A phase II study of pemetrexed as second-line chemotherapy for the treatment of metastatic castrate-resistant prostate cancer (CRPC); Hoosier Oncology Group GU03-67

Hahn, Noah M.; Zoň, Robin; Yu, Menggang; Ademuyiwa, Foluso O.; Jones, Tonye A.; Dugan, William; Whalen, Charles J.; Shanmugam, Ragavi; Skaar, Todd C.; Sweeney, C. J.

doi:10.1093/annonc/mdp244

Cited by 14 publications

(7 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Positive results treating castration recurrent CaP with methotrexate (39, 40), were not confirmed by later studies (41–43). We suggest that the high level of polyamine biosynthesis due to the secretory characteristics of prostate, uniquely stresses one-carbon metabolism and the methionine cycle, and is therefore central to the rationale behind applying antifolate therapy to CaP.…”

Section: Discussionmentioning

confidence: 91%

Dietary Folate Deficiency Blocks Prostate Cancer Progression in the TRAMP Model

Bistulfi

Foster

Karasik

et al. 2011

Cancer Prevention Research

View full text Add to dashboard Cite

Dietary folate is essential in all tissues to maintain several metabolite pools and cellular proliferation. Prostate cells, due to specific metabolic characteristics, have increased folate demand to support proliferation and prevent genetic and epigenetic damage. Although several studies found that dietary folate interventions can affect colon cancer biology in rodent models, impact on prostate is unknown. The purpose of this study was to determine if dietary folate manipulation, possibly being of primary importance for prostate epithelial cell metabolism, could significantly affect prostate cancer (CaP) progression. Strikingly, mild dietary folate depletion arrested CaP progression in 25/26 transgenic TRAMP mice, where tumorigenesis is prostate specific and characteristically aggressive. The significant effect on CaP growth was characterized by size, grade, proliferation and apoptosis analyses. Folate supplementation had a mild, non significant beneficial effect on grade. In addition, characterization of folate pools (correlated with serum), metabolite pools (polyamines, nucleotides), genetic and epigenetic damage, and expression of key biosynthetic enzymes in prostate tissue revealed interesting correlations with tumor progression. These findings indicate that CaP is highly sensitive to folate manipulation and suggest that antifolates, paired to current therapeutic strategies, might significantly improve treatment of CaP, the most commonly diagnosed cancer in American men.

show abstract

Section: Discussionmentioning

confidence: 91%

Dietary Folate Deficiency Blocks Prostate Cancer Progression in the TRAMP Model

Bistulfi

Foster

Karasik

et al. 2011

Cancer Prevention Research

View full text Add to dashboard Cite

show abstract

“…By studying prostate specific metabolism we pinpointed at least two ideal targets for CaP therapy; prostate's characteristically high dependency on folate, and the requirement for the methionine salvage pathway through the activity of MTAP. Previous studies have explored the use of anti-folate therapies, specifically methotrexate, to treat castration recurrent, chemotherapy refractory CaP [ 35 , 36 ]. In this clinical setting, anti-folate therapies were met with mixed results.…”

Section: Discussionmentioning

confidence: 99%

The essential role of methylthioadenosine phosphorylase in prostate cancer

et al. 2016

View full text Add to dashboard Cite

Prostatic epithelial cells secrete high levels of acetylated polyamines into the prostatic lumen. This distinctive characteristic places added strain on the connected pathways, which are forced to increase metabolite production to maintain pools. The methionine salvage pathway recycles the one-carbon unit lost to polyamine biosynthesis back to the methionine cycle, allowing for replenishment of SAM pools providing a mechanism to help mitigate metabolic stress associated with high flux through these pathways. The rate-limiting enzyme involved in this process is methylthioadenosine phosphorylase (MTAP), which, although commonly deleted in many cancers, is protected in prostate cancer. We report near universal retention of MTAP expression in a panel of human prostate cancer cell lines as well as patient samples. Upon metabolic perturbation, prostate cancer cell lines upregulate MTAP and this correlates with recovery of SAM levels. Furthermore, in a mouse model of prostate cancer we find that both normal prostate and diseased prostate maintain higher SAM levels than other tissues, even under increased metabolic stress. Finally, we show that knockdown of MTAP, both genetically and pharmacologically, blocks androgen sensitive prostate cancer growth in vivo. Our findings strongly suggest that the methionine salvage pathway is a major player in homeostatic regulation of metabolite pools in prostate cancer due to their high level of flux through the polyamine biosynthetic pathway. Therefore, this pathway, and specifically the MTAP enzyme, is an attractive therapeutic target for prostate cancer.

show abstract

“…Therefore, our observations that the CXCR2 antagonist had no effect upon the sensitivity of cells to pemetrexed may relate to the absence of a pemetrexed-induced increase in CXCL8 signaling and/or reflects that CXCL8 signaling may not regulate the broader spectrum of targets whose activity is modulated by pemetrexed. Although PC3 cells were sensitive and responded favourably to pemetrexed treatment, phase II studies in patients have failed to provide encouragement for the use of this agent as a second line chemotherapy for metastatic CRPC, suggesting that other resistance mechanisms relevant to this drug are at play in this disease setting [21], [22].…”

Section: Discussionmentioning

confidence: 99%

Constitutive and Treatment-Induced CXCL8-Signalling Selectively Modulates the Efficacy of Anti-Metabolite Therapeutics in Metastatic Prostate Cancer

Wilson¹,

Maxwell²,

Longley³

et al. 2012

PLoS ONE

View full text Add to dashboard Cite

BackgroundThe current study was undertaken to characterize the effect of anti-metabolites on inducing CXCL8 signaling and determining whether the constitutive and/or drug-induced CXCL8 signaling in metastatic prostate cancer (CaP) cells modulates their sensitivity to this class of agent.MethodsThe response of metastatic CaP cells to 5-Fluorouracil (5-FU), Pemetrexed or Tomudex was determined using cell count assays, flow cytometry and PARP cleavage analysis. Quantitative-PCR, ELISA and immunoblots were employed to determine effects of drugs or CXCL8 administration on target gene/protein expression.ResultsAdministration of 5-FU but not pemetrexed potentiated CXCL8 secretion and increased CXCR1 and CXCR2 gene expression in metastatic PC3 cells. Consistent with this, the inhibition of CXCL8 signaling using a CXCR2 antagonist, AZ10397767, increased the cytotoxicity of 5-FU by 4-fold (P<0.001), and increased 5-FU-induced apoptosis in PC3 cells (P<0.01). In contrast, while administration of AZ10397767 had no effect on the sensitivity of pemetrexed, the CXCR2 antagonist exerted the greatest effect in increasing the sensitivity of PC3 cells to Tomudex, a directed thymidylate synthase (TS) inhibitor. Subsequent experiments confirmed that administration of recombinant human CXCL8 increased TS expression, a response mediated in part by the CXCR2 receptor. Moreover, siRNA-mediated knockdown of the CXCL8-target gene Bcl-2 increased the sensitivity of PC3 cells to 5-FU.ConclusionsCXCL8 signaling provides a selective resistance of metastatic prostate cancer cells to specific anti-metabolites by promoting a target-associated resistance, in addition to underpinning an evasion of treatment-induced apoptosis.

show abstract

A phase II study of pemetrexed as second-line chemotherapy for the treatment of metastatic castrate-resistant prostate cancer (CRPC); Hoosier Oncology Group GU03-67

Cited by 14 publications

References 29 publications

Dietary Folate Deficiency Blocks Prostate Cancer Progression in the TRAMP Model

Dietary Folate Deficiency Blocks Prostate Cancer Progression in the TRAMP Model

The essential role of methylthioadenosine phosphorylase in prostate cancer

Constitutive and Treatment-Induced CXCL8-Signalling Selectively Modulates the Efficacy of Anti-Metabolite Therapeutics in Metastatic Prostate Cancer

Contact Info

Product

Resources

About