Tumor therapy: Guidance on apoptosis

19. November 2012
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Cancer treatment is usually based on the killing off of dividing cells. The easiest option to use would be where the tumour cells simply kill themselves via apoptosis. Using the support of a new substance, this now seems possible.

Undertaking a cancer treatment is, despite great experience, still a mode of treatment with uncertainties: How will a tumour respond to radiotherapy, or to chemo, or to cancer immunotherapy? How aggressive is a tumour? Which side effects will a patient get? For patients, aside from the latent fear of death the very strong associated side effects are often problematic.

“Often it is indeed such that an eight-week therapy leads to the prolonging of survival time by merely a few weeks. During this time many patients are only living for statistics, because they are in a very poor state”, says Prof. Dr. Bernhard Keppler, Dean of the Faculty of Chemistry, University of Vienna and head of the research platform Translational Cancer Therapy Research. A substance of a whole new class, a first-in-class compound, should now change matters. NKP-1339 is the name of the active ingredient which was developed as part of a joint project of the Faculty of Chemistry, University of Vienna and the Medical University of Vienna.

Apoptosis maintained

The substance attacks GRP78, the glucose related protein 78, a protein in cells which is responsible for waste collection: it disposes of misfolded proteins. If in a cell a certain amount of defective and misfolded proteins is exceeded then apoptosis is initiated, for example via the mitochondrial pathway. In tumour cells there are very very many misfolded proteins, but the accumulation of proteineous waste and purposeful cell death is prevented because production of GRP78 is upregulated in tumour cells. This mechanism, which is lethal to the organism, is suppressed by NKP-1339. Thus, the amount of GRP78 remains at a normal level and as soon as too much defective protein has accumulated, apoptosis is initiated.

Source: Prof. Dr. Bernhard Keppler

Preventing development of resistance

The possibility of developing resistance to drugs depends – among other things – on the fact that GRP78 is upregulated and damage-carrying cells are ensured their survival. Prof. Keppler explains: “We anticipate, as it were, a double benefit: on the one hand via regulation of the amount of GRP78 at a reasonable level, at the same time through a weakening in the development of resistance and therefore better effectiveness of other, combination-based enriched pharmaceutical preparations”, he says.

Good anti-tumour activity and high tolerability

In a completed phase I study, the scientists and doctors have now shown that the substance is cancer-inhibiting and well tolerated. About 30 patients were treated who had lung and colon carcinoma, head and neck tumours and neuroendocrine tumours, among others. With therapeutically relevant dosages there appeared only slight nausea and light fever as side effects – a good profile for an anti-cancer drug. Half of the patients responded to the therapy – a high rate considering that before inclusion in the study the patients were regarded as incurable and only had a short life expectancy.

NKP-1339 employed in a targeted manner

The low side-effect profile is probably related to the sophisticated mechanisms of transportation and action. NKP-1339 is a substance based on ruthenium. Ruthenium is a metal. It can, like iron, bind to the iron transporter transferrin. After infusion of NKP-1339, molecules bind within three minutes completely to albumin and transferrin. Since tumour cells, due to increased cellular respiration, show a greatly increased need for iron, and consequently a greatly increased transferrin receptor status, NKP-1339 is transported primarily and specifically to the tumour cells.

Furthermore in tumour cells a lower pH and a more reductive environment is to be found relative to healthy cells, due to its lactate metabolism. This situation is also taken advantage of by the scientists. Only through the reduction of Ru3+ to Ru2+ is the substance activated. This means that so long as NKP-1339 is bound to transferrin, it circulates in the body without affecting the tissue. On the other hand, in normal cells with physiological pH it is activated to only a minor extent.

Combination with established therapies is sensible

Prof. Keppler is now aiming for a phase II study, in which patients should especially be included who have tumours for which there are few treatment options. Particularly promising in phase I was the treatment of patients with neuroendocrine tumours. However for head and neck tumours and other cancers as well the treatment seems to be useful. “Compared to phase I data from now established therapeutics, such good results at such an early stage have rarely been seen. We are seeing a good response to therapy and good tolerance”, says Prof. Keppler. “What’s more we would like to soon study its interaction with other anti-cancer drugs”. Whether there are also clear benefits for patients when in combination with established therapies is still unclear. It will be just as interesting to then see whether other side effects occur, or if and how the side effect profiles of established therapies change. In the long term one will see whether interference with the mitochondrial pathway has effects elsewhere in the body.

New treatments effective

Obviously something is going on right now in the “tumour market”. As was reported a few weeks ago by DocCheck, immunisation using tumour-associated peptides against kidney cancer also seems to be effective. In the past, immunisation approaches failed regularly. Yet now it seems in many ways that new possibilities for the treatment of a wide variety of tumours and cancer are opening up.

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Medicine, Oncology

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2 comments:

Hanan Adel Hanan Adel
Hanan Adel Hanan Adel

This is very interesting.. keep up the good work.

#2 |
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very promising…will look forward to future reports

#1 |
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