Resistance to Castration – Resistance to Drugs

Abstract

Up to 70 % of newly diagnosed patients with advanced prostate cancer (PCa) will progress to castration-resistant prostate cancer (CRPC) and, in most cases (from 50 to 70 %), will develop hematogenous bone metastasis. Once PCa cells spread to the skeleton, cancer-related death becomes inevitable, with a death burden of more than 28,000 cases in 2012, in the United States (Semenas et al, Curr Drug Target, 13(10):1308–1323, 2012).

To date, therapeutic regimens are unable to revert this fatal progression (Semenas et al, Curr Drug Target, 13(10):1308–1323, 2012).

Thus, PCa bone metastatic prostate cancer still represents a major clinical challenge.

Prostate cancer biology is tightly linked to AR, which regulates epithelial proliferation and suppresses apoptosis both in normal and in cancer prostate tissue, and is involved in the progression of the disease toward a castration-resistant state (Hodgson et al, World J Urol, 30(3):279–285, 2012). Our knowledge of the molecular mechanisms, responsible for the acquired resistance to ADT in prostate cancer, has exponentially progressed during the last years. For instance, we have recently learnt that it may be associated with the occurrence of AR splicing variants (Hu et al. 2011).

Surgical castration has shown to induce regression of advanced disease 40-years before the cloning of androgen receptor (AR) (Huggins et al, Arch Surg, 43:209–223, 1941; Lubahn et al, Science, 240:327–330, 1988).

Since then, hormonal therapy was held over as the main available therapeutic option for aggressive prostate cancers. In the last decade, however, chemotherapy was introduced to targeting the epithelium of metastatic, hormone-resistant prostate cancer (Pinto et al, Tumour Biol, 33(2):421–426, 2012; Hodgson et al, World J Urol, 30(3):279–285, 2012). The cytotoxic conventional drug Docetaxel was approved by the Food and Drug Administration in 2004, and still represents the standard first-line treatment for patients with castration-resistant prostate cancer (CRPC) (Sartor et al, Oncologist, 16(11):1487–1497, 2011). It produces sensible palliative effects on bone-metastasis-related symptoms, but prolongs only modestly the survival of patients (Hodgson et al, World J Urol, 30(3):279–285, 2012; Tannock et al, N Engl J Med, 351:1502–1512, 2004; Petrylak et al, N Engl J Med, 351:1513–1520, 2004). Docetaxel acts mainly by inducing apoptosis of target epithelial cells. The common intrinsic defects of mCRPC in apoptosis pathways, such as BCL-2 overexpression and/or phosphatase and tensin homolog (PTEN) loss (Mathew, Dipaola, J Urol, 178:S36–S41, 2007; Galsky, Vogelzang, Ann Oncol, 21:2135–2144, 2010), may constitute the rationale of the unsatisfactory rate of cure attributable to this drug (Srigley et al, Histopathology, 60(1):153–165, 2012). In recent years, similar effects on survival have been demonstrated also for several other chemotherapeutic agents, such as mitoxantrone, etoposide, cisplatinum, vinblastine–estramustine and taclitaxel.

Following progression after treatment with docetaxel, new cabazitaxel (XRP6258)-prednisone treatment regimens have led to a significantly longer overall survival, and other novel agents are currently being evaluated, including the cell-based immunotherapy sipuleucel-T, the androgen biosynthesis inhibitors abiraterone acetate and MDV3100, the chemotherapic Cabazitaxel, as well as the radionuclide alpharadin/Radium 223 (bone microenvironment targeting agents) (Sartor et al, Oncologist, 16(11):1487–1497, 2011; Liu et al, Front Endocrinol (Lausanne), 3:72, 2012; Antonarakis, Armstrong, Prostate Cancer Prostatic Dis, 14(3):206–218, 2011). To date, they seem to offer a survival advantage to patients, and look promising to improve the prognosis of metastatic CRPC.

However, the real clinical benefit of these systemic therapies remains still transient, probably due also to the well-known clonal heterogeneity of advanced prostate cancers, and the overall survival of patients that holds frustratingly steady.

The high cost of these therapies and the increasing complexity of clinical decision making, further underscore the need to multiply the efforts to develop more potent chemotherapy agents and/or novel AR/inhibitors agents that may better overcome resistance mechanisms to existing therapies (Liu et al, Front Endocrinol (Lausanne), 2012; Hodgson et al, World J Urol, 30(3):279–285, 2012; Armstrong, George, Urol Oncol, 26:430–437, 2008; Schrijvers et al, Adv Ther, 27:285–296, 2010).

Several recently developed drug candidates, directed against the metastatic cancer microenvironments or niches, show promising results in this direction (Hodgson et al, World J Urol, 30(3):279–285, 2012).

The efficacy of the standard-of-care therapeutic intervention directed to mCRPC will be greatly improved by our increasing understanding of molecular mechanisms of the acquired resistance to ADT and chemotherapy, which is expected to provide valuable insights also to new unfailing biomarkers of resistance, therapeutic response and disease progression of prostate cancer, allowing us to personalize the therapy for the single patients with mCRPC (Liu et al, Front Endocrinol (Lausanne), 3:72, 2012; Antonarakis and Armstrong, Prostate Cancer Prostatic Dis, 14(3):206–218, 2011).

The knowledge of the molecular mechanisms underpinning prostate cancer progression is changing dramatically our therapeutic approach to its advanced, metastasizing phase, opening up the chance to design and develop novel agents targeting the multiple pathways responsible for the lethal cancer phenotype, in a more efficient and safer manner (Corcoran and Gleave, Histopathology, 60(1): 216–231, 2012).