Targeted Therapy: Farewell To The Chemo Cosh

5. June 2015

The world's population is getting older – and the presence of malignant diseases is increasing. Whereas chemotherapy, along with its only minor property of selectivity, previously occupied centre stage, researchers today seek to develop tailored therapies. The big leap from the lab to the field does not however always manage to be made.

Malignant diseases on the rise: in their World Cancer Report the World Health Organisation warns of dramatically increasing numbers. Researchers expect by 2030 to see about 21.6 million new cases, compared with 14 million in 2012. The number of deaths will rise as well, from 8.2 to 13 million. Top place in the list is held by lung cancer (13.0 percent), followed by breast cancer (11.9 percent), colorectal cancer (9.7 percent), liver cancer (9.1 per cent) and stomach cancer (8.8 percent). In addition to preventive measures used as part of a long-term approach, new tailor-made therapies are in demand. Studies show where the journey is going.

Virus hits cancer

Scientists at the German Cancer Research Center (DKFZ) in Heidelberg are taking the genus Parvovirus along with them on a tumour cell hunt. Parvovirus triggers serious illness in pets and livestock, but not in humans. Jürg PF Nüesch and his colleagues identified the enzyme PDK-1 (phosphoinositide-dependent kinase-1) as a potential target of attack. Without PDK-1 parvovirus is not able to multiply. In mice, the virus activates PDK1 via a mechanism that acts independently of growth factors. Healthy human cells do not express the key enzyme – and through this are protected. Things seem quite different with glioblastomas: in 36 percent of the examined tissue samples researchers found increased PDK1 levels. Cancer cells thus become independent of external growth factors, which makes biological sense. Externally supplied H1 parvovirus also benefit from this – and disintegrate malignant cells.

On the fast track to the tumour

Years will yet pass before the respective therapies arrive in the clinic. This is reason enough for scientists to optimise chemotherapy. Pulmonologists led by Sabine H. van Rijt, Munich, have developed nanocarriers intended for transporting known drugs in high doses to the lungs. Their artificial particles consist of a special envelope which was cleaved by proteases in the tumour tissue. These enzymes are missing in other areas of the lung and the nanoparticles remain intact. Used with targeted, highly-dosed application pharmaceutics would be more effective by a factor of 10 to 25 – without having serious consequences for the body. Nanoparticles can however do even more: already today doctors are working with a so-called nano-therm process using small iron oxide particles, which include a shell comprised of aminosilanes. The particles are introduced into tumours and heated by means of high frequency magnetic fields. This leads to the destruction of malignant cells.

Strong together

It’s not only with nanoparticles that molecular structures can be reached via targeted processes. Great potential is also tucked away in monoclonal bodies. The most recent example: the agent conjugate brentuximab with Hodgkin’s lymphoma. The primary treatment received by patients is indeed a combination of chemotherapy and radiotherapy. According to various publications the overall survival rate sits at between 80 and 90 percent. If, however, recurrences occur, high-dose chemotherapy plus stem cell transplantation remains an option – accompanied by a significantly poorer prognosis. As a further option, physicians now have brentuximab available to them. The conjugate includes an antibody against the CD30 antigen on tumour cells. The cytostatic monomethylauristatin E is present in addition to that. Local effects are primarily achieved via the chemical binding of these molecules. In their efforts to acquire approval researchers employed the antibody-drug conjugate in opposition to a placebo as a consolidation therapy for patients at high risk. The outcome was that median progression-free survival rate increased significantly from 24.1 to 42.9 months. Side effects occurred in the form of neutropenia and neuropathies. For this special group of patients there is nonetheless still great therapeutic value here.

Targeting instead of hitting with total flooding

This is not just one isolated case: with extremely rarely appearing adrenal carcinoma as well one pharmacological strategy involves the selection of suitable patient subgroups. Tumour cells produce, among other things, insulin-like growth factor 2 (IGF-II) on their surface. This gave good enough reason for researchers to seek out antagonists such as Linsitinib. However a phase III study involving 139 patients was disappointing: the oral compound when compared to placebo improved neither overall survival nor progression-free survival. Nevertheless, there were some surprises: four patients responded extremely well to the drug. For them, the disease was able to be controlled in each case for more than two years. And in three cases there was over the long-term a significant reduction in tumour mass – alongside surprisingly few side effects. Martin Fassnacht, Würzburg, Germany, presently plans further studies based on these results. He wants to find out what factors contribute decisively to the therapeutic effect – for instance, the influences of genetic information. Despite all the success there are still many challenges to overcome. But one thing is clear: targeted therapies are part of the future in the area of oncology.

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