients were treated with pemetrexed 500 mg/m2 IV infusion over 10 minutes(min) on day one followed immediately by gemcitabine 1500 mg/m2 IV over 30 min on day one, repeated every fourteen days. Planned enrollment was 40 patients. The primary endpoints were response rate and progression free survival (PFS). The secondary endpoints were toxicity and overall survival (OS) in months (mo).
Between December 2005 and December 2008, 16 patients with locally advanced or metastatic non clear cell renal cell carcinoma were enrolled. The trial was stopped due to lack of response and excessive toxicity. The overall response rate was 6.7% (95% exact CI: 0.2%–31.9%), no patients with renal cell carcinoma responded to therapy. The median number of cycles administered was 4 (range: 1–12 cycles), median PFS was 3.2 mo (95% CI: 1.875–>6 mo), and the 16-week PFS rate was 46.7% (95% CI: 19.8%–100%). The median OS was 23.2 mo (95% CI: 12.9–38.1 mo). The most common grade 3 or 4 toxicities were neutropenia (53%), leukopenia (53%), anemia (13%), fatigue (40%), and renal failure (13%).
Patients with non clear cell carcinoma metastatic renal cell carcinoma. The combination of pemetrexed and gemcitabine did not show clinical activity in this cohort of patients with non clear cell renal cell carcinoma.
PMCID: PMC3882166  PMID: 22706175
8.  Personalized Oncology Through Integrative High-Throughput Sequencing: A Pilot Study 
Science translational medicine  2011;3(111):111ra121.
Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8 amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogenactivated or extracellular signal–regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors, respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.
PMCID: PMC3476478  PMID: 22133722
9.  The Src Family Kinase/Abl Inhibitor Dasatinib Suppresses Proliferation and Enhances Differentiation of Osteoblasts 
Oncogene  2010;29(22):3196-3207.
Dasatinib, a dual Src family kinase and Abl inhibitor, is being tested clinically for the treatment of prostate cancer bone metastasis. Bidirectional interactions between osteoblasts and prostate cancer cells are critical in the progression of prostate cancer in bone, but the effect of dasatinib on osteoblasts is unknown. We found that dasatinib inhibited proliferation of primary mouse osteoblasts isolated from mouse calvaria and the immortalized MC3T3-E1 cell line. In calvarial osteoblasts from Col-luc transgenic mice carrying osteoblast-specific Collagen1α1 promoter-reporter, luciferase activity was inhibited. Dasatinib also inhibited FGF-2–induced osteoblast proliferation, but strongly promoted osteoblast differentiation, as reflected by stimulation of alkaline phosphatase activity, osteocalcin secretion, and osteoblast mineralization. To determine how dasatinib blocks proliferative signaling in osteoblasts, we analyzed the expression of a panel of tyrosine kinases, including Src, Lyn, Fyn, Yes, and Abl, in osteoblasts. In the Src family kinases, only Src was activated at a high level. Abl was expressed at a low level in osteoblasts. Phosphorylation of Src-Y419 or Abl-Y245 was inhibited by dasatinib treatment. Knockdown of either Src or Abl by lenti shRNA in osteoblasts enhances osteoblast differentiation, suggesting that dasatinib enhances osteoblast differentiation through inhibition of both Src and Abl.
PMCID: PMC2921959  PMID: 20228840
dasatinib; Src family kinase; osteoblast; prostate cancer; bone metastasis

Results 1-9 (9)