Sequencing current therapies in the treatment of metastatic prostate cancer

Valença, Loana Bueno; Sweeney, Christopher J.; Pomerantz, Mark

doi:10.1016/j.ctrv.2015.02.010

Cited by 37 publications

(20 citation statements)

References 101 publications

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“…PSMA is a novel and promising target for diagnostics and therapy of metastatic prostate cancer, especially when the androgen receptor is the persistent therapeutic target and pending cross resistances might occur in subsequent androgen-directed therapies [ 30 ]. Several groups focused on the relations between PSMA expression and other membrane antigens.…”

Section: Discussionmentioning

confidence: 99%

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy

et al. 2015

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BackgroundProstate-specific membrane antigen (PSMA) is a promising target for diagnostics and therapy of prostate carcinoma (PCa). Based on the hypothesis that PSMA expression can be modulated by variations in androgen deprivation therapy (ADT), we investigated the binding of a PSMA-directed radiopharmaceutical in vitro in order to get an insight of the interactions between altered premedication and PSMA expression before repetitive PSMA-directed PET/CT for therapy response and targeted therapy implementation.MethodsThe human castration-resistant PCa cell line VCaP (CRPC) was treated with either 1 nmol/L testosterone (T) over 20 passages yielding the androgen-sensitive cell line (revCRPC) or with 5 μmol/L abiraterone acetate (AA) generating the abiraterone-tolerant subtype CRPCAA. In these cell lines, T and AA were varied by either supply or withdrawal of T and AA. PSMA expression of the three cell culture models was detected by Western blot and immunohistochemical staining. For quantitative measurement of tracer uptake, 0.3 nmol/L 68Ga-labelled PSMA-HBED-CC peptide (100–300 kBq/ml) was added to different treated parallel cultures (n = 9 each). Time-dependent uptake per 106 cells of each culture was calculated and evaluated. PSMA mRNA expression was investigated by qPCR.ResultsPSMA expression increased dependently on intensified ADT in all three basic cell lines. 68Ga-PSMA-HBED-CC uptake almost doubled during 3 h in all cell lines (p < 0.01). Compared to the basic cells, pre-incubation with abiraterone for 48 h resulted in a significant increased uptake in CRPC (p < 0.001). In revCRPC, 48-h AA pre-incubation resulted in an eightfold higher uptake after 3 h (p < 0.001). Additional withdrawal of external testosterone increased the uptake up to tenfold (p < 0.01). The increase of PSMA expression upon ADT and AA treatments was confirmed by qPCR and Western blot data. Furthermore, in CRPCAA, 48-h AA withdrawal increased the uptake up to fivefold (p < 0.01).ConclusionsThe investigated three PCa cell culture subtypes represent a serial preclinical model of androgen deprivation therapy as a proxy for clinical situations with differing basal PSMA expression. The uptake of PSMA-binding tracers could be stimulated by therapeutic effective short-term variation in premedication in all stages of ADT response. These complex interactions have to be considered in the interpretation of diagnostic imaging using PSMA ligands as well as in the optimal timing of PSMA-based therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0145-8) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy

et al. 2015

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“…Unlike ER and AR that have been widely exploited as therapeutic targets in cancer (i.e., ER in breast cancer (EBCTCG et al 2011) and AR in prostate cancer (Valenca et al 2015)), less work has been carried out on targeting VDR. There are, however, several preclinical studies suggesting that targeting VDR with calcitriol or its synthetic analogues may have anti-cancer potential (Narvaez et al 2001, Flanagan et al 2003, Kasiappan et al 2014, Lungchukiet et al 2014, Chen et al 2015, Murray et al 2015.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D receptor as a target for breast cancer therapy

Murray¹,

Madden²,

Synnott³

et al. 2017

Endocrine-Related Cancer

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Considerable epidemiological evidence suggests that high levels of circulating vitamin D (VD) are associated with a decreased incidence and increased survival from cancer, i.e., VD may possess anti-cancer properties. The aim of this investigation was therefore to investigate the anti-cancer potential of a low calcaemic vitamin D analogue, i.e., inecalcitol and compare it with the active form of vitamin D, i.e., calcitriol, in a panel of breast cancer cell lines ( = 15). Using the MTT assay, IC concentrations for response to calcitriol varied from 0.12 µM to >20 µM, whereas those for inecalcitol were significantly lower, ranging from 2.5 nM to 63 nM ( = 0.001). Sensitivity to calcitriol and inecalcitol was higher in VD receptor (VDR)-positive compared to VDR-negative cell lines ( = 0.0007 and 0.0080, respectively) and in ER-positive compared to ER-negative cell lines ( = 0.043 and 0.005, respectively). Using RNA-seq analysis, substantial but not complete overlap was found between genes differentially regulated by calcitriol and inecalcitol. In particular, significantly enriched gene ontology terms such as cell surface signalling and cell communication were found after treatment with inecalcitol but not with calcitriol. In contrast, ossification and bone morphogenesis were found significantly enriched after treatment with calcitriol but not with inecalcitol. Our preclinical results suggest that calcitriol and inecalcitol can inhibit breast cancer cell line growth, especially in cells expressing ER and VDR. As inecalcitol is significantly more potent than calcitriol and has low calcaemic potential, it should be further investigated for the treatment of breast cancer.

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“…In addition, questions surrounding optimal treatment sequencing and combinations remain [15, 16] and are currently being examined by both prospective and retrospective studies. Indeed, the issue of resistance extends beyond patients developing refractory disease to continued therapy with one agent to other agents in the form of cross-resistance occurring not only in the context of drugs targeting the same pathway but also between drug classes [17–19].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Therapeutic Resistance in Prostate Cancer

2017

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Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing and combinations. This review outlines our current understanding of mechanisms of therapeutic resistance in progression to and after the development of castration resistance, highlighting targetable and reversible mechanisms of resistance.

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Sequencing current therapies in the treatment of metastatic prostate cancer

Cited by 37 publications

References 101 publications

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy

Alterations in androgen deprivation enhanced prostate-specific membrane antigen (PSMA) expression in prostate cancer cells as a target for diagnostics and therapy

Vitamin D receptor as a target for breast cancer therapy

Mechanisms of Therapeutic Resistance in Prostate Cancer

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