A preclinical study conducted by researchers at the University of Texas MD Anderson Cancer Center shows that an antibody-drug conjugate (ADC) that targets the surface protein MT1-MMP can act as a guided weapon in the eradication of osteosarcoma tumor cells can function without damaging normal tissues. This technology, which uses precision therapy targeting of cell surface proteins by a bicycle toxin conjugate (BTC), shows encouraging results for the treatment of osteosarcomas.
The results of the study were presented today by Dr. Yifei Wang, a pediatric research postdoctoral fellow, presented at the American Virtual Cancer Research Association (AACR) annual meeting. The study was conducted by Dr. Richard Gorlick, chairman and department head of, heads Pediatrics.
Osteosarcoma is the most common type of bone tumor in adolescents and young adults. The outcome of patients with osteosarcoma has not improved in the last few decades since the introduction of adjuvant chemotherapy.
Few alternative treatments are available for patients who cannot tolerate the side effects of chemotherapy. While novel immunotherapies have shown promising efficacy in hematological malignancies such as leukemia and lymphoma, little progress has been made in osteosarcoma in recent years.
It’s a novel approach to osteosarcoma and we now have the opportunity to explore new treatment options. This discovery represents a paradigm shift that will help us move faster. I anticipate there will be an influx of other drugs that can be tested, and since the drugs target a specific surface protein, they may be more effective and have fewer side effects. “
Richard Gorlick, MD, chairman and director of pediatrics
In this study, researchers developed an integrated bioinformatic approach using proteomic and transcriptomic data compiled from profile data from osteosarcoma cell lines, mouse models, hundreds of patient tumor samples, and thousands of normal human tissues. This approach identified surface proteins that are highly expressed on the surface of osteosarcoma cells but not in normal tissues. Results of analytical laboratory technology confirmed that specific proteins could be therapeutically targeted by ADC or BTC.
The team had previously identified four surface proteins, MT1-MMP, MRC2, CD276 and LRRC15, that were highly expressed on the cell surface of the osteosarcoma, but not in normal human tissues. A previous evaluation of CD276 and LRRC15 ADC showed encouraging antitumor activity and confirmed the research team’s approach.
In this study, researchers focused on MT1-MMP as a drug target and validated the expression of the target in patient samples. They then tested an MT1-MMP-directed BTC, BT1769, in preclinical osteosarcoma mouse models. The drug was found to be highly active in preclinical testing, with 50% of the mice showing a 100% improvement in response.
“We are thrilled with these results because this target and drug have not previously been reported in osteosarcoma,” said Wang. “This is the first in a series of other proteins identified by the same method.”
If this research is successful in clinical trials, it may open up new avenues for the treatment of osteosarcoma with higher efficacy and minimal toxicity. Gorlick and his lab are also working with MD Anderson’s Therapeutics Discovery team on new approaches to targeting antibodies.
The University of Texas MD Anderson Cancer Center