UH Cancer Center studies point to smarter ‘next-step’ use of antibody-drug treatment

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HONOLULU - Studies by researchers at the University of Hawaiʻi Cancer Center found that when breast cancers stop responding to a first antibody-drug treatment, changing the type of drug attached to the antibody can bring the treatment effect back in laboratory and animal models. The findings were presented at the prestigious San Antonio Breast Cancer Symposium on December 10, 2025, and offer clinicians a practical way to choose the next antibody-drug conjugate (ADC) treatment after progression.

An antibody-drug conjugate, or ADC, is a type of cancer treatment that works like a guided missile. Every ADC has two important parts. One part is an antibody that can find cancer cells by recognizing a unique marker on their surface - almost like a lock-and-key match. The second part is a very strong anti-cancer drug. The antibody carries this drug through the bloodstream and delivers it directly into the cancer cell.

Because the treatment is guided to cancer cells, it can attack the tumor more precisely and reduce the amount of medicine that reaches healthy tissues. Once the ADC attaches to its target on the cancer cell, the whole package is pulled inside, and the drug is released where it can do the most damage to the cancer.

However, several approved breast cancer ADCs use the same kind of drug (a DNA-targeting drug, topoisomerase I inhibitor). When these drugs are used in sequence, the treatment is not very effective in patients with metastatic breast cancer. The UH Cancer Center team found in a preclinical setting that this similarity can lead to cross-resistance. Crucially, switching to a different kind of cancer drug- a cell-division-blocking drug -combined to an antibody restored tumor control in resistant models.

"A simple takeaway is this: After a cancer progresses on one ADC, choose the next ADC with a different kind of drug," said Jangsoon (Jason) Lee, PhD, Associate Professor and Director of the Preclinical Core at the UH Cancer Center. "This drug-guided approach could help these smart treatments work longer for patients."

Lee presented the team's findings at the San Antonio Breast Cancer Symposium, considered the largest breast-cancer research meeting in the world. The symposium runs Dec. 9-12, 2025, in San Antonio, Texas.

Why it matters

• Rising use, hard choices: ADCs are being used in metastatic breast cancer care, but doctors have little evidence to guide which second ADC to use when the first stops working. Real-world reports suggest the second ADC often helps less if it uses the same drug type as the first.
• New insight: In lab models of both HER2-positive and triple-negative breast cancer, switching from a DNA-targeting drug to a cell-division-blocking drug restored tumor control - even though the tumors still displayed the same surface marker the antibody uses to find them. In plain terms, the problem wasn't the antibody locating and entering the cancer cell; it was that the original drug type had stopped working. Changing the drug type made the ADC treatment effective again.

"These findings by our University of Hawai'i Cancer Center research team show that drug resistance is not necessarily the end of the line for cancer patients," said Naoto T. Ueno, MD, PhD, Director of the UH Cancer Center. "Choosing the right kind of drug next could help more patients benefit from ADCs."

What the team did

The team built breast cancer models that had become resistant to two widely used ADCs, then tested follow-on ADCs that carried a different type of drug. In both lab dishes and mouse studies, this switch restored activity, supporting a practical drug-switching strategy after resistance.

What's next

The UH Cancer Center team is working with clinical partners to design studies that match the next ADC's drug to how a patient's tumor becomes resistant, aiming for longer-lasting benefit.

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About The University of Hawaiʻi Cancer Center

The University of Hawaiʻi Cancer Center is dedicated to saving lives in Hawaiʻi and the Pacific. It is inspiring hope by working to conquer cancer. The flagship priority is to understand and address cancer health disparities. The center strives to achieve this through research, education, patient care, and community outreach, focusing on the unique and diverse ethnic, cultural, and environmental characteristics of Hawaiʻi and the Pacific.

The UH Cancer Center is one of only 73 institutions designated by the National Cancer Institute (NCI), representing a significant mark of excellence, and is the only NCI-designated cancer center in Hawaiʻi and the Pacific. The center contributes more than $57 million to Hawai'i's economy through scientific research, clinical trials, and other activities.

As part of the University of Hawaiʻi at Mānoa, the UH Cancer Center operates out of facilities located in Kakaʻako. The center directly employs more than 300 faculty and staff, with an additional 200 affiliate members and cooperative agreements with organizations that are part of the Hawaiʻi Cancer Consortium. The consortium includes The Queen's Health Systems, Hawaiʻi Pacific Health, Kuakini Medical Center, Adventist Health Castle, Hawaiʻi Medical Service Association (HMSA), and the John A. Burns School of Medicine (JABSOM), all working together with the UH Cancer Center to advance cancer research and treatment in the state.

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