Nowadays, most cancer drugs target a protein or inhibit a critical cellular process. Modern therapies have varying levels of success, but often we overlook something. How these drugs get to the tumor.
As of now, the most common way to get a drug to a tumor is to target a protein that the tumors are overexpressing, or relying on a tumor’s general high resource demand. The drug would then be injected into the patient, and circulate through the bloodstream until it reaches the tumor. In the case of melanoma, there may be a better way of targeting therapies to tumors.
In-transit melanoma is a rare and dangerous type of skin cancer. There are chemo- and immunotherapies that could treat it, but a team from the Mayo Clinic in Florida wanted to try another route. They intended to develop a modern interpretation of an old school treatment for in-transit melanoma, called isolated limb infusion. It involves the direct injection of high dose chemotherapy directly into the affected area via a catheter. There tended to be high response rates to this older method, but results were not consistent.
The team redeveloped the method by effectively controlling the flow of blood in a tumor. They note that tumors often have non-functioning or closed blood vessels, which, if opened, may allow a drug to have increased exposure to the tumor itself. They developed a protocol of injecting saline bolus (a salt solution) followed by two phenylephrine (a vasoconstrictor) injections. The saline bolus would initiate a significant increase in blood flow through the tumor vasculature, while the phenylephrine would slow the blood flow afterward. They termed this dynamic control.
The team tested their method in a melanoma mouse model. The mice were treated with a negative control, dynamic control alone, the drug melphalan alone, or a combination of dynamic control and melphalan. The combination therapy had the best results, significantly outcompeting melphalan alone. Dynamic control was surprisingly better than the negative control used, although still nowhere near as effective as melphalan or combination therapy.
Other studies have done similar experiments, using vasoconstrictors (phenylephrine in this study’s case) to increase the effectiveness of a chemo- or immunotherapy. This study combined this with a targeted approach and was the first to measure the actual changes in blood flow during the procedure. While the method worked well in combination with chemotherapy, there was an interesting increase in survival for mice with dynamic control alone. The team postulates this could be due to increased immune activity, as dynamic control technically increases a tumor’s overall blood exposure.
The study concludes, “…we provide the first evidence that dynamic control of tumor vessels was feasible and directly observable via IVM using our protocol of volume expansion (saline bolus) plus phenylephrine.” They say this increased the effectiveness of drug delivery to the tumor, thereby improving the therapy overall. The best thing about this method is that it could work for many tumor presenting cancers, not just for in-transit melanoma.
Sources: Nature Scientific Reports, Moffit Cancer Center
