Send Orders for Reprints to
[email protected] 288
Current Gene Therapy, 2016, 16, 288-292
REVIEW ARTICLE
Different Gene Therapy Strategies: A Overview for Prostate Cancer Aline Gomes de Souza*, Victor Alexandre Felix Bastos, Isaura Beatriz Borges Silva, Karina Marangoni and Vivian Alonso Goulart Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlândia, MG, Brazil
ARTICLE HISTORY Received: May 22, 2016 Revised: October 28, 2016 Accepted: November 04, 2016 DOI: 10.2174/156652321666616111516 3044
Abstract: Gene therapy emerged as a mighty alternative for conventional treatment of multiple diseases. It has been defined as a product “that mediate their effects by transcription and/or translation of transferred genetic material and/or by integrating into the host genome and that are administered as nucleic acids, viruses, or genetically engineered microorganisms. The products may be used to modify cells in vivo or transferred to cells ex vivo prior to administration to the recipient”. The first therapeutic gene therapy human trial was conducted in 1990 by Michael R. Blaese, and besides its potential, the technique suffered a major drawback after the tragical death of Jesse Gelsinger, caused by his immune response against the viral vector used in his treatment. To date, gene therapy has regained some popularity and more than 2000 clinical trials are ongoing, most of them related to the treatment or prevention of various types of cancer. Nevertheless, some types of cancer contain a rare population of stem-like cells, capable of differentiation into tumor cells, promoting the re-incidence of tumors. Those cells are generally more resilient to chemotherapy and radiotherapy and are related to tumor initiation, progression, recurrence and metastasis. The human prostate cancer (PCa) is highly heterogeneous and multifactorial, and even the markers are not precise enough to predict the clinical outcome. Furthermore, even though currently therapies can efficiently remove the tumors, the re-incidence rates are high. Gene therapy offers a handful of treatments that can halt oncogenes activation, promote the expression of suppressor genes or target cancer cells directly and induce apoptosis. Besides the risks involved, gene therapy can be of great help in the treatment of cancers and other diseases. This review aims to address the safety and potential of different gene therapy strategies used in the treatment of cancers.
Keywords: Gene therapy, PCa, diagnosis, immunotherapy, viral vectors, miRNA. INTRODUCTION The prostate has an intense cellular heterogeneity, and is one of the organs most subjected to change during aging. Such changes can cause diseases such as prostatitis, benign prostatic hyperplasia (BPH) and in more severe cases, prostate cancer (PCa) [1]. PCa is a multifactorial and heterogeneous disease with his development not yet clearly understood [2]. The heterogeneity of cancer cells is usually explained by two models: clonal evolution model (stochastic) and the cancer stem cell model (CSC) [3, 4]. The classic, clonal evolution model postulates that all cancer cells are tumorigenic and the cure is related to the number of cells eliminated by therapy against the disease [5, 6]. While the CSC model, affirms with considerable evidence that some types of cancers, such as PCa, may contain a rare population of cells similar to stem cells, which are capable of differentiating into tumor cells. Thus, *Address correspondence to this author at the Laboratory of Nanobiotechnology, Institute of Genetics and Biochemistry, Federal University of Uberlândia (UFU), 38400-902, Uberlândia-MG, Brazil; Tel: +55 34 3225-8440; E-mail:
[email protected] 1566-5232/16 $58.00+.00
the CSCs have been related to tumor initiation, progression, recurrence, metastasis, and resistance to cancer therapy [7]. PCa usually responds well to castration therapy, however, often the success of this procedure is temporary, leading to recurrence of castration resistant PCa [8]. Even when subjected to other types of treatment, most patients still have a low survival and high tumor progression. The resistance process has been associated with the presence of prostate basal cells that are androgen-independent and hence persistent after castration [9, 10]. Thus, it is necessary the development of new treatments that targets both the initial process, when the cancer is still sensitive to hormone, and after the development of castration resistant when other treatments have failed. Currently standard treatments include surgery, chemotherapy, and radiotherapy; however, these are often incapable of completely eradicating a malignancy [11]. Nowadays, gene therapy studies have aided in the development of the novel antitumor treatment strategies to PCa [12, 13]. GENE THERAPY FOR PCa Gene therapy, defined as the introduction of genetic material into a target cell for therapeutic benefit, is a very prom© 2016 Bentham Science Publishers
Different Gene Therapy Strategies: A Overview for Prostate Cancer
ising treatment for many diseases, including cancer. To date, more than 2000 clinical trials employing gene transfer have taken place and in general a number of vehicles or vectors have been established as safe [14, 15]. Cancer is considered a multifactorial genetic disease, advanced approaches that target genetic alterations is one of the main objective in clinical research. Recent studies using small interfering RNA (siRNA), antisense oligonucleotides (AON), small hairpin RNA (shRNA), plasmid DNA and many others, are among new strategies for target specific genes that can be used in cancer treatment, diagnosis and prognosis [16]. Some of these strategies combine chemotherapy with the use of nucleic acids to overcome multidrug resistance or to promote cancer cells apoptosis. Other approaches can use tumor suppressor genes, pro-apoptotic genes or silencing anti-apoptotic genes, to develop effective gene therapy for cancer treatment [17]. Many efforts have been directed to improve early diagnosis and treatment of PCa [18]. One of the successes of molecular biology in recent years has been the elucidation of the mechanisms responsible for the origin and development of cancer, as well as the application of gene therapy as a proposal for the treatment and study of PCa [19]. Basically, the processes that originate tumors have two classes of genetic alterations, one being the oncogene activation and the other, being the loss of tumor suppressor gene expression due to alleles alterations in cancer cells. In prostate tumors re-activation of tumor growth has been observed in receptor-dependent androgen state, which can induce apoptosis of these cells by pro-apoptotic over-expressing tumor necrosis factor (TNF) and at the same time silence anti-apoptotic c-FLIP, allowing the development of a proapoptotic therapy which acts downstream and independently of androgen receptor (AR) signaling [20]. Some evidences indicate that in castration therapyresistant PCa cases, polyphosphate-4-phosphatase type II (INPP4B) has lower expression. This molecule can act as a potential tumor suppressor as its expression leads to a cascade that ends in the negative control of phosphatidylinositol 3-kinase (PI3K) pathway, which leads to blockage of cell malignant transformation. Thus, PCa cell line, PC-3, was transfected with this gene and significant reduction in cell growth and viability was observed, in addition to a decrease in pAKT levels that negatively regulate PI3K pathway, indicating that this process could be used as a combined treatment to inhibit tumor growth [21]. Similarly, Marangoni and contributors (data submitted for publication) demonstrated the effect of an RNA-aptamer internalized in PCa cell lines (LNCaP and PC-3) which promotes a pattern of combined characteristic gene expression of a benign biological phenotype, predicting a more favorable prognosis for PCa, since this pattern contributes to tumor inhibition. Using PC-3 cells, as subjects, a system to deliver siRNA specific to tumor was developed. This system utilizes siRNA molecules, complexed with atecollagen to facilitate selective absorption of siRNA into tumor cells. The siRNA target was the anti-apoptotic protein Bcl-xL, which is overexpressed in PCa. Overexpression of Bcl-xL leads to chemotherapy sensi-
Current Gene Therapy, 2016, Vol. 16, No. 4
289
tization loss by tumor cells. This work showed that siRNA was successfully delivered to cancer cells, and reduced the expression of Bcl-xL both in vitro and in vivo. This approach enhanced the chemosensitivity to cisplatin in tumor cells [22]. DIFFERENT STRATEGIES FOR GENE THERAPY Viral Strategy Viruses are known to have high selectivity for their host cells, and this can be explored in biotherapy. However some alternatives using virus still offer risks, in this way approaches using the insect viruses or baculoviruses have been proposed, since most of the native virus promoters are inactivated in human cells. The use of such vectors represent a promising strategy for the development of therapies to treat PCa. It has been reported that baculoviruses have the capacity to deliver genes in a variety of tissues and cells, including benign prostate and PCa cells line. Moreover they can introduce therapeutic genes into dividing or quiescent cells, indicating that it might also act in tumor stem cells of PCa [23]. Freytag et al. (1998) have designed an adenoviral strategy that combines oncolytic and suicide gene therapy. The Ad5-CD/TKrep vector containing a truncated E1B-55K gene, which codes for a viral protein that inactivates the p53 tumor suppressor gene. It was hypothesized that viruses lacking E1B-55K, preferentially replicate in cancer cells with mutant p53 genes, a quality commonly present in advanced PCa cells [24, 25]. Kubo et al. (2003) utilized a replication-defective adenovirus (Ad-OC-hsv-TK) containing the HSV-1 TK gene under the transcriptional control of the osteocalcin promoter. The reason for using the osteocalcin promoter to drive HSV-1 TK expression is that metastatic PCa, are typically driven to bone tissue. Thus, HSV-1 TK gene expression is directed to the metastatic lesions. Eleven subjects were submitted to two intralesional injections of Ad-OC-hsv-TK at three dose levels (5 × 109 to 5 × 1011 vp/injection) followed by 3 weeks of valacyclovir pro-drug therapy. Of 11 subjects, 1 (9%) exhibited a reduction of more than 50% of prostate-specific antigen (PSA) in serum after treatment; however, this event lasted less than 2 weeks. There were no objective radiological responses [26, 27]. Radiation therapy (RT) is an accepted treatment for localized PCa and the combination with gene therapy is an innovative proposal for better treatment and understanding of PCa. Fujita et al. (2014) evaluated the potential benefits of gene and radiotherapy in the prostate and bladder cancer models. In their work, combined adenoviral vector-mediated gene therapy and radiotherapy, were applied to 178-2 BMA and TSUPr1 cells in vitro, and colony formation and apoptosis were analyzed. In addition, combination therapies were administered to mice bearing subcutaneous 178-2 BMA and TSU-Pr1 tumors, and growth suppression and survival extension of tumor were compared with the monotherapies (AdGlipr1/AdGLIPR1 and radiotherapy) or control vector Adv/CMV/bgal, as well as single-cycle treatment with 2cycle treatment. The group concluded that combining AdGlipr1 (AdGLIPR1) with radiotherapy may achieve additive or
290 Current Gene Therapy, 2016, Vol. 16, No. 4
synergistic tumor control in selected prostate and bladder tumors, and additional treatment cycles may result in better therapeutic effects [28]. Arafat et al. (2015) tested the combined effect of radiotherapy and TRA-8 or Ad TRAIL (adenoviral encoding TRAIL) in PCa cells. Human PCa cell lines LNCaP, PC-3 and DU-145 were used in this study. Cells were treated with either TRA-8 alone or Ad/TRAIL, radiation alone, or a combination of each at different doses and intervals. Cell survival and radio sensitization were determined by MTS and colony-forming assay. Immunohistochemistry was used to detect BAX and Bcl-2. Real-time PCR (qPCR) was performed on mRNA of treated PCa cell lines. Finally, a murine model of subcutaneous PCa was used to evaluate the treatments effects in vivo. Cell survival, determined by MTS, showed that PCa cell lines treated with a combination of radiation and TRA-8 had significantly lower survival than cells treated with either radiation or TRA-8 alone. Colony forming and cell proliferation assays showed increased tumor cells death after combined treatment with TRA-8 or Ad/TRAIL and radiation than single agent alone. Mechanistic studies showed that the killing effect was due to induction of apoptosis, mostly caused by increased expression of BAX in TRA-8 or Ad/TRAIL treated cells. Additionally, RT-PCR showed an increased number of BAX in most cells treated with TRA-8 and radiation. The authors concluded that radiation and TRA-8 or Ad/TRAIL produced a synergistic effect in refractory PCa [29]. miRNA Strategy The knowledge that miRNA dysregulation plays a pivotal role in cancer has led to an increased awareness about the diagnostic and therapeutic potential of miRNAs. Therapeutic approaches using miRNAs consist in targeting oncogenic miRNAs or increasing the expression of tumor suppressor miRNAs, delivering those agents by viral transfer, nanoparticles or liposomes [30]. Studies have reported that miR-185 a tumor suppressor miRNA, was down regulated in PCa. Chen-Yi et al. (2016) studied interactions between miR-185 and the bromodomain 8 isoform 2 (BRD8 ISO2) to investigate indirect mechanisms of miR-185 with respect to AR function through BRD8 ISO2 in PCa cells lines (PC-3, LNCaP), and tissues obtained from patients who underwent radical prostatectomies. They concluded that miR-185 is capable of inhibiting AR expression directly by binding to the 3'- UTR region of AR mRNA, and they suggested that miR-185 and BRD8 ISO2 may be potential therapeutic targets for treating PCa [31]. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs. Kong et al. (2012) found that BR-DIM upregulates the expression of the let-7 family, consequently down-regulating the expression of EZH2, not only in PCa cell lines but also in human PCa tissue specimens. These results suggest that BR-DIM could serve as a novel agent for the inhibition of PCa progression and recurrence [32]. Some studies showed a gene related to decontrolled activation in malignancies, Frizzled (Fzd7), a co-receptor for the WNT signaling pathway. This gene can act as an oncogene
de Souza et al.
in several cancer types. The overexpression of Fzd7, commonly found in PCa, leads to activation of WNT signaling, and aberrant activation of this pathway. Fujita et al. (2014) showed that miR-613 is inversely correlated with Fzd7 expression. In different PCa cell lines an increased Fzd7 expression, and low miR-613 expression, indicates that overexpression of miR-613 can have an impact on PCa cell proliferation and invasion capability. Showing that Fzd7 can be used in therapy against PCa [25]. Others important genes can also be used as targets in the therapy against prostate cancer [33] or helping to better understand the resistance mechanisms of some tumor cells [34]. Immunotherapy Strategy PCa immunotherapy has been studied and shows encouraging results [35]. Chudley et al. (2012) reports the immunogenicity and clinical effects of a DNA fusion vaccine trial in PCa patients. The vaccine encoded a domain (DOM) from fragment C of tetanus toxin linked to an HLA-A2-binding epitope from prostate-specific membrane antigen (PSMA). The vaccine induced DOM-specific CD4 and PSMA-specific CD8 T cells, generating anti-PSMA responses in the majority of patients and significantly increases PSA-doubling time (PSA-DT). The authors also identified a relation between treatment time, that may serve to better identify a link between vaccine-induced immunity and clinical outcome [36]. Others Strategies Studies have been developed in order to improve delivery systems of genetic material to target cells. Zhihang et al. (2016) developed a theranostic nanoplex platform: the prostate-specific membrane antigen (PSMA), designed to deliver plasmid DNA encoding tumor necrosis factor related apoptosis-inducing ligand (TRAIL), and bacterial cytosine deaminase (bCD) as a prodrug enzyme. This combination strategy (TRAIL/5-FC/bCD) showed significant inhibition of tumor growth in vitro and in vivo. Results demonstrate that the PSMA-specific theranostic nanoplex can deliver genes and prodrug enzymes for therapy in metastatic PCa [31]. Using genetic engineered Escherichia coli, McBride et al. (2016) developed three types of Designer Biopolymers (DBPs) complexed with a reporter plasmid. It was noted that two of the polymers were able to effectively condense the genetic material into the cationic nanoparticles and overcome intra and extra cellular barriers transfecting PCa metastatic cell lines (PC-3), expressing TMTP-1 receptors. Both DBPs were capable of protecting DNA from serum endonuclease degradation, presented low toxicity, easy synthesis and showed high specificity to target cell lines [37]. Interference RNA (RNAi) has emerged as a potential therapeutic option against a variety of diseases, including cancer. However, development of safe and specific delivery vector remains a major obstacle for the clinical application of RNAi. Based on other studies, Luvino et al. (2013) developed an alternative way to efficiently transfect short interfering RNA (siRNA) using ketal based nucleolipids (KNLs). They prepared a complex with KNLs and siRNA that inhibit the Hsp27 targeting translation initiation site. Hsp27 is
Different Gene Therapy Strategies: A Overview for Prostate Cancer
known to have an overexpression in PCa, and is related to metastases, poor prognosis and resistance to radiation or chemotherapy. They observed that the complex Hsp27/ siRNA-KNL was capable of decreasing protein production, demonstrating that KNL successfully transfected siRNA and promoted gene silencing [38]. Fitzgerald et al. (2015) developed a 3D cell culture model of PCa bone metastasis. This in vitro model used collagen-based scaffolds to better replicate the physiological microenvironment. Three scaffolds with different compositions were used, siRNA nanoparticle delivery was evaluated. All three models were capable of permiting and maintaining cell infiltration, growth and viability, moreover, the structures allowed successful delivery of nanoparticles containing siRNA and transfection of PC-3 cells. Therefore, this systems can be optimized to delivery siRNA effectively, allowing penetration into bone, leading to an efficient alternative for PCa bone metastases treatment [39]. In addition, recent studies have shown the potential of specific aptamer selection and their usage for PCa diagnosis and therapy [40]. Souza et al. (2016) selected 8 aptamers against PC3 cells, using a combination of 3D cell culture and the SELEX technique. Those aptamers showed high specificity, qualifying them as potential tools for PCa therapy or detection [41]. Stem cells arise as a novel powerful source of vectors or cellular vehicles for gene therapy in cancer treatment. Some of the advantages to use stem cells are the fact that cancer is recognized as a stem cell disease, and stem cells do not show significant adverse effect, representing a safe and effective alternative for gene therapy in cancer. In PCa only mesenchymal stem cell (MSC) and neural stem cell (NSC) has been used in preclinical studies for gene therapy. The mechanism by which the stem cells mediates gene therapy is based on two phases. First, the coding gene from bacterial, yeast or viral source is delivered to the tumor’s mass by transduction of stem cells. Then the enzyme encoded by the gene acts converting less toxic prodrug to cytotoxic substances that targets the tumor, eliminating neighbor and surrounding tumor cells [42]. CONCLUSION In summary, there is no reason to discredit the gene therapy. In the near future, it could be a powerful tool to combat cancer and other diseases. Even if not used as a single therapy, data indicates that in combination with conventional radiotherapy or chemotherapy it can present effective result in tumor shrinkage, encouraging investments in this area.
Current Gene Therapy, 2016, Vol. 16, No. 4 [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
[22]
[23] [24]
CONFLICT OF INTEREST
[25]
The authors confirm that this article content has no conflict of interest.
[26] [27]
ACKNOWLEDGEMENTS Declared none.
[28]
REFERENCES [1]
Prajapati A, Gupta S, Mistry B, et al., Prostate stem cells in the development of benign prostate hyperplasia and prostate cancer: emerging role and concepts. Biomed Res Int 2013; 2013: 107954.
[29]
291
Barbieri CE, Tomlins SA. The prostate cancer genome: Perspectives and potential. Urol Oncol Semin Orig Investig 2014; 32: 95-102. Chen X, Rycaj K, Liu X, et al., New insights into prostate cancer stem cells. Cell Cycle 2013; 12: 579-86. Sampieri K, Fodde R. Cancer stem cells and metastasis. Semin Cancer Biol 2012; 22: 187-93. Spillane JB, Henderson MA. Cancer stem cells: A review. ANZ J Surg 2007; 77: 464-8. Tu S-M, Lin S-H. Prostate Cancer Stem Cells. Clin Genitourin Cancer 2012; 10: 69-76. Bapat SA. Evolution of cancer stem cells. Semin Cancer Biol 2007; 17: 204-13. Collins AT, Maitland NJ. Prostate cancer stem cells. Eur J Cancer 2006; 42: 1213-8. Shipitsin M, Polyak K. The cancer stem cell hypothesis: in search of definitions, markers, and relevance. Lab Invest 2008; 88: 45963. Wicha MS, Liu S, Dontu G. Cancer stem cells: An old idea - A paradigm shift. Cancer Res 2006; 66: 1883-90. Long RM, Morrissey C, Fitzpatrick JM, et al., Prostate epithelial cell differentiation and its relevance to the understanding of prostate cancer therapies. Clin Sci (Lond) 2005; 108: 1-11. Eder IE, Haag P, Bartsch G, et al., Gene therapy strategies in prostate cancer. Curr Gene Ther 2005; 5: 1-10. Nande R, Greco A, Gossman MS, et al., Microbubble-assisted p53, RB, and p130 gene transfer in combination with radiation therapy in prostate cancer. Curr Gene Ther 2013; 13: 163-74. Nathwani AC, Tuddenham EGD, Rangarajan S, et al., Adenovirusassociated virus vector-mediated gene transfer in hemophilia B. N Engl J Med 2011; 365: 2357-65. Simonelli F, Maguire AM, Testa F, et al., Gene therapy for Leber’s congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol Ther 2010; 18: 643-50. Izquierdo M. Short interfering RNAs as a tool for cancer gene therapy. Cancer Gene Ther 2005; 12: 217-27. Li J, Wang Y, Zhu Y, et al., Recent advances in delivery of drugnucleic acid combinations for cancer treatment. J Control Release 2013; 172: 589-600. Pestell RG, Nevalainen MT. PROSTATE CANCER. Totowa, USA: Humana Press, 2008. Ahmed KA, Davis BJ, Wilson TM, et al., Progress in gene therapy for prostate cancer. Front Oncol 2012; 2: 172. Nastiuk KL, Krolewski JJ. Opportunities and challenges in combination gene cancer therapy. Adv Drug Deliv Rev 2015; 98: 35-40. Ding H, Sun Y, Hou Y, et al., Effects of INPP4B gene transfection combined with PARP inhibitor on castration therapy-Resistant prostate cancer cell line, PC3. Urol Oncol Semin Orig Investig 2014; 32: 720-6. Mu P, Nagahara S, Makita N, et al., Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl-xL and cisplatin against prostate cancer. Int J Cancer 2009; 125: 2978-90. Kaikkonen MU, Ylä-Herttuala S, Airenne KJ. How to avoid complement attack in baculovirus-mediated gene delivery. J Invertebr Pathol 2011; 107: S59-70. Freytag SO, Rogulski KR, Paielli DL, et al., A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum Gene Ther 1998; 9: 1323-33. Lupold SE, Rodriguez R. Adenoviral gene therapy, radiation, and prostate cancer. Rev Urol 2005; 7: 193-202. Freytag SO, Stricker H, Movsas B, et al., Prostate cancer gene therapy clinical trials. Mol Ther 2007; 15: 1042-52. Kubo H, Gardner TA, Wada Y, et al., Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoterdriven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. Hum Gene Ther 2003; 14: 227-41. Fujita T, Satoh T, Timme TL, et al., Combined therapeutic effects of adenoviral vector-mediated GLIPR1 gene therapy and radiotherapy in prostate and bladder cancer models. Urol Oncol 2014; 32: 92-100. Arafat W, Zhou T, Naoum GE, et al., Targeted radiotherapy potentiates the cytotoxicity of a novel anti-human DR5 monoclonal
292 Current Gene Therapy, 2016, Vol. 16, No. 4
[30] [31] [32]
[33]
[34]
[35]
antibody and the adenovirus encoding soluble TRAIL in prostate cancer. J Egypt Natl Canc Inst 2015; 27(4): 205-15. Abba ML, Patil N, Leupold JH, et al., MicroRNAs as novel targets and tools in cancer therapy. Cancer Lett 2016 [Epub ahead of print]. DOI: 10.1016/j.canlet.2016.03.043. Chen Z, Penet MF, Krishnamachary B, et al., PSMA-specific theranostic nanoplex for combination of TRAIL gene and 5-FC prodrug therapy of prostate cancer. Biomaterials 2016; 80: 57-67. Kong D, Heath E, Chen W, et al., Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. PLoS One; 7. [Epub ahead of print] 2012. DOI: 10.1371/journal.pone.0033729. Orfanelli U, Jachetti E, Chiacchiera F, et al., Antisense transcription at the TRPM2 locus as a novel prognostic marker and therapeutic target in prostate cancer. Oncogene 2015; 34: 2094102. Azad AA, Volik S V, Wyatt AW, et al., Androgen receptor gene aberrations in circulating cell-free DNA: Biomarkers of therapeutic resistance in castration-resistant prostate cancer. Clin Cancer Res 2015; 21: 2315-24. Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010; 363: 411-22.
de Souza et al. [36]
[37] [38]
[39]
[40] [41] [42]
Chudley L, McCann K, Mander A, et al., DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8+ T-cell responses and increases PSA doubling time. Cancer Immunol Immunother 2012; 61: 2161-70. McBride JW, Massey AS, McCaffrey J, et al., Development of TMTP-1 targeted designer biopolymers for gene delivery to prostate cancer. Int J Pharm 2016; 500: 144-153. Luvino D, Khiati S, Oumzil K, et al., Efficient delivery of therapeutic small nucleic acids to prostate cancer cells using ketal nucleoside lipid nanoparticles. J Control Release 2013; 172: 95461. Fitzgerald KA, Guo J, Tierney EG, et al., The use of collagenbased scaffolds to simulate prostate cancer bone metastases with potential for evaluating delivery of nanoparticulate gene therapeutics. Biomaterials 2015; 66: 53-66. Marangoni K, Neves AF, Rocha RM, et al., Prostate-specific RNA aptamer: promising nucleic acid antibody-like cancer detection. Sci Rep 2015; 5: 12090. Souza AG, Marangoni K, Fujimura PT, et al., 3D Cell-SELEX: Development of RNA aptamers as molecular probes for PC-3 tumor cell line. Exp Cell Res 2016; 53: 641-7. Kim JH, Lee HJ, Song YS. Stem Cell Based Gene Therapy in Prostate Cancer. 2014. [Epub ahead of print]. DOI: 10.1155/ 2014/549136.
