Factors implicated in radiation therapy failure and radiosensitization of prostate cancer

Abstract

Tissue markers may be helpful in enhancing prediction of radiation therapy (RT) failure of prostate cancer (PCa). Among the various biomarkers tested in Phase III randomized trials conducted by the Radiation Therapy Oncology Group, p16, Ki-67, MDM2, COX-2, and PKA yielded the most robust data in predicting RT failure. Other pathways involved in RT failure are also implicated in the development of castration-resistant PCa, including the hypersensitive androgen receptor, EGFR, VEGF-R, and PI3K/Akt. Most of them are detectable in PCa tissue even at the time of initial diagnosis. Emerging evidence suggests that RT failure of PCa results from a multifactorial and heterogeneous disease process. A number of tissue markers are available to identify patients at high risk to fail RT. Some of these markers have the promise to be targeted by drugs currently available to enhance the efficacy of RT and delay disease progression.

Figure 1

Lymphovascular invasion is detected by the endothelial marker D2-40 in a prostatectomy specimen (a). Androgen receptor (AR) immunohistochemistry detects disseminated prostate cancer cells in lymph nodes classified as negative for cancer upon routine histological examination. Original magnifications: (a) (×400), (b) (×300).

Figure 2

Androgen receptor (AR) status in hormone- and radio- naïve PCa, Gleason 3 + 4 = 7 (Figure 2(a)). The AR is expressed at higher levels when compared with adjacent benign acini (arrows), indicating a hypersensitive pathway. Proliferation activity usually correlates with the Gleason grade. Figure 2(b) shows an example of a PCa, Gleason 3 + 3 = 6, with relatively high proliferation activity (MIB-1 index > 10%), which implies a higher risk of RT failure than the Gleason grade would suggest. Original magnifications: (a) (×300), (b) (×400).

Figure 3

Hormone- and radio-naïve PCa (Gleason 4 + 4 = 8) with strong membraneous HER2/neu expression (Figure 3(a)), indicating that the outlaw pathway is relevant for tumor progression under standard ADT and RT. Local PCa recurrence after salvage radiotherapy (Figure 3(b)). High levels of bcl-2 expression indicate that standard ADT is insufficient for local tumor control. Since docetaxel inhibits the antiapoptotic function of bcl-2, ADT combined with docetaxel may be more successful for local tumor control than standard ADT alone. Original magnifications: (a) (×400), (b) (×100).

Figure 4

Conventional PCa (Gleason 4 + 4 = 8) detected in a needle biopsy. Chromogranin A (CGA) immunohistochemistry reveals extensive neuroendocrine (NE) differentiation, which presents a multidrug-resistant phenotype in PCa (a). Immunohistochemical detection of somatostatin receptors in NE PCa cells (b) provides a therapeutic target for somatostatin analogues. Original magnifications: (a) (×100), (b) (×300).