VAL 201 – An Inhibitor of Androgen Receptor-associated Src
Currently, docetaxel plus prednisone every three weeks is the preferred first-line treatment for CRPC. Docetaxel is a well established anti-mitotic chemotherapy agent and in the TAX 327 Phase III clinical trial was shown to confer an overall survival advantage of three months, when compared to mitoxantrone.6,7 Oncology Group showed a similar survival benefit.8
therapies are also associated with undesirable side effects including impotence, tumour flare and loss of bone mass.17
Some of these side A study by the Southwest
In April 2010, the FDA approved the use of the immunotherapy sipuleucel-T for men with less advanced disease. Treatment with sipuleucel-T is only recommended for patients with a good performance level, and not those with symptomatic, rapidly progressive or visceral disease. Sipuleucel-T is an autologous cancer vaccine, produced by exposing the patient’s antigen-presenting cells (APCs) to a recombinant fusion protein (PA2024), after first being collected from the patient’s white blood cell fraction.9
PA2024 is a
prostate antigen, prostatic acid phosphatase, fused to granulocyte macrophage colony-stimulating factor (an activator of immune cells). The activated APCs are then re-infused back into the patient. In a Phase III clinical trial the sipuleucel-T treatment arm was shown to extend the mean survival by 4.1 months as compared with placebo.10
Cabazitaxel (plus prednisone) also gained approval by the FDA in 2010 as a therapeutic option for patients who have previously failed docetaxel-based chemotherapy.11
effects are due to the fact that castration therapy, in addition to abolishing the receptor-dependent signalling pathways, also inhibits the receptor’s transcriptional action which affects positive actions of androgens such as neuroprotection and bone preservation. In principle, new therapies could be developed that are more specific, abolishing receptor-dependent signalling but preserving AR transcriptional action.
Src Inhibitors as a Potential Treatment Option for Prostate Cancer
The Src family kinases (SFKs) have emerged as important targets in cancer therapy.18
been reported in prostate cancer tissue and cell lines,19–21
Increased Src activity or expression has and levels of
Src is a non-receptor tyrosine kinase and has an important role in tumour development and bone metabolism. Src signalling is particularly important in prostate cancer, where bone is the usual site of metastatic spread.3
Src have been found to be highest in tissue specimens from patients with CRPC.21 signalling,22,23
Cabazitaxel is a semi-synthetic
taxane derivative with antimitotic activity. Approval was based on the results of a Phase III trial comparing cabazitaxel with mitoxantrone, with a 2.4-months improvement in overall survival seen in the cabazitaxel treatment arm (HR 0.72, p<0.0001).12
Treatment caused a
high rate of grade 3–4 neutropenia, that was observed in 81.7 % of patients in the cabazitaxel treatment arm.
In 2011, the FDA approved the use of abiraterone acetate plus prednisone for patients with metastatic CRPC who have previously been treated with docetaxel. Abiraterone is an androgen synthesis inhibitor, and selectively and irreversibly inhibits both the 17α-hydrolxylase and the C17,20-lyase function of the enzyme cytochrome P450 c17.13
of testosterone/dihydrotestosterone from weak adrenal androgens.14
This is a key enzyme required for the synthesis A
Phase III, randomised, placebo-controlled clinical trial demonstrated a statistically significant improvement in overall survival in patients treated with abiraterone (14.8 months versus 10.9 months in the abiraterone and placebo treatment arms, respectively).15
Castration-resistant prostate cancer is now the second most common cause of male cancer-related mortality in the US.1
Although several
treatments have been shown to extend the survival of patients, subsequent treatment options remain limited, and current approved therapies have only been shown to provide a four-month overall survival advantage at best.6,10,12,15
there is also evidence that Src may be involved in the transition from castration-sensitive to CRPC.25,28
Proliferation in response to androgen involves Src
and a number of studies have demonstrated that inhibiting Src activity strongly reduces prostate cancer growth.24–27
Additionally, Because metastatic bone disease is
responsible for a significant proportion of morbidity and mortality associated with advanced prostate cancer, treatment strategies that inhibit tumour activity and osteoclast activity could be beneficial in treating advanced CRPC.
There are several Src inhibitors in development that have shown preclinical activity against prostate cancer cells and these include: dasatinib; saracatinib; AZM475271; CGP76030; CGP77675; PD180970; and KX2-391. The majority of Src inhibitors are in Phase I or preclinical development, however dasatinib is currently approved for treating patients with myelogenous leukaemia and as a second-line treatment for patients with Philadelphia-chromosome-positive acute lymphoblastic leukaemia. Dasatinib is a multitargeted inhibitor of receptor tyrosine kinases, and its main targets include Bcr/Abl, Src, C-Kit and the ephrin receptors along with several other tyrosine kinases.29
Saracatinib (also known as AZD0530) is another Src inhibitor that is further along the developmental pipeline and is an orally active multitargeted inhibitor of Src, Yes, Lck and Bcr/Abl. Saracatinib has been shown to inhibit Src in a dose-dependent manner, and inhibit proliferation and migration in a range of prostate cancer cell lines,24 however in a Phase II trial treating patients with advanced CRPC, saracatinib showed little clinical efficacy as a monotherapy.30
New therapies are needed to both
extend patient survival and improve patient quality of life. Additionally, new treatments are required for therapeutic intervention prior to CRPC development. The current first-line treatment for prostate cancer is a combination of radiotherapy, radical surgery and hormone therapy. Surgery and radiotherapy are generally effective but often have undesirable effects including incontinence and loss of sexual function.16
Hormone (castration) therapy acts in one of two ways: either blocking the release of luteinising-hormone releasing hormone (LHRH) through LHRH agonists such as leuprolide (Eligard®, Lupron®, Viadur® and goserelin [Zoladex®]), or through anti-androgens such as bicalutamide (Casodex®). However, hormone
EUROPEAN ONCOLOGY & HAEMATOLOGY
The majority of the current Src inhibitors in development are either multitargeted (and also inhibit other receptors) or completely inhibit all Src activity, or both.31
The exception to this is VAL 201, a novel
deca-peptide that is currently under development for the treatment of CRPC. VAL 201 specifically targets AR-associated/activated Src, leaving Src activity and DNA synthesis unaffected in AR-negative cells, and is the first example of a specific inhibitor of steroid-receptor-dependent signal transducing activity.
Overview of the Mechanism of Action of VAL 201
In human mammary and prostate cancer cells, steroid hormones or epidermal growth factor (EGF) trigger association of the AR-estradiol
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