Researchers investigating new neuroblastic treatments – one of the most common childhood carcinoma – have found that the combination of two drugs produced tumors disappears in mice, making it more effective than any other drug tested on these animals.
Professor Murrai Norris, deputy director of the Australian Institute of Child Research, Sydney, Australia, said today (Thursday) at the 30th EORTC-NCI-AACR Symposium on Molecular Targeting and Cancer Therapy in Dublin, Ireland, that the findings were unusual and very significant. However, he warned that it would take some time before the combination of drugs is tested in children and, if successful, become available more widely to treat children of this disease, although both drugs are currently undergoing clinical trials in a range of adult adult cancers.
Neuroblastoma is one of the most common carcinoma in children and is the leading single cause of death in children under five years of age. It is often found in the adrenal glands at the top of the kidneys. Despite the use of intense regimens of treatment, children with the most aggressive forms of neuroblastoma have less than 50% survival rates.
Prof Norris said: "In order to investigate neuroblastoma in the laboratory, we used a genetically modified neuroblastoma mouse model that closely recapitulates the clinical characteristics of the disease, and these mice spontaneously develop neuroblastomas within a few weeks after delivery. We found that when we combined CBL0137 and panobinoostat for the treatment of neuroblastoma mice, tumors have disappeared and never returned during the entire experiment, while tumors continued to grow in mice who did not receive treatment or just treatment for the drug.
"This is a very important finding because this combination of drugs is the most effective therapy we have seen in this mice model of neuroblastomas. It is unusual to see this effect, especially in these mice where it develops neuroblastly within seven weeks of labor and is aggressive in the U, CBL0137 / panobinostat is more effective than any other current combination of clinical chemotherapy that our laboratory tested in these mice. "
CBL0137, belonging to a new class of drugs called curaxins, attacks the structure of cancer cells, but is a safe drug that does not damage DNA in normal cells. Prof Norris and his colleagues used RNA sequencing technology to detect changes in drug-induced tumors to see that the combination of CBL0137 and panobinostat inhibits neuroblastoma growth.
"Our results suggest that these drugs work through two different mechanisms that offer a double attack, one of these mechanisms being a direct attack on the cancer cells itself, killing them by inhibiting DNA repair, and then another mechanism is involved, causing a robust immune response. This is very exciting and we hope to facilitate the clinical development of effective and non-toxic treatments for childhood cancer, "he said.
"Unlike conventional chemotherapy drugs that interact with DNA, CBL0137 is harmful to non-DNA and is therefore relatively less toxic. The development of CBL0137 combined therapies has the potential to reduce acute and long-term undesirable effects and increase the quality of life of children with cancer by extending survival rates for these children Another important implication is that the CBL0137 / panobinostat combination can activate an immune response that can significantly increase the effectiveness of immunotherapeutic drugs that are otherwise not effective for neuroblastoma. "
Researchers continue their laboratory work to further investigate how the combination of these two drugs activates the immune response and tests CBL0137 / panobinostat with other immunotherapeutic drugs in mice. In the clinical trial of phase I CBL0137 in children with neuroblastoma and other severe treatments in children, it is planned to start in 2019, after completion of clinical phase I trial in adults with solid carcinoma and pre-treated blood cancers. The trial of CBL0137 only in children should be successfully completed before testing the combination of two drugs can be planned, which means it will be several years before it is known whether the therapy can be used wider.
Further laboratory studies by Professor Norris and colleagues also showed that CBL0137 and panobinoostat slowed the growth of aggressive leukemia in childhood in mice and significantly increased survival.
In addition to the approval of CBL0137 for phase I clinical trials in adults, the FDA has already approved a panobiostat for multiple myeloma and is being tested in clinical trials for a range of other cancers.
Co-Chair of the EORTC-NCI-AACR Symposium, Dr James L. Gullei, who is the head of the NIH / NCI Cancer Research Center in the United States, who is an expert in immunotherapy for cancer, but who was not involved in this study, commented: "Although this is the result of work done in code mice, they are very interesting and point to the exciting possibility that this combination of drugs can work more efficiently than single agents in children with this rare but aggressive tumor, in patients desperately needing better treatments. We expect the results of clinical trials with interest Vanja. "
Way of directing Achillon heel neuroblastoma
Abstract no. 24, "Destabilization of chromatin by the CBL0137 and panobinoostat leads to a complete regression of the tumor of neuroblastomas of the child in immunocompetent transgenic mice." Posters in the center of attention, exhibition hall, 13.00, Thursday, November 15th.