Prostate Cancer
VAL 201 – An Inhibitor of Androgen Receptor-associated Src and a Potential Treatment of Castration-resistant Prostate Cancer
Ferdinando Auricchio1 and Antimo Migliaccio1 1. Professor, Department of General Pathology, II University of Naples
Abstract
Prostate cancer is the second leading cause of cancer death in men in the US. The initial treatment of metastatic prostate cancer is androgen deprivation (castration) therapy and this is achieved through either surgical or medical castration, however these therapies are also associated with undesirable side effects including impotence, tumour flare and loss of bone mass. Over time, nearly all patients with metastatic disease become resistant to androgen deprivation, progressing to castration-resistant prostate cancer (CRPC), and at this stage of the disease the prognosis is extremely poor (<50 % survival at two years). Currently there are few treatment options for CRPC. Only four have been found to extend survival and none are curative. Effective treatment of CRPC is a major unmet clinical need, and the identification of alternative therapeutic targets is an active focus of research. In this article we discuss the development of a new agent, Val 201 as a potential future treatment for CRPC. VAL 201 targets the association of androgen receptor with Src, a non-receptor tyrosine kinase signal-transduction protein that is important in tumour cell proliferation, and represents a novel and exciting approach for cancer chemotherapy.
Keywords Castration-resistant prostate cancer, androgen receptor, VAL 201, Src, tumour cell proliferation
Disclosure: Ferdinando Auricchio and Antimo Migliaccio are registered as the inventors of VAL 201, which is object of international patent. The authors have no other conflicts of interest to declare. Acknowledgements: Editorial assistance was provided by Janet Manson at Touch Briefings and funded by ValiRx. Received: 31 January 2012 Accepted: 17 February 2012 Citation: European Oncology & Haematology, 2012;8(1):32–5 Correspondence: Ferdinando Auricchio, Department of General Pathology, II University of Naples, Via L. De Crecchio, 7, 80138 Naples, Italy. E:
ferdinando.auricchio@
unina2.it
Support: The publication of this article was funded by ValiRx. The views and opinions expressed are those of the authors and not necessarily those of ValiRx.
In 2010, prostate cancer was the most commonly found malignant cancer in men, comprising 28 % of all new cancer cases.1
In the US, it is
the second leading cause of cancer death in men, with annual mortality rates of approximately 30,000 deaths per year.1
Symptoms of the
disease include: frequent and/or painful urination; difficulty in starting or stopping urination; changes in sexual function; and weight loss. Diagnosis of the disease is confirmed by biopsy. Factors that impact a patient’s prognosis include the stage of cancer (whether it is localised, locally advanced or metastatic), the Gleason score (a score system based on tumour morphology and histology) and the level of prostate- specific antigen in the blood. In the UK, approximately 20 % of men with primary prostate cancer present with incurable metastatic disease.2 Prostate cancer metastasises preferentially to bone,3
and metastatic
bone disease is responsible for a significant proportion of morbidity and mortality associated with the advanced stages of this disease. During prostate cancer progression, activation of the androgen receptor (AR) by androgens such as testosterone and dihydrotestosterone stimulates cell proliferation and inhibits apoptosis in prostate cancer cells. The initial treatment of metastatic prostate cancer is androgen deprivation (castration) therapy and this is achieved through either surgical or medical castration. Over time nearly all patients with metastatic disease become resistant to androgen deprivation, progressing to castration- resistant prostate cancer (CRPC) which is usually fatal.
32
Development of Castration-resistant Prostate Cancer
There are multiple mechanisms that can drive disease progression to CRPC, and most involve the AR pathway.4
Resistance to castration
therapy can be due to altered AR sensitivity, amplification of AR or mutations. Alternative splicing of the AR gene can lead to the expression of ARs lacking the ligand-binding domain and which are constitutively active. Additionally, CRPC can be caused by ectopic androgen synthesis, such as androgen synthesis by the adrenal glands, the tumour itself or increased conversion of extra-gonadal androgens to testosterone. Other mechanisms of progression to CRPC include modulation of AR co-regulators (again leading to increased signalling of the AR pathway) and, lastly, there can be activation of compensatory AR-independent pathways, which lead to cell proliferation and inhibition of apoptosis.
Current Treatments for Castration-resistant Prostate Cancer
Prior to 2010 docetaxel was the only approved agent for CRPC, and currently only three other systemic agents have demonstrated an increase in overall survival in patients with metastatic CRPC. Mitoxantrone, a type II topoisomerase inhibitor, has not demonstrated a survival improvement but remains a palliative therapeutic option.5
© TOUCH BRIEFINGS 2012
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