| 1. |
- Ulfarsson, Elfar, et al.
(författare)
-
Expression and growth dependency of the insulin-like growth factor I receptor in craniopharyngioma cells : A novel therapeutic approach
- 2005
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 11:13, s. 4674-4680
-
Tidskriftsartikel (refereegranskat)abstract
- Craniopharyngioma is a rare benign intracranial epithelial tumor that, however, often recurs and sometimes kills the affected patients, one-third of which are children. In many cases, the patients acquire growth hormone deficiency and postoperatively need substitution. Generally, growth hormone promotes local release of insulin-like growth factor I (IGF-I), which in turn activates the IGF-I receptor (IGF-IR) if present. Together, these circumstances raise the question whether IGF-IR may be involved in craniopharyngioma growth. To address this issue, we analyzed phenotypically well-characterized primary low-passage craniopharyngioma cell lines from nine different patients for IGF-IR expression and IGF-I dependency. Two of the cell lines showed no/very low expression of the receptor and was independent on IGF-I, whereas five cell lines exhibited a strong expression and was clearly contingent on IGF-I. The two remaining cell lines had low receptor expression and IGF-I dependency. Upon treatment with an IGF-IR inhibitor, cells with high IGF-IR expression responded promptly with decreased Akt phosphorylation followed by growth arrest. These responses were not seen in cells with no/very low receptor expression. Growth of cell lines with tow IGF-IR expression was only slightly affected by IGF-IR inhibition. Taken together, our data suggest that IGF-IR may be involved in the growth of a subset of craniopharyngiomas and points to the possibility of the involvement of IGF-IR inhibitors as a treatment modality to obtain complete tumor-free conditions before growth hormone substitution. © 2005 American Association for Cancer Research.
|
|
| 2. |
- Girnita, Ada
(författare)
-
Targeting insulin-like growth factor-1 receptor in cancer
- 2004
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a multi-step process where the accumulation of several genetic and epigenetic alterations drives the transformation of a normal cell to a malignant cell, skipping the normal control of defense, repair and apoptosis. During the selection process towards a malignant phenotype, the transforming cells make use of normal (physiological) extracellular signaling pathways to create growth advantage over normal cells. In this context, insulin-like growth factor 1 receptor (IGF-1R) emerges as an important factor responsible for the transformation and proliferation of malignant cells. IGF-1R confers protection against apoptosis, maintains the malignant phenotype, and defends against antitumor therapy. In contrast, the IGF-1R is not an absolute requirement for normal cell growth. The multiple functions of IGF-1R in cancer development coupled with its redundancy in maintaining cell growth make this receptor an attractive target for cancer treatment. Until recently there were multiple strategies to block the IGF-1R pathway in order to prevent growth and to increase apoptosis of malignant cells. However, none of them has so far presented the necessary requirements for clinical use. In this context, co-inhibition of the highly homologous insulin receptor cannot be accepted for a pharmaceutical agent. This study presents two different principles to specifically target the IGF-1R One is to modulate physiological mechanisms to degrade and therewith inactivate the receptor. This approach is still at a basic research level. The other principle is a small molecule strategy to reduce the catalytic activity of IGF-1R. Relating to the first principle, we recently showed that the oncoprotein MDM2 serves as a ligase (E3) in ubiquitination of IGF-1R. We demonstrated a physical association of IGF-1R to MDM2 and that a mixture of MDM2 and IGF-1R in an in vitro assay resulted in ubiquitination of IGF-1R. IGF-1R. In cultured cells, an increase in MDM2-mediated IGF-1R ubiquitination caused degradation of the receptor and induced cell death. The IGF-1R ubiquitination may be involved in receptor function and open the possibility of modulating this processing to block the receptor activity and therewith cause tumor regression. Relating to the second principle, we identified a small molecule (PPP) that specifically inhibited tyrosine phosphorylation of IGF-1R and induced apoptotic cell death in a selective manner. PPP interfered with the activation loop of the receptor kinase and did not affect the ATP binding. It decreases the activities of the two major signaling pathways (P13K and MAPK pathway) in an IGF-1R I specific manner and provoked a strong G2 arrest in vitro systems. It had a remarkably inhibitory effect in tumor growth in vivo and decreased the metastasis potential both in vivo and in vitro in IGF-1R 1 positive tumor cells. The obtained results of this thesis highlight the possibility to target the IGF-1R as a therapeutic option for cancer.
|
|
| 3. |
- Krakowski, Isabelle, et al.
(författare)
-
Association of metformin use and survival in patients with cutaneous melanoma and diabetes
- 2023
-
Ingår i: The British journal of dermatology. - : Oxford University Press (OUP). - 1365-2133 .- 0007-0963. ; 188:1, s. 32-40
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive.OBJECTIVES: To investigate the association between metformin use and survival among patients with CM and diabetes.METHODS: All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses.RESULTS: Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4-6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57-0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS: the HR for prediagnostic use was 0.90 (95% CI 0.86-0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97-0.98) for 0-6 months to 0.59 (0.49-0.70) for 24-30 months of use. No association was found for metformin use and MSS.CONCLUSIONS: Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose-response pattern. However, further research regarding the underlying mechanisms is warranted.
|
|
| 4. |
|
|
