Seattle Children's researchers are poised to launch clinical studies with aclarubicin, a less toxic chemotherapy, aiming to improve outcomes for children with high-risk leukemia and other cancers. The goal is to reduce the long-term toxicities associated with current treatments while maintaining efficacy.
The Need for Less Toxic Therapies
While cure rates for childhood cancers have improved, over 95% of survivors experience significant health issues by age 45. Common anthracyclines, like doxorubicin, can cause long-term effects such as heart problems, infertility, and secondary cancers. Dr. Jay Sarthy, a hematologist-oncologist at Seattle Children's, emphasizes the importance of reducing toxicity without compromising efficacy to improve the quality of life for young cancer survivors.
Aclarubicin: A Promising Alternative
Aclarubicin, an anthracycline widely used in Asia, has shown promise due to its safety and effectiveness. In preclinical studies, aclarubicin demonstrated superior cancer cell killing with reduced toxicity compared to doxorubicin. "We showed you can give this drug at the highest levels ever administered, and we had 100% survival in the model. It just shows how promising it could be," said Dr. Sarthy.
Molecular Mechanism and Reduced Cardiotoxicity
Research indicates that aclarubicin's mechanism of action differs from doxorubicin. While both drugs kill rapidly dividing cancer cells, doxorubicin also damages DNA and dislodges histones, leading to cardiotoxic effects. Aclarubicin primarily damages chromatin, the structure controlling gene expression, without directly damaging DNA, potentially reducing the risk of long-term heart problems.
Clinical Trial Plans and Regulatory Hurdles
Dr. Sarthy is collaborating with international teams to develop aclarubicin clinical trials at Seattle Children's and Fred Hutchinson Cancer Center. The drug is not patentable, posing a challenge for funding clinical trials due to lack of industry investment. Once approved by the FDA, Dr. Sarthy plans to import the drug from China, leveraging data from Chinese oncologists to optimize dosing and identify target cancers. Initial trials will focus on demonstrating safety, followed by consortium trials to assess efficacy and combination therapies.
Collaborative Research Efforts
Dr. Sarthy is working with multiple teams to further understand aclarubicin's mechanism of action. These collaborations range from testing the drug in zebrafish models to planning clinical trials, integrating basic research with clinical applications. "We're doing everything from testing aclarubicin in zebrafish to ultimately running clinical trials, and to me, that’s the most exciting thing — being able to study the basic mechanism and then seeing how the drug does in patients," he said.
