Treatment formulated by researchers at the Children’s Hospital of Philadelphia (CHOP) demonstrate success in overcoming drug resistance and lesser toxicities for aggressive tumours.
High-risk solid tumours like neuroblastomas, Ewing sarcoma, and rhabdomyosarcoma are difficult to cure due to the lack of response to therapy. Conventional chemotherapy administered through the vein or orally is only able to deliver a small amount of treatment to the tumour, rendering the treatment ineffective. Drug resistance and occurrence of severe side effects such as diarrhoea, bone marrow suppression and secondary malignancies are some challenges that researchers are battling to overcome.
A recent breakthrough study by researchers at CHOP have discovered an enhanced treatment developed in their lab able to result in long-term remissions in 80 to 100 percent of mice with drug-resistant or high-risk solid tumours. The study was published in Cancer Research, a journal of the American Association for Cancer Research.
The researchers developed a prodrug, which is only converted into a pharmacologically active drug in the body. This active drug belongs to a family of camptothecins which are known to promote cell death and destroy tumours. Other common forms of this drug are well-known for it high-toxicity and limited efficacy. In order to overcome these two limitations, the team formulated a prodrug that links four residues of a pharmacologically enhanced drug, SN22, through a breakable bond to a four-arm polyethylene glycol scaffold. The structure of SN22 enable the extension of the drug’s circulation time, allowing 50 to 100 times more uptake of the drug by the tumour.
Modifying its structure also protects SN22 from inactivation by external enzymes as well as being transported out of tumour cells by cell transporters. Taken together, the modifications assist in accumulation of the drug in the tumour cells.
Having tested on several mouse models, the research team found that delivery of the new drug resulted in complete clearance of the tumour in all models together with complete remissions which lasted for more than six months within 80 to 100 percent of all cases.
“The results of our studies show that the cancer therapeutic we developed is highly effective in treating at least three different types of high-risk paediatric solid tumours with intrinsic or acquired drug resistance," said Garrett M. Brodeur, MD, Director of the Cancer Predisposition Program at CHOP and co-senior author of the study, along with Michael Chorny, PhD, and Ivan Alferiev, PhD.
“Given that this treatment is also likely to be much less toxic than most cancer therapies for these types of tumours, in addition to showing remarkable therapeutic effects against aggressive disease, we think these results warrant further exploration of the agent in clinical trials." Added Dr Brodeur.
This novel prodrug was also tested to be less toxic when compared to other compounds from the same drug family. By contrast, the SN22 prodrug displayed fewer adverse effects and reduced exposure to healthy organs.
“Taken together, the superior efficacy and improved biocompatibility of our prodrug, which we demonstrated in several clinically relevant models of high-risk cancer, make it a highly promising new therapeutic capable of addressing the considerable limitations of current treatments," said Dr Chorny.
“Our strategy is readily scalable, and we look forward to assessing its effectiveness and safety in patients."