Summary
Background
Basal cell carcinoma (BCC) represents the most common nonmelanoma skin cancer worldwide, affecting mainly adult, fair‐skinned individuals. The World Health Organization ...distinguishes aggressive and nonaggressive forms, of which prototypical variants of the latter are primary nodular and superficial BCC.
Objectives
To demonstrate noninferiority of BF‐200 ALA (a nanoemulsion gel containing 5‐aminolaevulinic acid) compared with MAL (a cream containing methyl aminolaevulinate) in the treatment of nonaggressive BCC with photodynamic therapy (PDT). Noninferiority of the primary efficacy variable (overall patient complete response 12 weeks after last PDT) would be declared if the mean response for BF‐200 ALA was no worse than that for MAL, within a statistical margin of Δ = −15%.
Methods
The study was a randomized, phase III trial performed in Germany and the U.K. with ongoing 5‐year follow‐up. Of 281 randomized patients, 138 were treated with BF‐200 ALA and 143 with MAL. Patients received two PDT sessions 1 week apart. Remaining lesions 12 weeks after the second PDT were retreated. Illumination was performed with a red light source (635 nm, 37 J cm−2). The results shown include clinical end points and patients’ reassessment 12 months after the last PDT. The study was registered with EudraCT (number 2013‐003241‐42).
Results
Of the BF‐200 ALA‐treated patients, 93·4% were complete responders compared with 91·8% in the MAL group. The difference of means was 1·6, with a one‐sided 97·5% confidence interval of −6·5, establishing noninferiority (P < 0·0001). The results for secondary efficacy parameters were in line with the primary outcome. Recurrence rates 12 months after the last treatment were ≤ 10%.
Conclusions
Treatment of nonaggressive BCC with BF‐200 ALA‐PDT is highly effective and well tolerated with proven noninferiority to MAL‐PDT. It demonstrates low recurrence rates after 1 year of follow‐up.
What's already known about this topic?
Photodynamic therapy (PDT) using BF‐200 aminolaevulinic acid (ALA) gel is registered and highly effective in the treatment of mild‐to‐moderate actinic keratosis and field cancerization.
BF‐200 ALA gel was recently approved for the treatment of superficial and/or nodular basal cell carcinoma (BCC) unsuitable for surgical treatment.
PDT using methyl aminolaevulinate (MAL) cream is approved for the treatment of thin or nonhyperkeratotic and nonpigmented actinic keratoses, Bowen disease, and superficial and nodular BCCs when other therapies are considered less appropriate.
What does this study add?
BF‐200 ALA‐PDT is confirmed to be significantly noninferior to MAL‐PDT for the treatment of nonaggressive BCC.
Treatment‐emergent adverse events were comparable between the two patient groups, with similar or slightly lower recurrence rates for BF‐200 ALA gel compared with MAL cream after 12 months.
Plain language summary available online
Respond to this article
BF‐200 ALA gel vs. MAL cream for BCC Morton, C.A.; Dominicus, R.; Radny, P. ...
British journal of dermatology (1951),
August 2018, 20180801, Letnik:
179, Številka:
2
Journal Article
Recenzirano
Summary
Basal cell carcinoma (BCC), also known as rodent ulcer, is the most common type of non‐melanoma skin cancer worldwide. It affects about 3–10% of people. This study from the U.K. and Germany ...aimed to find out if BF‐200 ALA gel would work as well as (is non‐inferior to) the already authorised MAL cream in the treatment of non‐aggressive BCC lesions. Both medications are applied topically (on the skin) to the tumour, which is then illuminated with a certified lamp. The illumination causes a chemical reaction that affects the cancer cells so that they eventually die. This kind of procedure is called photodynamic therapy (PDT). Patients in the study were put into the two groups by chance (randomized): 138 in the BF‐200 ALA group and 143 in the MAL group. The treatment scheme for both drugs was the same. Initially, patients had two PDTs one week apart. Four and 12 weeks after the second PDT, patients visited the doctor again, who assessed the treated lesions and patient's health. If all lesions were gone by week 12, the patient entered the 5‐year follow‐up study. In case of remaining lesions, patients received two more PDTs before entering the follow‐up. During the follow‐up, doctors monitor the health of the patients and assess if any of the treated lesions come back. The study found that there was no difference between the two groups, which means that BF‐200 ALA gel worked as well as the already approved MAL cream. In 113 of 121 patients (93.4%) treated with BF‐200 ALA and 101 of 110 patients (91.8%) treated with MAL, lesions disappeared completely. 87% of the BF‐200 ALA‐treated patients rated their satisfaction with the PDT as “very good or good”; 86% of the MAL‐treated patients said the same. Almost all patients experienced mild to moderate local side effects related to the study medications. Common side effects at the application site, which affected more than 1 of 10 patients, were pain, skin reddening (erythema), itching (pruritus), and tissue swelling (oedema). Side effects were similar for both medications. At 12‐month follow‐up, lesions reappeared in 8.4% of the BF‐200 ALA‐treated patients and in 8.5% of the MAL‐treated patients. The follow‐up is still ongoing; further results will be reported after the end of the study. This study showed that BF‐200 ALA gel is as effective and well‐tolerated as MAL cream in the treatment of non‐aggressive BCC. Based on these findings, the European Medicine Agency (EMA) granted approval for BF‐200 ALA for the treatment of non‐aggressive BCC.
Linked Article: Morton et al. Br J Dermatol 2018; 179:309–319
In roots of Arabidopsis (Arabidopsis thaliana), l-lactate is generated by the reduction of pyruvate via l-lactate dehydrogenase, but this enzyme does not efficiently catalyze the reverse reaction. ...Here, we identify the Arabidopsis glycolate oxidase (GOX) paralogs GOX1, GOX2, and GOX3 as putative l-lactate-metabolizing enzymes based on their homology to CYB2, the l-lactate cytochrome c oxidoreductase from the yeast Saccharomyces cerevisiae. We found that GOX3 uses l-lactate with a similar efficiency to glycolate; in contrast, the photorespiratory isoforms GOX1 and GOX2, which share similar enzymatic properties, use glycolate with much higher efficiencies than l-lactate. The key factor making GOX3 more efficient with l-lactate than GOX1 and GOX2 is a 5- to 10-fold lower Km for the substrate. Consequently, only GOX3 can efficiently metabolize l-lactate at low intracellular concentrations. Isotope tracer experiments as well as substrate toxicity tests using GOX3 loss-of-function and overexpressor plants indicate that l-lactate is metabolized in vivo by GOX3. Moreover, GOX3 rescues the lethal growth phenotype of a yeast strain lacking CYB2, which cannot grow on l-lactate as a sole carbon source. GOX3 is predominantly present in roots and mature to aging leaves but is largely absent from young photosynthetic leaves, indicating that it plays a role predominantly in heterotrophic rather than autotrophic tissues, at least under standard growth conditions. In roots of plants grown under normoxic conditions, loss of function of GOX3 induces metabolic rearrangements that mirror wild-type responses under hypoxia. Thus, we identified GOX3 as the enzyme that metabolizes l-lactate to pyruvate in vivo and hypothesize that it may ensure the sustainment of low levels of l-lactate after its formation under normoxia.
Protein regulator of cytokinesis 1 (PRC1) is a microtubule-binding protein with essential roles in mitosis and cytokinesis. PRC1 is frequently overexpressed in cancer cells where it could contribute ...to chromosomal instability. Due to its nuclear localization in interphase, it has been speculated that PRC1 has additional functions that are involved in its pro-tumorigenic functions. In this study we investigated the potential nuclear functions of PRC1 in a lung cancer cell line. Genome wide expression profiling by RNA sequencing revealed that the expression of PRC1 results in activation of the p53 pathway and inhibition of the pro-proliferative E2F-dependent gene expression. A mutant of PRC1 that is unable to enter into the nucleus regulated the same gene sets as wildtype PRC1, suggesting that PRC1 has no nuclear-exclusive functions in A549 cells. Instead, induction of p53 by PRC1 correlates with multinucleation and depends on the localization of PRC1 to the midbody, suggesting that the induction of p53 is a consequence of overexpressed PRC1 to interfere with the normal function of PRC1 during cytokinesis. Activation of p53 by PRC1 results in cellular senescence but not in apoptosis. In conclusion, while PRC1 is frequently overexpressed in many cancers, the p53 pathways may initially protect cancer cells from the negative effects of PRC1 overexpression on cytokinesis. Because depletion of PRC1 also results in p53-pathway activation and senescence, levels of PRC1 need to be tightly regulated to allow unperturbed proliferation. Targeting the expression or function of PRC1 could create a therapeutic vulnerability for the treatment of cancer.
Abstract
YAP, the key protein effector of the Hippo pathway, is a transcriptional co-activator that controls the expression of cell cycle genes, promotes cell growth and proliferation and regulates ...organ size. YAP modulates gene transcription by binding to distal enhancers, but the mechanisms of gene regulation by YAP-bound enhancers remain poorly understood. Here we show that constitutive active YAP5SA leads to widespread changes in chromatin accessibility in untransformed MCF10A cells. Newly accessible regions include YAP-bound enhancers that mediate activation of cycle genes regulated by the Myb-MuvB (MMB) complex. By CRISPR-interference we identify a role for YAP-bound enhancers in phosphorylation of Pol II at Ser5 at MMB-regulated promoters, extending previously published studies that suggested YAP primarily regulates the pause-release step and transcriptional elongation. YAP5SA also leads to less accessible ‘closed’ chromatin regions, which are not directly YAP-bound but which contain binding motifs for the p53 family of transcription factors. Diminished accessibility at these regions is, at least in part, a consequence of reduced expression and chromatin-binding of the p53 family member ΔNp63 resulting in downregulation of ΔNp63-target genes and promoting YAP-mediated cell migration. In summary, our studies uncover changes in chromatin accessibility and activity that contribute to the oncogenic activities of YAP.
YAP activation in cancer is linked to poor outcomes, making it an attractive therapeutic target. Previous research focused on blocking the interaction of YAP with TEAD transcription factors. Here, we ...took a different approach by disrupting YAP's binding to the transcription factor B-MYB using MY-COMP, a fragment of B-MYB containing the YAP binding domain fused to a nuclear localization signal. MY-COMP induced cell cycle defects, nuclear abnormalities, and polyploidization. In an AKT and YAP-driven liver cancer model, MY-COMP significantly reduced liver tumorigenesis, highlighting the importance of the YAP-B-MYB interaction in tumor development. MY-COMP also perturbed the cell cycle progression of YAP-dependent uveal melanoma cells but not of YAP-independent cutaneous melanoma cell lines. It counteracted YAP-dependent expression of MMB-regulated cell cycle genes, explaining the observed effects. We also identified NIMA-related kinase (NEK2) as a downstream target of YAP and B-MYB, promoting YAP-driven transformation by facilitating centrosome clustering and inhibiting multipolar mitosis.
Summary
Phospholipase D (PLD) and its cleavage product phosphatidic acid (PA) are crucial in plant stress‐signalling. Although some targets of PLD and PA have been identified, the signalling pathway ...is still enigmatic. This study demonstrates that the phosphoprotein At5g39570, now called PLD‐regulated protein1 (PLDrp1), from Arabidopsis thaliana is directly regulated by PLDα1. The protein PLDrp1 can be divided into two regions with distinct properties. The conserved N‐terminal region specifically binds PA, while the repeat‐rich C‐terminal domain suggests interactions with RNAs. The expression of PLDrp1 depends on PLDα1 and the plant water status. Water stress triggers a pldα1‐like phenotype in PLDrp1 mutants and induces the expression of PLDrp1 in pldα1 mutants. The regulation of PLDrp1 by PLDα1 and environmental stressors contributes to the understanding of the complex PLD regulatory network and presents a new member of the PA‐signalling chain in plants.
Significance Statement
This manuscript reports PLDrp1 protein as a target of PLD. This protein specifically binds to phosphatidic acid.
Summary Phospholipase D (PLD) and its cleavage product phosphatidic acid (PA) are crucial in plant stress-signalling. Although some targets of PLD and PA have been identified, the signalling pathway ...is still enigmatic. This study demonstrates that the phosphoprotein At5g39570, now called PLD-regulated protein1 (PLDrp1), from Arabidopsis thaliana is directly regulated by PLDalpha1. The protein PLDrp1 can be divided into two regions with distinct properties. The conserved N-terminal region specifically binds PA, while the repeat-rich C-terminal domain suggests interactions with RNAs. The expression of PLDrp1 depends on PLDalpha1 and the plant water status. Water stress triggers a pldalpha1-like phenotype in PLDrp1 mutants and induces the expression of PLDrp1 in pldalpha1 mutants. The regulation of PLDrp1 by PLDalpha1 and environmental stressors contributes to the understanding of the complex PLD regulatory network and presents a new member of the PA-signalling chain in plants. Significance Statement This manuscript reports PLDrp1 protein as a target of PLD. This protein specifically binds to phosphatidic acid.
Summary
Phospholipase D (
PLD
) and its cleavage product phosphatidic acid (
PA
) are crucial in plant stress‐signalling. Although some targets of
PLD
and
PA
have been identified, the signalling ...pathway is still enigmatic. This study demonstrates that the phosphoprotein At5g39570, now called
PLD
‐regulated protein1 (
PLD
rp1), from
Arabidopsis thaliana
is directly regulated by
PLD
α1. The protein
PLD
rp1 can be divided into two regions with distinct properties. The conserved N‐terminal region specifically binds
PA
, while the repeat‐rich C‐terminal domain suggests interactions with
RNA
s. The expression of
PLD
rp1 depends on
PLD
α1 and the plant water status. Water stress triggers a
pld
α
1
‐like phenotype in
PLD
rp1
mutants and induces the expression of
PLD
rp1 in
pld
α
1
mutants. The regulation of
PLD
rp1 by
PLD
α1 and environmental stressors contributes to the understanding of the complex
PLD
regulatory network and presents a new member of the
PA
‐signalling chain in plants.
Significance Statement
This manuscript reports PLDrp1 protein as a target of PLD. This protein specifically binds to phosphatidic acid.
PDF
