New therapeutic approaches in targeting PCSCs

Despite progress in the therapeutic approaches that significantly increased the survival rate of PC patients, most prostate aggressive tumors become resistant to currently used treatment protocols. PC that initially responded well to a standard chemotherapy often recur with selective outgrowth of tumor cell subpopulations and get resistant not only to the original chemotherapeutic agent but also to other therapeutics. Thus, for most patients with relapse of castration-resistant metastatic PC currently no curative treatment exists. It has been suggested that AR expression in PC is modulated by CSCs and the CSC model may be responsible for the degree of sensitivity to anti-androgen therapy [114], [115].

The majority of studies to date have focused on the identification of characteristics that potentially could define CSCs. However, more questions have been raised on the issue which of these characteristics would be better suited as target and now research has seemed to shift towards identifying the way these CSCs behave that make them different from bulk tumor cells. Two important features of acute myeloid leukemia (AML) that allowed to discovery of new therapeutic agents were CD34+/CD38- and CD33+. Anti-CD33 antibodies have become an important aspect of CSCs targeted therapy. A drug called Gemtuzumab ozogamacin or Mylotarg, approved by the FDA in 2000, combines the cytotoxic antibiotic calicheamicin with the monoclonal anti-CD33 antibody [116].

Androgen-Independent miRNAs

Up-regulated

Down-regulated

miR-184

miR-128b

miR-361

miR-221

miR-424

miR-222

miR-616

miR-146a/b

miR-148a

miR-663

Cancer Stem Cell, Invasion or Metastasis Related miRNAs

Up-regulated

Down-regulated

miR-377

miR-34a

miR-141

miR-143

miR-145

miR-15

miR-16

Common Cancer Related miRNAs

Up-regulated

Down-regulated

miR-182

miR-125b

miR-96

miR-15a/16-1

miR-375

miR-34a

miR-205

miR-145

miR-221

miR-222

miR-181b

Table 2. Up- and down-regulated microRNAs in postate cancer [113]

miR-200c

Table 2. Up- and down-regulated microRNAs in postate cancer [113]

Novel therapeutic strategies against locally advanced and/or metastatic hormone-refractory prostate cancers (HRPCs) by targeting different oncogenic signaling cascade elements are listed in Table 3. Recent studies have revealed that the blockade of these tumorigenic signaling cascades could be beneficial as adjuvant therapy in the early phases of PC for decreasing the risk of relapse as well as in the late stages for improving the efficacy of current androgen deprivation therapy, radiotherapy, and/or systemic chemotherapy and patient survival rates [117]. Inhibition of the epidermal growth factor (EGFR) pathway by anti-EGFR antibody or EGFR tyrosine kinase inhibitor causes a cell cycle arrest, inhibits invasion and/ or induces apoptosis in metastatic PC cells when applied in vitro or in vivo [118-120]. Blockade of the SHH signaling pathway, which is important in stem cell self-renewal, by cyclopamine leads to long-term PC regression without recurrence, strongly suggesting a connection between this pathway and PCSCs [121]. Salinomycin, a structurally related compound to monensin, was recently identified as a potent PCSC inhibitor [122]. It inhibited the growth of PCs, but did not affect non-malignant prostate epithelial cells. That salinomycin impaired PCSC growth and function was evident by the findings of reduced CD44+ cell fraction and ALDH activity. Moreover, salinomycin reduced the expression of MYC, AR and ERG; induced oxidative stress; and, inhibited NF-kB activity and cell migration.

Regulation of the cell cycle is frequently altered in PC, in part, by the interplay of activation of oncogenic cascades with diverse hormones, growth factors, and cytokines. Thus, inhibitors of cell cycle regulatory proteins have become an area of increased interest in targeting CSCs [123]. The cyclin-dependent kinase inhibitor VMY-1-103 inhibited at very low concentrations the Erb-2/Erb-3/heregulin-induced cell proliferation in LNCaP PC cells. [124]. It was also observed that VMY-1-103 induced apoptosis via decreased mitochondrial membrane polarity; and induced p53 phosphorylation, caspase-3 activation, and PARP cleavage in these PC cells, which do express endogen wild type p53. But, VMY-1-103 failed to induce apoptosis in the p53-null PC cell line PC3 [124]. These results, strongly suggest that VMY-1-103 may be an effective therapeutic agent, either alone or in combinations with other drugs, in treating PC.

Adhesion receptors of the integrin family, particularly av-integrins, have functions including bone homing by cancer cells, tumor-induced angiogenesis, and osteoclastic bone resorption. Targeting of integrins by an av-integrin antagonist (GLPG0187) could inhibit the de novo formation and progression of bone metastases in PC by antitumor (including inhibition of epi-thelial-to-mesenchymal transition and the size of the PCSC population), antiresorptive, and antiangiogenic mechanisms [125].

Targeting the local microenvironment niche and stromal components of the CSCs would comprise two other promising therapeutic approaches. For instance, it is known that particularly the combined use of antiangiogenic agents with cytotoxic drugs inhibits tumor growth and invasion. Combining docetaxel with the EGFR-targeting agent cetuximab and the antiangiogenic agent sunitinib (SUTENT) inhibits tumor growth approximately 50% at the end of the 3rd week dosing schedule [126]. Targeting the fibroblast-to-myofibroblast transition with halofuginone (inhibitor of collagen type I) may also synergize with low doses of chemotherapy in achieving a significant antitumor effect, avoiding the need of high-dose chemotherapy and its toxicity without impairing treatment efficacy [57]. These results all support the idea that targeting PCSCs, their further differentiated progenies, and microenvironment could be more effective to counteract PC transition to invasive and metastatic stages.

Target

Effect

Molecules

Reference

EGFR signaling pathway

Anti-EGFR antibody

Cetuximab, Erbitux, mAb-C225, IMCC225

[118, 120]

EGFR tyrosine kinase inhibitor

Gefinib, Erlotinib, EKB-569

GDC-0449

[127]

SHH signaling pathway

Signaling inhibition

Cyclopamine Anti-SHH antibody

[121] [128]

Cell signaling pathway

Reducing ALDH activity and CD44+ cell fraction

Salinomycin

[122]

STAT3 signaling pathwaySTAT3 signaling inhibitor

Galiellalactone

[78]

WNT/p-Catenin

Suppression of the WNT co-receptor LRP6

Silibinin

[129]

signaling pathway

expression

Cell cycle

Cyclin-dependent kinase inhibitor

VMY-1-103

[124]

Adhesion receptors

av-integrin antagonist

GLPG0187

[125]

Collagen type I inhibitor

Halofuginone

[57]

Niche and stromal

Anti-angiogenic agent

Sunitinib, SUTENT

[126]

components

Telomerase reverse transcriptase (hTERT) promoter-induced CXCR4 knockdown

siRNA

[130]

Table 3. Novel targets for therapy against advanced prostate cancer

Table 3. Novel targets for therapy against advanced prostate cancer

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