Androgen receptor signaling

Androgens are the primary regulators of prostate cancer cell growth and proliferation, and androgen deprivation almost always results in an initial clinical response by inducing apoptosis or arrest in the G1 phase of the cell cycle. Inevitably, men will cease responding to first-line hormonal maneuvers, but it has long been recognized that second-line hormonal therapies can often be associated with a clinical response. Initially this response was presumed to be related to extragonadal production of androgens. An additional factor underlying such responses may also reside within prostate cancer tissue itself. Several studies have demonstrated amplification and increased expression of androgen receptor in xenografts with hormone resistance and in prostate cancer tissues from patients with CRPC. In vitro and in vivo, increased androgen receptor expression has been shown to be required for transformation of prostate cell lines from a hormone-sensitive to a hormone-refractory phenotype, with the effect being ligand-dependent and genotropic. High androgen receptor levels were also associated with a change in the effect of bicalutamide from an androgen receptor antagonist to agonist providing a further basis for antiandrogen withdrawal affecting a positive clinical response. Inhibition of the androgen receptor in hormone-refractory tumor models has also been shown to induce regression. Prostate cancer cells and human tissues also possess the biochemical machinery to synthesize androgens, invoking an autocrine/paracrine mechanism for castration-resistant progression. Ligand-independent mechanisms may occur through androgen receptor splice variants lacking the ligand binding domain that are constitutively active. In light of our evolving understanding of the mechanisms of castration resistance, a strategy to develop more potent inhibitors of extragonadal androgen production and antagonists of the androgen receptor has been a rational and active area for drug development. Results of clinical trials of 2 such agents targeting mechanisms of androgen receptor activation, abiraterone acetate (Couger Biotechnology Inc) and MDV3100 (Medivation Inc), have recently been reported. The early results of these clinical trials are encouraging and confirm clinically that CRPC commonly remains dependent on androgen receptor signaling.

Abiraterone acetate is an orally administered medication that inhibits the cytochrome P450 enzyme CYP17A1. This enzyme has dual function as a 17α-hydroxylase and C _17,20 -lyase; both these functions are necessary to synthesize androgens from cholesterol precursors. Treatment doses at all levels studied were well tolerated in a phase I trial that enrolled patients with CRPC who were chemotherapy naive. Reported toxicities were largely anticipated in light of the mechanism of action of abiraterone with mineralcorticoid excess (hypertension, hypokalemia, edema). In most cases these were easily controlled by administration of an aldosterone antagonist (eplerenone) or corticosteroids. PSA decreases of 30% or more and 50% or more were observed in 66% and 57% of patients, respectively. High rates of response have been observed in several phase II trials of abiraterone in patients with CRPC who were chemotherapy naive and who had progressed after docetaxel therapy. A phase II trial recently reported data from 27 chemotherapy-naive patients with CRPC, and PSA decreases of more than 50% from baseline were observed in 85% of patients. In another early report of a phase II trial of 47 patients who had previously received docetaxel, 51% of patients were noted to have a PSA decrease of 50% or more. Of 35 patients with measurable disease, 6 (17%) had a partial response. Seventeen patients remained on therapy for more than 6 months and the median duration of treatment was an impressive 167 days. An improvement in performance status was seen in 23% of patients compared with baseline. Treatment was well tolerated with only grade 1 to 2 adverse events reported. Data from another phase II trial suggest that patients who have previously received cytotoxic chemotherapy, but who have not received prior high dose ketoconazole (which also suppresses steroidogenesis through P450-dependent enzymes), may have increased rates of response and time to PSA progression compared with those who have been exposed to ketoconazole.

A randomized, double-blind, placebo-controlled trial of abiraterone and prednisone has completed accrual of a planned enrolment of 1158 patients with CRPC who are progressing after docetaxel ( http://clinicaltrials.gov identifier: NCT00638690). Patients were randomized 2:1 in favor of abiraterone, and the trial is powered to detect a difference in median overall survival of 15 months in the abiraterone-prednisone group versus 13 months in the placebo-prednisone group (hazard ratio [HR] = 0.80). A second phase III trial with abiraterone has been initiated in patients with CRPC who are chemotherapy naive and asymptomatic or minimally symptomatic (not requiring opiate analgesics). The primary end points for this study are overall survival and progression-free survival with an estimated enrolment of 1000 patients (NCT00887198).

MDV3100 is a potent novel small androgen receptor antagonist that prevents nuclear translocation and DNA binding of androgen receptor, and, unlike bicalutamide, possesses no agonistic activity. A first-in-man, multicenter phase I/II dose-escalation study has been reported and shows encouraging clinical results. Treatment has been well tolerated and early results indicate that at 12 weeks, 57% of chemotherapy-naive patients and 45% of chemotherapy-pretreated patients had a 50% or greater decrease in PSA compared with baseline. Data to date suggest a dose response, especially in patients previously treated with chemotherapy. Given this, 160 mg/d has been selected as the dosage for a phase III trial in which approximately 1200 patients with CRPC who have progressed after docetaxel will be randomized 2:1 in favor of MDV3100 versus placebo (NCT00974311). The primary end point of the trial is overall survival.

Vascular endothelial growth factor and receptor

Growth beyond a few millimeters and the ability to metastasize are dependent on a malignant tumor’s ability to recruit new vasculature in a process known as angiogenesis. Several mediators of angiogenesis have been identified, including vascular endothelial growth factor (VEGF) which signals through VEGF receptors (VEGFR) 1 and 2 to promote angiogenesis. Elevated VEGFR, notably VEGFR-2, has been associated with progression of prostate cancer in the TRAMP model and is also over expressed in human prostate cancers. In patients with metastatic CRPC, increased plasma VEGF as a continuous or dichotomous variable has been correlated with poor prognosis and disease progression. Antitumor effects have been observed with inhibition of the VEGF/VEGFR pathways in experimental models of prostate cancer. The combination of VEGF inhibition with chemotherapy may result in an indirect antitumor effect by enhancing permeability via vascular normalization. Given this sound preclinical rationale, targeting of the VEGF pathway is a reasonable therapeutic approach for patients with prostate cancer and 3 such agents are currently in phase III trials: bevacizumab (Genentech), aflibercept (Sanofi-Aventis) and sunitinib (Pfizer Inc).

Bevacizumab is a monoclonal antibody directed against VEGF-A and causes potent inhibition of VEGFR signaling and angiogenesis. Bevacizumab has reported single agent activity in renal cell cancer, and is approved for use in combination with chemotherapy for patients with metastatic colorectal, breast, and lung cancers. Bevacizumab-associated toxicities include hypertension, thromboembolism, hemorrhage, gastrointestinal perforation, and proteinuria. The Cancer and Leukemia Group B (CALGB) has conducted a phase II trial of bevacizumab in combination with docetaxel-estramustine chemotherapy in patients with metastatic CRPC. A PSA decrease of more than 50% from baseline occurred in 81% of patients, and the median time to progression (for objective disease or PSA) was in the 9 months range. Overall survival for the group was 21 months. A phase III randomized placebo-controlled trial evaluating the effects on overall survival from docetaxel, prednisone, and bevacizumab versus docetaxel and prednisone has fully accrued the planned 1020 subjects and results are awaited (NCT00110214). Bevacizumab has also been tested in combination with docetaxel and RAD001 (an inhibitor of mTOR) in chemotherapy-naive patients, and in combination with satraplatin (an oral chemotherapy) in patients previously treated with docetaxel. Both combinations were reasonably well tolerated, but more later-phase data will be required to establish efficacy and to determine whether either of these combinations will find a role in the standard treatment of CRPC.

Aflibercept (VEGF Trap) is a recombinantly produced fusion protein consisting of human VEGF receptor extracellular domains fused to the Fc portion of human immunoglobulin (Ig) G1. Aflibercept is a potent inhibitor of VEGF-A, VEGF-B, and other VEGF family members like placental growth factor that bind to VEGFR-1 and VEGFR-2, by binding and inactivating these circulating factors. Given the similar mechanism of action, the adverse events are comparable with those seen with bevacizumab. Phase I trials have demonstrated the safety of aflibercept in combination with docetaxel. A phase III, randomized, double-blind, placebo-controlled trial is underway for patients with metastatic CRPC (NCT00519285).

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor including the receptor kinase activity of VEGFR, platelet-derived growth factor receptor, and KIT. Sunitinib has been shown to significantly improve progression-free survival in metastatic renal cell cancer and is therefore approved for use. A phase II study investigating sunitinib in patients with metastatic CRPC has been presented. This trial determined progression based on clinical and radiological (ie, non-PSA based) parameters, with the primary objective being to determine whether sunitinib therapy was associated with a clinical progression-free survival of 12 weeks in more than 30% of patients. All patients had received 1 or 2 prior chemotherapies including docetaxel. A 12-week progression-free survival was attained in 78.9% of patients. Forty-seven percent of patients discontinued therapy because of toxicity and there were 2 early deaths. A phase III study has been initiated that will randomize patients with CRPC progressing after docetaxel to receive sunitinib or placebo in a 2:1 fashion (in favor of sunitinib). The primary end point is overall survival, and a planned 819 patients will be enrolled (NCT00676650). More recently, a phase II study was presented looking at sunitinib in combination with docetaxel as a first-line treatment in 55 patients with metastatic CRPC. Although the PSA response rate was encouraging with 31 (56%) patients showing a PSA response, the combination resulted in an increase in adverse events with a rate of febrile neutropenia of 15% and dose reductions were required for sunitinib (26% of patients) and docetaxel (33% of patients).

Other VEGFR targeted agents have also been studied in prostate cancer. Sorafenib is an orally administered multitargeted kinase inhibitor and has inhibitory action against Raf kinase, PDGFR, VEGFR-2 and -3, and c-kit pathways. Sorafenib has proven efficacy for treatment of advanced renal cell carcinoma and hepatocellular carcinoma. In prostate cancer, phase II trials of single agent sorafenib used in the pre- or post-docetaxel setting have reported modest activity with a low rate of PSA responses and a median progression-free survival of 2 to 4 months. However, discordant responses in these trials were seen with increasing PSA levels but improved scans or symptoms, suggesting that PSA may not be reliable as a marker of an antitumor effect with sorafenib. Interest has also been garnered surrounding the hypothesis that sorafenib may potentiate the effects of docetaxel. A phase I dose-escalation study recently reported that the combination of docetaxel and sorafenib was well tolerated with no dose-limiting toxicity observed at the doses tested; the recommended dose of sorafenib was 400 mg twice daily given continuously with standard dose docetaxel 75 mg/m ² every 3 weeks. There was, however, a high rate of febrile neutropenia (8 of 24 patients) and uncomplicated neutropenia (5 of 24 patients). Preliminary results of a phase II study using docetaxel and sorafenib as first-line treatment in men with CRPC also showed discordant PSA/clinical response. A similar finding was reported recently in a phase II study in which patients who had progressed on docetaxel or mitoxantrone were rechallenged with the same chemotherapy on which they had progressed in addition to sorafenib. Fourteen patients were evaluable at the time of reporting. Of these, 11 (73%) had stable disease radiographically for a median time of 6.7 months. Six of 14 (42%) patients had a decrease in PSA level after adding sorafenib. PSA responses did not correlate with radiographic changes or clinical benefit.

Cediranib is an orally administered small molecule that potently inhibits VEGFR tyrosine kinase. A phase II study using cediranib after progression on docetaxel has recently been reported. The primary end point was progression-free survival as determined by clinical and radiographic criteria (ie, not PSA level). Twenty-three of 34 enrolled patients were evaluable; of those, 13 showed tumor shrinkage and 4 met the criteria for partial response. As with the previous studies, PSA levels did not correlate well with imaging responses.

Vascular endothelial growth factor and receptor

Growth beyond a few millimeters and the ability to metastasize are dependent on a malignant tumor’s ability to recruit new vasculature in a process known as angiogenesis. Several mediators of angiogenesis have been identified, including vascular endothelial growth factor (VEGF) which signals through VEGF receptors (VEGFR) 1 and 2 to promote angiogenesis. Elevated VEGFR, notably VEGFR-2, has been associated with progression of prostate cancer in the TRAMP model and is also over expressed in human prostate cancers. In patients with metastatic CRPC, increased plasma VEGF as a continuous or dichotomous variable has been correlated with poor prognosis and disease progression. Antitumor effects have been observed with inhibition of the VEGF/VEGFR pathways in experimental models of prostate cancer. The combination of VEGF inhibition with chemotherapy may result in an indirect antitumor effect by enhancing permeability via vascular normalization. Given this sound preclinical rationale, targeting of the VEGF pathway is a reasonable therapeutic approach for patients with prostate cancer and 3 such agents are currently in phase III trials: bevacizumab (Genentech), aflibercept (Sanofi-Aventis) and sunitinib (Pfizer Inc).

Bevacizumab is a monoclonal antibody directed against VEGF-A and causes potent inhibition of VEGFR signaling and angiogenesis. Bevacizumab has reported single agent activity in renal cell cancer, and is approved for use in combination with chemotherapy for patients with metastatic colorectal, breast, and lung cancers. Bevacizumab-associated toxicities include hypertension, thromboembolism, hemorrhage, gastrointestinal perforation, and proteinuria. The Cancer and Leukemia Group B (CALGB) has conducted a phase II trial of bevacizumab in combination with docetaxel-estramustine chemotherapy in patients with metastatic CRPC. A PSA decrease of more than 50% from baseline occurred in 81% of patients, and the median time to progression (for objective disease or PSA) was in the 9 months range. Overall survival for the group was 21 months. A phase III randomized placebo-controlled trial evaluating the effects on overall survival from docetaxel, prednisone, and bevacizumab versus docetaxel and prednisone has fully accrued the planned 1020 subjects and results are awaited (NCT00110214). Bevacizumab has also been tested in combination with docetaxel and RAD001 (an inhibitor of mTOR) in chemotherapy-naive patients, and in combination with satraplatin (an oral chemotherapy) in patients previously treated with docetaxel. Both combinations were reasonably well tolerated, but more later-phase data will be required to establish efficacy and to determine whether either of these combinations will find a role in the standard treatment of CRPC.

Aflibercept (VEGF Trap) is a recombinantly produced fusion protein consisting of human VEGF receptor extracellular domains fused to the Fc portion of human immunoglobulin (Ig) G1. Aflibercept is a potent inhibitor of VEGF-A, VEGF-B, and other VEGF family members like placental growth factor that bind to VEGFR-1 and VEGFR-2, by binding and inactivating these circulating factors. Given the similar mechanism of action, the adverse events are comparable with those seen with bevacizumab. Phase I trials have demonstrated the safety of aflibercept in combination with docetaxel. A phase III, randomized, double-blind, placebo-controlled trial is underway for patients with metastatic CRPC (NCT00519285).

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor including the receptor kinase activity of VEGFR, platelet-derived growth factor receptor, and KIT. Sunitinib has been shown to significantly improve progression-free survival in metastatic renal cell cancer and is therefore approved for use. A phase II study investigating sunitinib in patients with metastatic CRPC has been presented. This trial determined progression based on clinical and radiological (ie, non-PSA based) parameters, with the primary objective being to determine whether sunitinib therapy was associated with a clinical progression-free survival of 12 weeks in more than 30% of patients. All patients had received 1 or 2 prior chemotherapies including docetaxel. A 12-week progression-free survival was attained in 78.9% of patients. Forty-seven percent of patients discontinued therapy because of toxicity and there were 2 early deaths. A phase III study has been initiated that will randomize patients with CRPC progressing after docetaxel to receive sunitinib or placebo in a 2:1 fashion (in favor of sunitinib). The primary end point is overall survival, and a planned 819 patients will be enrolled (NCT00676650). More recently, a phase II study was presented looking at sunitinib in combination with docetaxel as a first-line treatment in 55 patients with metastatic CRPC. Although the PSA response rate was encouraging with 31 (56%) patients showing a PSA response, the combination resulted in an increase in adverse events with a rate of febrile neutropenia of 15% and dose reductions were required for sunitinib (26% of patients) and docetaxel (33% of patients).

Other VEGFR targeted agents have also been studied in prostate cancer. Sorafenib is an orally administered multitargeted kinase inhibitor and has inhibitory action against Raf kinase, PDGFR, VEGFR-2 and -3, and c-kit pathways. Sorafenib has proven efficacy for treatment of advanced renal cell carcinoma and hepatocellular carcinoma. In prostate cancer, phase II trials of single agent sorafenib used in the pre- or post-docetaxel setting have reported modest activity with a low rate of PSA responses and a median progression-free survival of 2 to 4 months. However, discordant responses in these trials were seen with increasing PSA levels but improved scans or symptoms, suggesting that PSA may not be reliable as a marker of an antitumor effect with sorafenib. Interest has also been garnered surrounding the hypothesis that sorafenib may potentiate the effects of docetaxel. A phase I dose-escalation study recently reported that the combination of docetaxel and sorafenib was well tolerated with no dose-limiting toxicity observed at the doses tested; the recommended dose of sorafenib was 400 mg twice daily given continuously with standard dose docetaxel 75 mg/m ² every 3 weeks. There was, however, a high rate of febrile neutropenia (8 of 24 patients) and uncomplicated neutropenia (5 of 24 patients). Preliminary results of a phase II study using docetaxel and sorafenib as first-line treatment in men with CRPC also showed discordant PSA/clinical response. A similar finding was reported recently in a phase II study in which patients who had progressed on docetaxel or mitoxantrone were rechallenged with the same chemotherapy on which they had progressed in addition to sorafenib. Fourteen patients were evaluable at the time of reporting. Of these, 11 (73%) had stable disease radiographically for a median time of 6.7 months. Six of 14 (42%) patients had a decrease in PSA level after adding sorafenib. PSA responses did not correlate with radiographic changes or clinical benefit.

Cediranib is an orally administered small molecule that potently inhibits VEGFR tyrosine kinase. A phase II study using cediranib after progression on docetaxel has recently been reported. The primary end point was progression-free survival as determined by clinical and radiographic criteria (ie, not PSA level). Twenty-three of 34 enrolled patients were evaluable; of those, 13 showed tumor shrinkage and 4 met the criteria for partial response. As with the previous studies, PSA levels did not correlate well with imaging responses.

Apoptosis

Resistance to apoptosis or programmed cell death is another mechanism attributed to prostate cancer progression and treatment resistance. The bcl-2 gene (B-cell leukemia-lymphoma gene 2) is the prototype of a class of oncogenes that contributes to neoplastic progression by enhancing tumor cell survival through inhibition of apoptosis. Bcl-2 is a mitochondrial membrane protein that was initially identified in follicular lymphoma. By heterodimerizing with Bax and other proapoptotic regulators it prevents release of cytochrome c and subsequent activation of the apoptotic cascade. The selective and competitive dimerization between pairs of these antagonists and agonists of the Bcl-2 family of proteins determines how a cell responds to an apoptotic signal. Over-expression of bcl-2 has been shown to be associated with treatment resistance. In prostate cancer, bcl-2 has been found to be expressed in clinical samples of androgen-dependent and -independent disease, and experimental and clinical studies report that increased expression of bcl-2 confers, or is associated with, the development of androgen independence and treatment resistance. G3139 (Genta, Inc) is an 18-mer phosphorothioate antisense oligonucleotide complimentary to the first 6 codons of the initiating sequence of the human bcl-2 mRNA. In preclinical prostate cancer models, G3139 and other bcl-2 antisense oligonucleotides have shown significant activity in inhibiting expression of bcl-2 , delaying time to the development of androgen independence, and enhancing the effects of chemotherapy by increased apoptosis. Phase I trials with prolonged infusions of G3139 as a single agent or in combination with chemotherapy have shown good tolerability. Initial results have been reported from a randomized phase II trial in 115 patients with CRPC, which was conducted by the European Organisation for Research and Treatment of Cancer (EORTC). Patients randomized to receive combination therapy received a median of 2 fewer cycle of treatment (6 vs 8 cycles), and the PSA response rate was numerically lower in the combination therapy arm (37% vs 46%). Further trials for this agent in CRPC are not known to be planned.

One possible explanation for a lack of clinical benefit being observed with G3139 is that there are several prosurvival bcl-2 family members. The specific targeting of only 1 member may simply be insufficient to overcome apoptotic resistance exerted by the other bcl-2 family members. This hypothesis is supported by preclinical testing in which enhanced regressions in cancer models treated with combined targeting of antiapoptotic bcl-2 family members was observed. AT101 (Ascenta Therapeutics, Inc) is a small molecule inhibitor of multiple antiapoptotic Bcl-2 family members (Bcl-2, Bcl-X _L , Bcl-W, Mcl-1) derived from gossypol, which is a natural compound from cotton seeds. AT101 has single agent and combination activity in vitro and in vivo. In a single agent phase II trial with 23 chemotherapy-naive patients with CRPC, 2 (9%) had decreases in PSA level of 50% or more that were confirmed and 5 (22%) additional patients had decreases in PSA level ranging from 3% to 54%. Adverse events included diarrhea, fatigue, nausea, anorexia, and small bowel obstruction necessitating dose reduction. A phase I/II trial of AT101 in combination with standard docetaxel and prednisone with escalating doses of AT101 has been completed and a recommended phase II dose was identified with several PSA responses observed. Based on the promising early clinical data, a randomized phase II trial is currently ongoing. The accrual goal is 220 patients with chemotherapy-naive metastatic CRPC, and the trial is designed to evaluate docetaxel with or without AT101 with a primary end point of overall survival (NCT00571675).

Chaperone proteins

The heat shock protein-90 (Hsp90) molecular chaperone complex is essential for androgen receptor stability and maturation, and has been identified as a potential therapeutic target for CRPC. Hsp90 also acts as a chaperone to several other client proteins associated with malignant progression (Akt, Raf-1, HER-2, and hypoxia-inducible factor-1α). Hsp90 is an ATP-dependent chaperone, and several specific inhibitors have been developed against its ATPase activity. Small molecule inhibitors of histone deacetylase (HDAC) can also result in the loss of Hsp90 ATP binding activity through acetylation and subsequent degradation of androgen receptor. HDAC inhibitors are also of interest as the frequently occurring TMPRSS2:ETS gene fusions in prostate cancer may result in epigenetic reprogramming including upregulation of HDAC-1 and downregulation of its targets with resultant susceptibility to HDAC inhibition.

17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin antibiotic. In preclinical models it has exhibited antitumor activity and is presumed to act by binding to the Hsp90 ATP binding site. Phase I trials have demonstrated the safety of the agent in humans, however a recent phase II trial in patients with CRPC reported only minimal clinical activity. Similarly, HDAC inhibitors in phase II trials involving patients with CRPC have yet to demonstrate any clinically significant activity. Despite these early failures, other Hsp90 and HDAC inhibitors continue to be evaluated.

Clusterin is another chaperone protein of interest. Clusterin exists as an intracellular truncated 55-kDa nuclear form (nCLU) which is proapoptotic and a 75- to 80-kDa secreted heterodimer disulfide-linked glycoprotein (sCLU), which has been shown to be antiapoptotic. Clusterin has been defined mostly in its role of inhibiting apoptosis. Clusterin expression is induced after therapeutic stress and functions as a cytoprotective chaperone similar to an ATP-independent small heat shock protein, and is transcriptionally activated by heat shock factor-1. Clusterin’s ability to inhibit apoptosis has also been shown to act through inhibition of activated Bax, a critical proapoptotic Bcl-2 family member. Furthermore, over-expression of clusterin leads to activation of the PI-3Kinase/Akt pathway through the megalin cell surface receptor. Clusterin expression increases in response to cell stress induced by a variety of factors in xenograft models and forced over-expression of clusterin confers resistance to radiation, hormone treatment, and chemotherapy, whereas inhibition of clusterin expression enhances apoptotic death from these treatment modalities. Clusterin has been associated with androgen-independent progression in preclinical models of prostate cancer. Clusterin is over-expressed in a variety of human cancers including prostate, in which its expression increases after castration and with castration-resistant disease.

OGX-011 (OncoGenex Pharmaceuticals Inc) is a second-generation phosphorothioate antisense molecule with a prolonged tissue half-life. OGX-011 has been shown to significantly decrease sCLU expression through inhibition of clusterin mRNA translation in vitro and in vivo. Phase I trials have established that OGX-011 can inhibit clusterin expression in prostate cancer tissues in humans and that standard doses of chemotherapy can be delivered with OGX-011 at biologically active doses. A randomized phase II trial of OGX-011 with mitoxantrone or docetaxel in patients with CRPC that had previously progressed on or within 3 months of completing docetaxel reported tolerability but also interesting antitumor activity. In patients treated with the combination of mitoxantrone and OGX-011, 27% had a decrease in PSA level of more than 50% from baseline, and median overall survival was 11.4 months. In those subjects who received OGX-011 with docetaxel, 40% had a 50% decrease in PSA level from baseline and a median overall survival of 14.7 months. Another phase II study with OGX-011 randomized 82 patients with chemotherapy-naive metastatic CRPC to receive first-line docetaxel with or without OGX-011. Decreases in PSA level were similar between groups, although there appeared to be fewer patients with progression as best response and a longer time to progression in the doceaxtel/OGX-011 combination therapy group. Mature results from this study reported a median overall survival of 16.9 months for the docetaxel group and 23.8 months for those subjects treated with docetaxel/OGX-011 combination. In a multivariate analysis factors significantly associated with an improved overall survival were an Eastern Collaborative Oncology Group (ECOG) performance status of 0 versus 1, presence of bone or lymph node metastases only versus other metastases, and treatment arm assignment to OGX-011 plus docetaxel versus docetaxel alone (HR = 0.49, 95% CI 0.28–0.85). A phase III trial is being planned to compare docetaxel/OGX-011 versus docetaxel in patients with metastatic CRPC with a primary end point of overall survival.

Insulinlike growth factor-1 receptor

The insulinlike growth factor (IGF) axis is composed of 2 peptide growth factors (IGF-I and -II), 2 transmembrane receptors (IGF-IR and -IIR), 6 IGF binding proteins (IGFBP-1 to -6), and IGFBP proteases. Among their many actions, IGFs regulate cellular processes of proliferation, differentiation, and apoptosis, and as a result have been implicated as having a critical role in the development of several malignancies. In a metaregression analysis, elevated concentrations of IGF-I and risk of prostate cancer have been correlated, and high plasma IGF-I and low IGFBP-3 have been associated with more advanced stage prostate cancer. IGF-IR, IGF-I and -II, and IGFBP-2 have all been reported to be over expressed in human primary prostate cancer compared with normal prostate tissue. Levels are also increased in advanced and metastatic disease. An increasing body of evidence has linked activation of the IGF axis with androgen-independent progression of prostate cancer. These findings have made targeting the IGF axis an attractive concept for prostate cancer. Using a variety of methods to block IGF signaling, preclinical studies have supported this theory.

Humanized monoclonal antibodies specific to IGF-IR, selected to have limited agonistic effect or affinity to the homologous insulin receptor, have entered clinical testing. Testing in prostate cancer has been initiated with 2 humanized monoclonal therapeutic antibodies against IGF-IR: CP-751,871 (Pfizer Inc) and IMC-A12 (ImClone Systems Inc). Both agents have been well tolerated in early clinical studies. The tolerability of the regimen was demonstrated in a phase I trial of the combination of CP-751,871 and docetaxel. A randomized phase II of docetaxel with or without CP-751,871 has been conducted and results are pending (NCT00313781). A single agent phase II study with IMC-A12 in asymptomatic, chemotherapy-naive patients with CRPC was reported recently. Thirty-one patients were enrolled, and the trial was designed to assess safety and antitumor activity. The most common adverse events related to IMC-A12 were fatigue and hyperglycemia; the hyperglycemia was asymptomatic and easily managed in most cases. Other related events included thrombocytopenia, hyperkalemia, and pneumonia. Nineteen of the 31 patients had disease stability for 6 months or more, and 5 patients continue on IMC-A12. Further studies are planned.