New Treatment Scheduling Strategy May Help Cancer Drugs Stay Effective Longer

Key Highlights

• Working to solve a long-standing challenge in cancer care, Moffitt researchers developed a mathematical framework for identifying treatment schedules that fight cancer while helping delay drug resistance, a process in which tumors gradually stop responding to therapy.
• Alternating periods of treatment with planned breaks kept tumors under control while helping the drug remain effective for longer.
• The findings suggest that adjusting when and how targeted therapies are given may help extend their effectiveness without necessarily changing the total amount of drug administered.

TAMPA, Fla. - Researchers at Moffitt Cancer Center have developed a new strategy for designing cancer treatment schedules that may help slow the development of drug resistance, one of the biggest challenges in cancer care.

The study, published in Cancer Research , was led by Jeffrey West, Ph.D., assistant member in Moffitt's Integrated Mathematical Oncology Department, in collaboration with senior author Alexander Anderson, Ph.D., director of the Center of Excellence for Evolutionary Therapy at Moffitt.

Many targeted cancer therapies work well at first but lose effectiveness as cancer cells adapt and become resistant. Researchers have long known that the amount of drug a patient receives matters, but West and his colleagues wanted to know if varying the treatment schedule, not just altering the dose, has an impact on how cancers build resistance.

They found that the curvature, or the shape, of a drug's dose-response curve can help predict whether a tumor is more likely to benefit from steady, continuous treatment, or from

schedules that alternate between higher and lower doses. A mathematical model that predicts how the curve changes in response to treatment provided a mathematical roadmap for identifying when switching dosing protocols could offer an advantage.

The team partnered with Andriy Marusyk, PhD, a researcher in the Tumor Microenvironment and Metastasis Department at Moffitt, who tested these predictions in mice with non-small cell lung cancer treated with alectinib, a targeted therapy used for tumors driven by ALK gene alterations. As expected, continuous dosing initially produced stronger tumor control than intermittent dosing schedules with the same overall drug exposure.

The researchers also found another effect. While continuous dosing produces the best immediate response, dosing schedules with periodic breaks in treatment appear to slow the development of drug resistance. The models suggested that when treatment was paused, tumors become responsive to the drug again, potentially allowing it to remain effective for a longer period.

Based on these findings, the researchers designed alternative dosing schedules that combined periods of continuous and intermittent treatment. While continuous dosing produced the strongest immediate tumor control, the researchers found evidence that intermittent treatment periods could help slow the development of drug resistance. By combining the two approaches, they developed hybrid schedules designed to balance short-term tumor control with the goal of keeping therapies effective for longer.

The strategy has not yet been tested in people, and additional studies will be needed before clinical trials can begin.

"By understanding how tumors respond to both drug dose and dose variation, we may be able to design treatment strategies that keep therapies working longer and delay the emergence of resistance," West said.

Q&A with Jeffrey West, Ph.D., senior and corresponding author, Integrated Mathematical Oncology Department, Moffitt Cancer Center

What led you to suspect that the timing and pattern of drug dosing could be just as important as the total amount of drug given?

The paper is based on the concept of antifragility, which states that any system is classified as antifragile if it receives some benefit from stress and volatility. This concept is the opposite of fragility: harm induced by stress. We hypothesized that tumors might be antifragile because they follow an evolutionary process which constantly adapts to new challenges. Secondly, we hypothesized that changes in treatment timing will alter the ability of a tumor to evolve, and thus, shifting it from antifragile to fragile.

Your study suggests that treatment breaks may actually help preserve a drug's strength. Why would that happen?

Treatment breaks have one beneficial effect and one harmful effect. A break in treatment allows the tumor to regrow. Yet, resistance mechanisms are often quite costly for a tumor cell to maintain, and these mechanisms are often lost during a break from treatment. It takes some time to regain the resistance mechanism again, allowing treatment to be more effective after a break in treatment.

What's next?

In this manuscript, we only tested fixed treatment schedules, but we know from our work at the Center of Excellence for Evolutionary Therapy at Moffitt that each patient has a unique, evolutionary response to response to treatment. We plan to use what we've learned about dose response curvature to design the next iteration of evolutionary therapies that are personalized to individual patient response dynamics.

This study was supported by the Cancer Systems Biology Consortium (U01CA232382, U54CA274507) and the Physical Sciences in Oncology Network (U54CA193489).

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