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Department of Oncology
Division of Clinical Tumour Immunology
Department of Pathology and Cytology
Department of Clinical Chemistry
The protein Bcl-2 was originally described in association with B-cell lymphoma. Today Bcl-2 is considered a key antiapoptotic factor that can prevent or delay the onset of programmed cell death. As antitumour reactivity generally results in tumour cell apoptosis, inhibition of apoptosis is probably an important mechanism by which tumour cells in melanoma can escape therapeutic control.
A prognostic significance of Bcl-2 expression has been reported in primary melanomas, with higher Bcl-2 expression in melanomas that later metastasised.(1) Similarly, in patients with regional lymph node metastases, Bcl-2 positivity was associated with significantly shorter survival.(2) However, others found no prognostic value of Bcl-2 expression.(3) A link between Bcl-2 expression and therapeutic efficacy has been reported, as vaccination with a genetically modified interleukin (IL)-2-producing melanoma cell line resulted in tumour cell apoptosis only in Bcl-2- negative areas and not in Bcl-2-expressing parts of the metastases.(4) As previously demonstrated, Bcl-2 seems to play a major role in the resistance of malignant melanoma to biochemotherapy by protecting tumour cells from induction of apoptosis, as significantly higher Bcl-2 protein expression was observed in metastases of biochemotherapy-treated patients, compared with untreated individuals.(5) In another recent study, researchers in our team compared, at mRNA and protein levels, Bcl-2 expression after biochemotherapy with expression in untreated patients. Significantly higher Bcl-2 mRNA expression was found among untreated patients, showing a discrepancy with our previous results, where the highest Bcl-2 expression at the protein level was found in the group of treated patients (unpublished data). Discrepancies between detection of Bcl-2 protein and mRNA expression have been reported in several studies, for example, in prostate cancer,(6) lymphoid tissue(7) and sentinel lymph nodes from melanoma patients.(8) The detection of high Bcl-2 mRNA and low protein levels suggests a regulation mechanism at the post-transcriptional level.
Several reports have shown the promising possibility of downregulating Bcl-2 using antisense oligonucleotides in various malignancies.(9–15) A recent large randomised phase III trial in metastatic malignant melanoma comparing the addition of Bcl-2 antisense therapy, oblimersen sodium (Genasense), to the widely used chemotherapeutic drug dacarbazine (DTIC) produced important responses and showed a significant benefit in progression-free survival. However, the study failed to show a benefit in overall survival compared with DTIC alone.
Despite various treatment strategies being investigated over the years, prognosis is still poor for the majority of patients with systemic malignant melanoma. A better understanding of the mechanisms by which tumours escape therapeutic control is needed, as are new treatment modalities. There is also a need for predictive tests identifying patients with a high probability of responding to different treatment modalities, and for tests that monitor patients during treatment to individualise future treatment schedules better.
Our research team has previously shown the importance of the amount of tumour-infiltrating CD4+ lymphocytes analysed from a fine-needle aspirate before start of treatment to be a responder to interferon-alpha as a single drug or to biochemotherapy.(16,17) In the later study, the amount of CD4+ lymphocytes also showed a significant correlation to time to progression and to overall survival.
As demonstrated in a previous report, Bcl-2 seems to play a major role in the resistance of metastatic malignant melanoma to biochemotherapy.(5) In the study, all 10 patients treated showed a high expression of Bcl-2 by tumour cells in areas of unaffected tumour growth. In contrast, in untreated patients, a high expression of Bcl-2 by tumour cells in these areas was found in five out of 13 patients only. The significantly higher expression of Bcl-2 by tumour cells in areas of unaffected tumour growth after therapy compared with untreated patients showed the possibility that clones with a high expression of Bcl-2 are protected from apoptosis, which in many patients eventually results in progressive disease. Supporting this concept, the study also showed a difference in Bcl-2 expression in areas of unaffected tumour growth (ie, in areas of treatment failure) and of histopathological regressive changes. We found these observations to be compatible with a clonal selection, leaving Bcl-2 positive tumour cells unaffected after biochemotherapy.
We previously reported on the importance of analysing the amount of regressive changes in metastases after biochemotherapy, as extensive regressive changes after treatment (ie, >-75% of the section area) showed a significant correlation with increased overall survival.(18) However, even in the group of melanoma patients with important durable remissions, many will eventually have recurrences, showing the need for additional treatment, such as Bcl-2 antisense therapy in the group showing remaining Bcl-2 positive clones after biochemotherapy.
Thus, the analysis of Bcl-2 expression in melanoma metastases, both at protein and mRNA levels, before initiation of Bcl-2 antisense therapy seems to be of importance for selecting the right patients benefiting the most from this treatment strategy. The monitoring of the same parameters during treatment would increase the knowledge of treatment effects, thus leading to better individualised treatment schedules for the future.
There is still a great need for a better understanding of the mechanisms of tumour escape during treatment to optimise the combination of different treatment modalities. Thus, to achieve this goal, the choice of treatment modality and schedule has to be based on careful individual monitoring before entering a patient into a trial. For example, in immunotherapy trials, analyses of tumour-infiltrating inflammatory cells should be performed and Bcl-2 positivity should be monitored when Bcl-2 antisense therapy is the treatment of choice (both measurements should be carried out when combined treatment modalities are used). This would considerably increase the cost–benefit of the treatment strategies chosen in terms of patient adverse reactions and healthcare costs. These approaches will also allocate “the right patient to the right trial”, thereby reducing the need for a high number of patients included in a trial to show any benefit or extensive trials being performed over years without showing significant benefit due to the heterogeneity in the patient population entering the trial.