Overcoming Drug Resistance to Treat High-Risk Neuroblastomas
Abstract
Neuroblastoma (NB) is the most common and deadly solid tumor of childhood, accounting for 8%-10% of pediatric cancers and 15% of childhood cancer deaths. The clinical behavior is heterogeneous, from tumors that spontaneously regress and disappear to tumors that grow relentlessly. Over half of all NBs fall into a high-risk category and have a 40% survival rate, despite aggressive therapy that includes surgery, radiation therapy, chemotherapy, immunotherapy, and stem cell transplantation. Despite this intensive therapy, over half of these patients do not survive, frequently because they are either resistant to therapy initially, or they acquire drug resistance following initial treatment. Also, survivors frequently have serious short- and long-term toxicities that can be life-threatening or debilitating. Therefore, we need novel approaches to therapy that are more effective and less toxic than currently used therapy and which can overcome common mechanisms of drug resistance. Less than 1% of most chemotherapy agents actually reach the tumor, which explains why they do not always work. Also, most drugs are small and quickly infiltrate normal tissues and organs, which explains why patients experience significant side effects. We have developed a compound (PEG-[SN22]4) that is related to a clinically used chemotherapy agent, irinotecan, but it has several distinct advantages. First, our agent is designed to stay in the circulation for a long time, which allows much more of the drug to accumulate in the tumor, but it prevents drug accumulation in most normal tissues. We can achieve drug levels in the tumor that are 50-100 times higher than those achieved with the same dose of a conventional agent (irinotecan). Second, irinotecan is converted in the liver to SN38, which is an active agent, but our compound delivers four SN22 molecules directly to the tumor. SN22 is chemically designed so it cannot be easily pumped out of the cancer cells, and it cannot be easily inactivated and removed from the tumor. This means the drug concentrations in the tumor are much higher, and they last a longer time, so this overcomes many common mechanisms of drug resistance. We plan to test PEG-[SN22]4 to treat neuroblastoma in different animal models of high-risk NB. This includes new tumors that occur spontaneously and have never been treated as well as tumors derived from recurrences, so they are more likely to be drug resistant and difficult to treat. We have already shown that our compound can completely eradicate tumors in some models using just four weekly doses of the drug given intravenously. We plan to treat tumor models that are harder to treat, to test different doses and schedules of this agent, and to determine what, if any, toxicities occur to normal tissues and organs after treatment. We know it is unlikely that any single drug or compound will cure high-risk NBs in patients, especially once they have become drug resistant. Therefore, we also plan to treat the most challenging NB tumor models with our compound combined with at least two other agents (temozolomide or olaparib) that should enhance the efficacy of SN22 treatment. Based on our preliminary studies, we expect this agent to be much more effective against tumors and much less toxic to patients than irinotecan or related chemotherapy agents. Although tested here in high-risk NB models, we also have preliminary evidence that this compound is equally effective in treating other high-risk solid tumors in children, such as rhabdomyosarcoma or Ewing sarcoma, and it could potentially be used to treat other solid tumors in children, adolescents, or even adults. The impact of our studies is considerable, as this compound can achieve both greater efficacy and less toxicity than conventional treatment, saving lives, and reducing side effects. Furthermore, we have already partnered with PEEL Therapeutics to bring PEG-[SN22]4 to a phase 1 clinical trial. The preliminary studies sup
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110536
Entities
People
- Garrett M Brodeur
Organizations
- United States Army