Conditions: Hormone-refractory Prostate Cancer Adenocarcinoma of the Prostate Hormone-resistant Prostate Cancer Prostate Cancer Recurrent Prostate Cancer
Keywords: prostate
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 38
Healthy volunteers: no

Brief summary:
The purpose of this research study is to find out if a new anti-cancer drug, dasatinib (Sprycel®), previously approved for treatment of some forms of leukemia, will be safe and helpful in treating patients with hormone-refractory prostate cancer.

This is a research study because the study drug, dasatinib (Sprycel®), has not been evaluated for safety or effectiveness in patients with hormone-refractory prostate cancer. The drug is approved by the Food and Drug Administration for treatment of some forms of leukemia; thus, dasatinib (Sprycel®) is not an investigational drug. It has been given safely to hundreds of patients already. However its safety and usefulness in this study population (prostate cancer) is unknown.

Subjects who agree to participate will take 150mg (3 pills) of dasatinib (Sprycel®) daily by mouth for as long as the drug benefits them. During this time, the subject will periodically return to the office for blood/urine tests, X-rays, imaging scans, and/or to complete questionnaires.

Detailed description:
Metastatic prostate adenocarcinoma is initially dependent on exogenous androgens for survival and growth; hence, androgen blockade is a key initial intervention for these patients. Whether by orchiectomy or by biochemical blockade, androgen deprivation produces objective regression of prostate cancer in \>90% of patients for an average of 1.5-2yrs. Afterwards, however, the remaining prostate cancer cells become independent of exogenous androgen and resume their growth. At this stage the disease is referred to as hormone-refractory prostate cancer (HRPC).

Treatment for HRPC remains unsatisfactory. Only two interventions have been proven through randomized, prospective studies to confer a survival advantage. Docetaxel administered along with prednisone or estramsutine increases overall survival by approximately 3 months, compared with patients treated with mitoxantrone (1,2). In addition, a cell-based vaccine (APC8015) has recently been shown to confer a similar survival advantage for patients with HRPC (3). In 127 patients with HRPC randomized to receive the APC8015 vaccine or unactivated autologous peripheral blood mononuclear cells, there was a 4.5-month increase in median overall survival for the treated cohort (p = 0.01). Thus additional therapeutic tools are needed.

Although the mechanisms whereby androgen-independence develops are not yet fully clarified (7), it is known that malignant progression of prostate cancer involves upregulation of autocrine growth factors and their receptors (8). The process of autocrine reprogramming facilitates autonomous growth and metastasis of the tumor cells. For this reason many of the major novel therapeutic approaches for prostate cancer, currently in clinical trials, are directed against growth factor signaling pathways involving tyrosine kinase receptors and their downstream signaling messengers. Among these, recent evidence suggests a centrol role for the non-receptor tyrosine kinase c-src, in the development, growth, and metastasis of many human cancers (9,10), including prostate carcinomas. Several SFKs are present in prostate cancer cells, including c-src, yes, lck, and lyn (11). SFKs are thought to mediate the signaling pathways of several growth factors and stressors, such as lysophosphatidic acid, bombesin, androgens, and hypoxia (12-15). In prostate cancer cells that are androgen-independent, activation of SFKs is constitutive, rather than ligand-regulated (16). SFKs in turn regulate such diverse prostate cell pathways as VEGF production (15), and FAK signaling (17). Among the response phenotypes mediated by SFKs include cell spreading and attachment, migration and invasion. Genetic and pharmacologic inhibitors of SFKs have been tested on prostate cancer cell lines. Thus two pyrrolopyrimidine c-src inhibitors were shown to inhibit production of the protease MMP-9, as well as the functional ability of the cells to invade Matrigel (18). These phenotypes occurred at inhibitor concentrations that did not significantly affect cell proliferation. In contrast a peptide inhibitor of the lyn kinase inhibited the proliferation of prostate cancer cell lines in culture, and reduced the growth of DU145 xenografts in nude mice (19). Thus a spectrum of responses have been seen in prostate cancer cells or tumors treated with SFK inhibitors, including inhibition of growth.

Arms:
arm 1: Patients receive oral dasatinib once daily in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Dasatinib
Intervention descriptions: intervention 1: 150mg (3 pills) orally daily for as long as the drug benefits

Protocol document: