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Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post‐transplantation cyclophosphamide (PTCy) to prevent graft‐versus‐host disease (GVHD). Sirolimus exposure–response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T‐cells, including conventional (Tcons) and regulatory T‐cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T‐cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration–effect association are needed for QSP modeling. [ABSTRACT FROM AUTHOR]

Busulfan is hepatically metabolized through glutathione (GSH) conjugation; in vitro, this process depletes hepatocyte GSH stores and generates the cytotoxic metabolite γ‐glutamyldehydroalanylglycine, which is too unstable to be quantitated in vivo. We sought to evaluate if pre‐graft (i.e., immediately before allograft infusion) concentrations of busulfan metabolites' and of endogenous metabolomic compounds (EMCs) representing the glutathione pathway were associated with clinical outcomes in hematopoietic cell transplant (HCT) recipients receiving busulfan. The clinical outcomes evaluated were relapse, acute graft versus host disease (GVHD), chronic GVHD, non‐relapse mortality, and neutrophil nadir. In pre‐graft samples obtained from patients immediately before allograft infusion, our objectives were to evaluate for: (1) the presence of busulfan and its metabolites tetrahydrothiophenium ion (THT+), tetrahydrothiophene 1‐oxide, sulfolane, and 3‐hydroxysulfolane (N = 124); (2) EMCs using a global metabolomics assay (N = 77); and (3) the association of the busulfan metabolites and the EMCs with clinical outcomes. In the pre‐graft samples, busulfan and THT+ could not be detected. THT 1‐oxide, sulfolane, and 3‐hydroxysulfolane were quantitated in 9.6%, 26%, and 58% of pre‐graft samples; their concentrations were not associated with clinical outcomes. Four pre‐graft EMCs were statistically significantly associated with the neutrophil nadir. The pre‐graft EMCs were not associated with the other clinical outcomes. In conclusion, busulfan's metabolites are present in patients' plasma immediately before allograft infusion; the neutrophil nadir is associated with pre‐graft EMCs. Future research should investigate the association of clinical outcomes with the concentrations of busulfan's metabolites and EMCs in the pre‐graft plasma from allogeneic HCT recipients. [ABSTRACT FROM AUTHOR]

Abstract: The expression of Nuclear Protein 1 (NUPR1) is associated with chemoresistance in multiple malignancies. We previously reported that NUPR1 functions as a transcriptional cofactor for the p300–p53 complex and transcriptionally regulates p21 expression. In the present study we investigated the activity of NUPR1 in p53-deficient, triple-negative, inflammatory SUM159 breast cancer cells. Our studies reveal that NUPR1 confers growth benefit and chemoresistance by causing Akt-mediated phosphorylation and subsequent cytoplasmic re-localization of p21 and activation of the anti-apoptotic Bcl-xL protein. Our findings elucidate a NUPR1-PI-3-K/Akt-phospho-p21 axis that functions in p53-negative, inflammatory breast cancer cells to enhance chemoresistance in breast cancer. [Copyright &y& Elsevier]

The inactivation of tumor-related genes through the aberrant methylation of promoter CpG islands is thought to contribute to tumor initiation and progression. We therefore investigated promoter methylation events involved in cutaneous melanoma by screening 30 genes of interest for evidence of promoter hypermethylation, examining 20 melanoma cell lines and 40 freshly procured melanoma samples. Utilizing quantitative methylation-specific PCR, we identified five genes (SOCS1, SOCS2, RAR-beta 2, TNFSF10C, and TNFSF10D) with hypermethylation frequencies ranging from 50% to 80% in melanoma cell lines as well as freshly procured tissue samples. Eighteen genes (LOX, RASSF1A, WFDC1, TM, APC, TFPI2, TNFSF10A, CDKN2A, MGMT, TIMP3, ASC, TPM1, IRF8, CIITA-PIV, CDH1, SYK, HOXB13, and DAPK1) were methylated at lower frequencies (2–30%). Two genes (CDKN1B and PTEN), previously reported as methylated in melanoma, and five other genes (RECK, IRF7, PAWR, TNFSF10B, and Rb) were not methylated in the samples screened here. Daughter melanoma cell lines showed identical methylation patterns when compared with original samples from which they were derived, as did synchronous metastatic lesions from the same patient. We identified four genes (TNFSF10C, TNFSF10D, LOX, and TPM1) that have never before been identified as hypermethylated in melanoma, with an overall methylation frequency of 60, 80, 50, and 10%, respectively, hypothesizing that these genes may play an important role in melanoma progression. [ABSTRACT FROM AUTHOR]

Utilizing gene microarray profiling of melanoma samples, we have recently identified a novel gene overexpressed in both thick primary and metastatic melanomas. This gene, progestagen-associated endometrial protein (PAEP), has never before been implicated in the oncogenic processes of melanoma, with its true function in oncogenesis and tumour progression relatively unknown. Overexpression of the PAEP gene in freshly procured thick primary and metastatic melanoma samples (58%) and daughter cell lines (77%) is confirmed by quantitative RT-PCR, immunohistochemistry, Western blotting and mass spectrometric analysis. We suggest that PAEP gene overexpression is involved with melanoma tumour progression as well as an aggressive phenotype. Transfection of melanoma cells with PAEP small interfering RNA (siRNA) reveals a significant decrease in soft agar colony formation and a marked inhibition of both cell migration and cell invasion. Furthermore, we establish stable melanoma transfectants via PAEP lentiviral small hairpin RNA (shRNA), examine their growth characteristics in a murine xenograft model and reveal that tumour growth is significantly inhibited in two separate melanoma cell lines. Our data strongly implicate the PAEP gene as a tumour growth promoter with oncogenic properties and a potential therapeutic target for patients with advanced melanoma.