scholarly journals Telomerase as a new target for the treatment of hormone-refractory prostate cancer

2004 ◽  
Vol 11 (3) ◽  
pp. 407-421 ◽  
Author(s):  
Annamaria Biroccio ◽  
Carlo Leonetti
Keyword(s):  
Prostate Cancer ◽  
Reverse Transcriptase ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Telomere Maintenance ◽  
Telomeric Dna ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Gene ◽  
Reverse Transcriptase Enzyme ◽  
Androgen Ablation

Prostate cancer is the leading cause of cancer-related deaths in men. Androgen ablation is the mainstay of treatment for advanced prostate cancer. This therapy is very effective in androgen-dependent cancer; however, these cancers eventually become androgen independent, rendering anti-androgen therapy ineffective. The exploration of novel modalities of treatment is therefore essential to improve the prognosis of this neoplasia. Telomeres are specialized heterochromatin structures that act as protective caps at the ends of chromosomes. Telomere maintenance in the majority of tumor cells is achieved by telomerase, a reverse transcriptase enzyme that catalyzes the synthesis of further telomeric DNA. Telomerase is detected in the majority of prostate cancers, but not in normal or benign prostatic hyperplasia tissue. Moreover, the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of telomerase, is regulated by androgens as well as by different oncogenes including Her-2, Ras, c-Myc and Bcl-2, which seem to play an important role in prostate cancer progression. Thus, telomerase may represent a very good candidate for targeted therapy in prostate tumors. To inhibit telomere maintenance by telomerase, approaches that directly target either telomerase and telomeres or the telomerase regulatory mechanisms have been used. Moreover, strategies targeting telomerase-positive cells as a means to directly kill the tumor cells have been tested. This review summarizes the most promising results achieved by anti-telomerase strategy in different solid tumors. Most of the telomeraseassociated therapies described here have proved very promising for the treatment of prostate cancer. On the basis of the good results obtained and considering the multigenic defects of human tumors, including prostate cancer, the combination of anti-telomerase strategies with conventional drugs and/or molecules capable of interfering with oncogenic pathways could efficiently improve the response of this neoplasia.

scholarly journals Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

2016 ◽  
Vol 113 (34) ◽  
pp. E5024-E5033 ◽  
Author(s):  
Priyanka L. Patel ◽  
Anitha Suram ◽  
Neena Mirani ◽  
Oliver Bischof ◽  
Utz Herbig
Keyword(s):  
Dna Damage ◽  
Cancer Progression ◽  
Ectopic Expression ◽  
Telomerase Activity ◽  
Early Event ◽  
Telomere Dysfunction ◽  
Telomeric Dna ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Gene ◽  
In Cells

Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc–dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.

Gold Nanoprobe-Based Detection of Human Telomerase Reverse Transcriptase (hTERT) Gene Expression

2015 ◽  
Vol 14 (4) ◽  
pp. 485-490 ◽  
Author(s):  
Mohammad Pourhassan-Moghaddam ◽  
Nosratollah Zarghami ◽  
Afshin Mohsenifar ◽  
Mohammad Rahmati-Yamchi ◽  
Hadis Daraee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Reverse Transcriptase ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Htert Gene ◽  
Human Telomerase ◽  
Gold Nanoprobe

Variation in UDP glucouronyltransferase (UGT) genes associated with prostate cancer mortality.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 44-44
Author(s):  
M. Kohli ◽  
D. W. Mahoney ◽  
H. S. Chai ◽  
D. W. Hillman ◽  
D. R. Rider ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Advanced Prostate Cancer ◽  
Cox Regression ◽  
Prostate Cancer Progression ◽  
Androgen Ablation ◽  
Principle Components Analysis ◽  
Specific Mortality ◽  
Cancer Specific Mortality

44 Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients. Methods: We successfully genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression. Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS<7. After a median follow-up of 1.8 years (IQ range: 0.8–3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table . Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers. [Table: see text] No significant financial relationships to disclose.

scholarly journals REPRODUCTIVE FUNCTION AND ANTITUMOR ACTIVITY: DIFFERENT ROLES FOR THE HYPOTHALAMIC HORMONE GnRH

2020 ◽  
Author(s):  
Patrizia Limonta ◽  
Marcella Motta ◽  
Roberta M. Moretti ◽  
Monica Marzagalli ◽  
Fabrizio Fontana ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cells ◽  
Biological Effects ◽  
Molecular Target ◽  
Cytotoxic Drug ◽  
Gnrh Agonists ◽  
Gnrh Analog ◽  
Androgen Ablation ◽  
Hypothalamic Hormone ◽  
Wide Range

The decapeptide GnRH (Gonadotropin-Releasing Hormone), whose amino acidic sequence was discovered by Dr. A.V. Schally, was initially identified as the key hypothalamic hormone involved in the control of reproductive functions. GnRH, by binding to specific receptors (GnRH-R) at the pituitary level, stimulates the synthesis and secretion of the two gonadotropins (LH, luteinizing hormone and FSH, follicle stimulating hormone) and the downstream production of steroid hormones at the gonadal level. At present, these receptors represent the molecular targets of the standard pharmacological treatments for hormone-related tumors, such as androgen-dependent prostate cancer. Actually, chronic administration of synthetic GnRH agonists induces the desensitization of pituitary receptors and, subsequently, the suppression of testicular androgen production. The physiological role of GnRH in reproductive functions, and its regulation, represented a very important line of research for professor Martini and His colleagues. In the last three decades it has become increasingly clear that GnRH-R are expressed also in a wide range of tumors, both related and unrelated to the reproductive system; in particular GnRH-R are expressed in prostate cancers after development of resistance to androgen ablation therapy (castration resistant prostate cancer, CRPC), a tumor known to be refractory to standard chemotherapy. Activation of these receptors by means of GnRH agonists is associated with a significant antiproliferative/antimetastatic/antiangiogenic activity. These different biological effects at pituitary vs. prostate tissues are related to specific intracellular signal transduction pathways. Based on these observations, tumor GnRH-R are presently considered an effective molecular target for novel therapies (‘targeted’ therapies). In particular, GnRH-based bioconjugates, in which a standard cytotoxic drug is linked to a GnRH analog, have been developed. The rationale for this ‘targeted’ therapy is that the GnRH analog behaves as the targeting moiety by binding to GnRH-R in tumors, thus specifically delivering (targeting) the cytotoxic drug to tumor cells. At the level of tumor cells, the bioconjugate is internalized and degraded at the lysosomal level; in this way the anticancer drug is specifically released into the tumor cells to exert its cytotoxic effects, while sparing normal cells. In conclusion, GnRH-R are expressed not only at the pituitary level but also in a wide range of tumor tissues; these receptors are at present under investigation as an effective molecular target for the development of novel therapeutic strategies.

scholarly journals Gene Expression Alterations during Development of Castration-Resistant Prostate Cancer Are Detected in Circulating Tumor Cells

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 39 ◽  
Author(s):  
Andreas Josefsson ◽  
Karin Larsson ◽  
Eva Freyhult ◽  
Jan-Erik Damber ◽  
Karin Welén
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Progression ◽  
Expression Patterns ◽  
Therapy Resistance ◽  
Castration Resistant Prostate Cancer ◽  
Cancer Specific Survival ◽  
Castration Resistant

Development of castration-resistant prostate cancer (CRPC) is associated with alterations in gene expression involved in steroidogenesis and androgen signaling. This study investigates whether gene expression changes related to CRPC development can be identified in circulating tumor cells (CTCs). Gene expression in paired CTC samples from 29 patients, before androgen deprivation therapy (ADT) and at CRPC relapse, was compared using a panel including 47 genes related to prostate cancer progression on a qPCR platform. Fourteen genes displayed significantly changed gene expression in CTCs at CRPC relapse compared to before start of ADT. The genes with increased expression at CRPC relapse were related to steroidogenesis, AR-signaling, and anti-apoptosis. In contrast, expression of prostate markers was downregulated at CRPC. We also show that midkine (MDK) expression in CTCs from metastatic hormone-sensitive prostate cancer (mHSPC) was associated to short cancer-specific survival (CSS). In conclusion, this study shows that gene expression patterns in CTCs reflect the development of CRPC, and that MDK expression levels in CTCs are prognostic for cancer-specific survival in mHSPC. This study emphasizes the role of CTCs in exploring mechanisms of therapy resistance, as well as a promising biomarker for prognostic and treatment-predictive purposes in advanced mHSPC.

scholarly journals SLX4IP and telomere dynamics dictate breast cancer metastasis and therapeutic responsiveness

2020 ◽  
Vol 3 (4) ◽  
pp. e201900427
Author(s):  
Nathaniel J Robinson ◽  
Chevaun D Morrison-Smith ◽  
Alex J Gooding ◽  
Barbara J Schiemann ◽  
Mark W Jackson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Clinical Manifestations ◽  
Metastatic Breast ◽  
Disseminated Tumor Cells ◽  
Telomere Maintenance ◽  
Metastatic Progression ◽  
Metastatic Relapse

Metastasis is the leading cause of breast cancer-related death and poses a substantial clinical burden owing to a paucity of targeted treatment options. The clinical manifestations of metastasis occur years-to-decades after initial diagnosis and treatment because disseminated tumor cells readily evade detection and resist therapy, ultimately giving rise to recurrent disease. Using an unbiased genetic screen, we identified SLX4-interacting protein (SLX4IP) as a regulator of metastatic recurrence and established its relationship in governing telomere maintenance mechanisms (TMMs). Inactivation of SLX4IP suppressed alternative lengthening of telomeres (ALT), coinciding with activation of telomerase. Importantly, TMM selection dramatically influenced metastatic progression and survival of patients with genetically distinct breast cancer subtypes. Notably, pharmacologic and genetic modulation of TMMs elicited telomere-dependent cell death and prevented disease recurrence by disseminated tumor cells. This study illuminates SLX4IP as a potential predictive biomarker for breast cancer progression and metastatic relapse. SLX4IP expression correlates with TMM identity, which also carries prognostic value and informs treatment selection, thereby revealing new inroads into combating metastatic breast cancers.

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