Objective To explore the prognostic and predictive value of baseline variables in 512 patients with metastatic castration-resistant prostate cancer from the phase III Immunotherapy for Prostate ...Adenocarcinoma Treatment (IMPACT) trial who were randomized to receive sipuleucel-T or control. Methods The most powerful of these prognostic factors, baseline prostate-specific antigen (PSA), was subdivided into quartiles to evaluate treatment effect patterns. Cox regression analyses were used to assess predictors of overall survival (OS) and sipuleucel-T treatment effect within PSA quartiles. Median OS was estimated by the Kaplan-Meier method. Results PSA was the strongest baseline prognostic factor ( P <.0001). Furthermore, the sipuleucel-T treatment effect appeared greater with decreasing baseline PSA. The OS hazard ratio for patients in the lowest baseline PSA quartile (≤22.1 ng/mL) was 0.51 (95% confidence interval, 0.31-0.85) compared with 0.84 (95% confidence interval, 0.55-1.29) for patients in the highest PSA quartile (>134 ng/mL). Estimated improvement in median survival varied from 13.0 months in the lowest baseline PSA quartile to 2.8 months in the highest quartile. Estimated 3-year survival in the lowest PSA quartile was 62.6% for sipuleucel-T patients and 41.6% for control patients, representing a 50% relative increase. Conclusion The greatest magnitude of benefit with sipuleucel-T treatment in this exploratory analysis was observed among patients with better baseline prognostic factors, particularly those with lower baseline PSA values. These findings suggest that patients with less advanced disease may benefit the most from sipuleucel-T treatment and provide a rationale for immunotherapy as an early treatment strategy in sequencing algorithms for metastatic castration-resistant prostate cancer.
We report a novel quantum dot (QD)−aptamer(Apt)−doxorubicin (Dox) conjugate QD−Apt(Dox) as a targeted cancer imaging, therapy, and sensing system. By functionalizing the surface of fluorescent QD ...with the A10 RNA aptamer, which recognizes the extracellular domain of the prostate specific membrane antigen (PSMA), we developed a targeted QD imaging system (QD−Apt) that is capable of differential uptake and imaging of prostate cancer cells that express the PSMA protein. The intercalation of Dox, a widely used antineoplastic anthracycline drug with fluorescent properties, in the double-stranded stem of the A10 aptamer results in a targeted QD−Apt(Dox) conjugate with reversible self-quenching properties based on a Bi-FRET mechanism. A donor−acceptor model fluorescence resonance energy transfer (FRET) between QD and Dox and a donor−quencher model FRET between Dox and aptamer result when Dox intercalated within the A10 aptamer. This simple multifunctional nanoparticle system can deliver Dox to the targeted prostate cancer cells and sense the delivery of Dox by activating the fluorescence of QD, which concurrently images the cancer cells. We demonstrate the specificity and sensitivity of this nanoparticle conjugate as a cancer imaging, therapy and sensing system in vitro.
Defects in genes in the DNA repair pathways significantly contribute to prostate cancer progression. We hypothesize that overexpression of DNA repair genes may also drive poorer outcomes in prostate ...cancer. The ribonucleotide reductase small subunit M2 (RRM2) is essential for DNA synthesis and DNA repair by producing dNTPs. It is frequently overexpressed in cancers, but very little is known about its function in prostate cancer.
The oncogenic activity of RRM2 in prostate cancer cells was assessed by inhibiting or overexpressing RRM2. The molecular mechanisms of RRM2 function were determined. The clinical significance of RRM2 overexpression was evaluated in 11 prostate cancer clinical cohorts. The efficacy of an RRM2 inhibitor (COH29) was assessed
and
. Finally, the mechanism underlying the transcriptional activation of RRM2 in prostate cancer tissue and cells was determined.
Knockdown of RRM2 inhibited its oncogenic function, whereas overexpression of RRM2 promoted epithelial mesenchymal transition in prostate cancer cells. The prognostic value of RRM2 RNA levels in prostate cancer was confirmed in 11 clinical cohorts. Integrating the transcriptomic and phosphoproteomic changes induced by RRM2 unraveled multiple oncogenic pathways downstream of RRM2. Targeting RRM2 with COH29 showed excellent efficacy. Thirteen putative RRM2-targeting transcription factors were bioinformatically identified, and FOXM1 was validated to transcriptionally activate RRM2 in prostate cancer.
We propose that increased expression of RRM2 is a mechanism driving poor patient outcomes in prostate cancer and that its inhibition may be of significant therapeutic value.
One limitation of current biodegradable polymeric nanoparticles is their inability to effectively encapsulate and sustainably release proteins while maintaining protein bioactivity. Here we report ...the engineering of PLGA–polycation nanoparticles with a core–shell structure that act as a robust vector for the encapsulation and delivery of proteins and peptides. The optimized nanoparticles can load high amounts of proteins (>20 % of nanoparticles by weight) in aqueous solution without organic solvents through electrostatic interactions by simple mixing, thereby forming nanospheres in seconds with diameters <200 nm. The relationship between nanosphere size, surface charge, PLGA–polycation composition, and protein loading is also investigated. The stable nanosphere complexes contain multiple PLGA–polycation nanoparticles, surrounded by large amounts of protein. This study highlights a novel strategy for the delivery of proteins and other relevant molecules.
Polymer–polycation nanoparticles have been used as nuclei to readily adsorb large amounts of protein (>20 % of the nanoparticles by weight) to form new hybrid nanospheres with diameters <200 nm in aqueous solutions without organic solvents through electrostatic interactions. This model system was used to demonstrate the relationships between nanosphere size, surface charge, polymer–polycation composition, and protein loading.
Targeted uptake of therapeutic nanoparticles in a cell-, tissue-, or disease-specific manner represents a potentially powerful technology. Using prostate cancer as a model, we report docetaxel ...(Dtxl)-encapsulated nanoparticles formulated with biocompatible and biodegradable poly(D,L-lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG) copolymer and surface functionalized with the A10 2'-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate-specific membrane antigen (PSMA), a well characterized antigen expressed on the surface of prostate cancer cells. These Dtxl-encapsulated nanoparticleaptamer bioconjugates (Dtxl-NP-Apt) bind to the PSMA protein expressed on the surface of LNCaP prostate epithelial cells and get taken up by these cells resulting in significantly enhanced in vitro cellular toxicity as compared with nontargeted nanoparticles that lack the PSMA aptamer (Dtxl-NP) (P < 0.0004). The Dtxl-NP-Apt bioconjugates also exhibit remarkable efficacy and reduced toxicity as measured by mean body weight loss (BWL) in vivo body weight loss of 7.7 ± 4% vs. 18 ± 5% for Dtxl-NP-Apt vs. Dtxl-NP at nadir, respectively (mean ± SD); n = 7. After a single intratumoral injection of Dtxl-NP-Apt bioconjugates, complete tumor reduction was observed in five of seven LNCaP xenograft nude mice (initial tumor volume of ≈300 mm³), and 100% of these animals survived our 109-day study. In contrast, two of seven mice in the DtxI-NP group had complete tumor reduction with 109-day survivability of only 57%. Dtxl alone had a survivability of only 14%. Saline and nanoparticles without drug were similarly nonefficacious. This report demonstrates the potential utility of nanoparticle-aptamer bioconjugates for a therapeutic application.
MicroRNAs (miRNAs) play important roles in cancer formation and progression by suppressing the production of key functional proteins at the post-transcriptional level in a sequence-specific manner. ...While differential expression of miRNAs is widely observed in cancers including prostate cancer (PCa), how these miRNAs are transcriptionally regulated is largely unknown. MiRNA-221 and miRNA-222 (miR-221/-222) are well-established oncogenes and overexpressed in breast, liver, pancreas, and lung cancer, but their expression and biological functions in PCa remain controversial. Both up and down regulation have been observed in patient samples. Specifically, studies have demonstrated miR-221/-222 function as oncogenes, and promote PCa cell proliferation and the development of castration-resistant prostate cancer (CRPC). However, the expression level of miR-221/-222 is downregulated in several miRNA expression profiling studies. In this study, we demonstrate miR-221/-222 are androgen receptor (AR)-repressed genes and reside in a long primary transcript (pri-miRNA). Derepression of miR-221/-222 after androgen deprivation therapy (ADT) may enhance PCa cell proliferation potential through promoting G1/S phase transition. This function is likely transient but important in the development of CRPC. Downregulation of miR-221/-222 subsequently occurs once AR activity is restored through AR overexpression in CRPC. Our findings shed light on the complexity of transcriptional regulation of miRNAs in PCa and suggest context-dependent targeting of oncogenic miRNAs.
PROSTVAC, a viral vector-based immunotherapy, prolonged median overall survival (OS) by 8.5 months versus placebo in metastatic castration-resistant prostate cancer in a phase II study. This phase ...III study further investigated those findings.
Patients were randomly assigned to PROSTVAC (Arm V; n = 432), PROSTVAC plus granulocyte-macrophage colony-stimulating factor (Arm VG; n = 432), or placebo (Arm P; n = 433), stratified by prostate-specific antigen (less than 50 ng/mL
50 ng/mL or more) and lactate dehydrogenase (less than 200
200 U/L or more). Primary end point was OS. Secondary end points were patients alive without events (AWE)-namely, radiographic progression, pain progression, chemotherapy initiation, or death-at 6 months and safety. The study design was a superiority trial of PROSTVAC (Arm V or Arm VG) versus Arm P. Three interim analyses were planned.
At the third interim analysis, criteria for futility were met and the trial was stopped early. Neither active treatment had an effect on median OS (Arm V, 34.4 months; hazard ratio, 1.01; 95% CI, 0.84 to 1.20;
= .47; Arm VG, 33.2 months; hazard ratio, 1.02; 95% CI, 0.86 to 1.22;
= .59; Arm P, 34.3 months). Likewise, AWE at 6 months was similar (Arm V, 29.4%; odds ratio, 0.96; 95% CI, 0.71 to 1.29; Arm VG, 28.0%; odds ratio, 0.89; 95% CI, 0.66 to 1.20; placebo, 30.3%). Adverse events were similar for the treatment and placebo groups, with the most common being injection site reactions (62% to 72%) and fatigue (21% to 24%). Arrhythmias were the most common cardiac-related events (1.4% to 3.5%). There were no reports of either myocarditis or pericarditis. Serious treatment-related events occurred in less than 1% of all patients.
Whereas PROSTVAC was safe and well tolerated, it had no effect on OS or AWE in metastatic castration-resistant prostate cancer. Combination therapy is currently being explored in clinical trials.
Previous sequencing studies revealed that alterations of genes associated with DNA damage response (DDR) are enriched in men with metastatic castration-resistant prostate cancer (mCRPC).
, a DDR and ...cancer susceptibility gene, is frequently deleted (homozygous and heterozygous) in men with aggressive prostate cancer. Here we show that patients with prostate cancer who have lost a copy of
frequently lose a copy of tumor suppressor gene
; importantly, for the first time, we demonstrate that co-loss of both genes in early prostate cancer is sufficient to induce a distinct biology that is likely associated with worse prognosis.
We prospectively investigated underlying molecular mechanisms and genomic consequences of co-loss of
and
in prostate cancer. We used CRISPR-Cas9 and RNAi-based methods to eliminate these two genes in prostate cancer cell lines and subjected them to
studies and transcriptomic analyses. We developed a 3-color FISH assay to detect genomic deletions of
and
in prostate cancer cells and patient-derived mCRPC organoids.
In human prostate cancer cell lines (LNCaP and LAPC4), loss of
leads to the castration-resistant phenotype. Co-loss of
-
in human prostate cancer cells induces an epithelial-to-mesenchymal transition, which is associated with invasiveness and a more aggressive disease phenotype. Importantly, PARP inhibitors attenuate cell growth in human mCRPC-derived organoids and human CRPC cells harboring single-copy loss of both genes.
Our findings suggest that early identification of this aggressive form of prostate cancer offers potential for improved outcomes with early introduction of PARP inhibitor-based therapy.
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