New Potential Therapeutics, Including BT169, Open Options in Osteosarcoma

Integrated proteomic and transcriptomic surfaceome profiling have helped identify new targets in osteosarcoma, which may in turn help in manufacturing new drug conjugates, such as the MT1-MMP–targeting Bicycle toxin conjugate BT169, for a patient population with quite an unmet need, according to Richard Gorlick, MD.

In the preclinical analysis, investigators identified 1156 highly expressed surface proteins in osteosarcoma cell lines and patient-derived xenograft tissues through quantitative mass spectrometry.¹ While 129 overexpressed proteins were identified through the public mass spectrometry database, RNA sequencing data identified 195 overexpressed plasma membrane–associated genes in osteosarcoma vs normal tissue.

In particular, 3 targets were validated: MT1-MMP, CD276, and MRC2. MT1-MMP was prioritized by investigators due to having the highest absolute expression level in osteosarcoma.

Gorlick said that not only could these findings pave the way for incorporating established agents into osteosarcoma treatment strategies, but also open opportunities to develop new toxin conjugates.

“Next, [we are] going to be testing several [other targets]to see if there is potential there, as well,” said Gorlick, a senior author on the study. “A number of protein targets have been identified that are not even associated with known drugs. Our hope is that by vastly increasing the number of drugs that are available to treat [patients with] osteosarcoma, we are going to make progress in the treatment of this [patient population].”

In an interview with OncLive during the virtual 2021 AACR Annual Meeting, Gorlick, head of the Division of Pediatrics at The University of Texas MD Anderson Cancer Center, expanded on the process of identifying these novel targets in osteosarcoma and the clinical implications of this research for these patients.

OncLive: What has been the challenge of utilizing ADCs in osteosarcomas?

Gorlick: Osteosarcoma is a disease where we need new treatments, and a few ADCs have been [examined]. The challenge has been that, prior to this work, we did not know a lot of the surface targets that were relevant. A [few] were tested just because they had a little bit of expression in osteosarcoma and were known to be expressed in more common cancers. Most notably, HER2 has a little bit of expression in osteosarcoma; that is obviously a very well-known target in breast cancer.

We have tried, but they have not worked that great, [partially] because there is not enough of the protein target on the cells’ surface to drive the effectiveness of those treatments. There are more attempts at trying to target those [types] of proteins, but we think the proteins that have been identified will be even better and are much more promising.

What methods were utilized to help identify these targets?

The method that was predominantly used to analyze the proteins was mass spectrometry to analyze the proteins, both on whole protein extracts, as well as membrane extracts from patient-derived osteosarcoma xenograft models. These were human tumors that were [implanted] in immunocompromised mice [and allowed] to grow. They faithfully recapitulate osteosarcoma that we get from patients directly.

We were able to analyze those models comprehensively, and then we went back to patient samples to confirm that the proteins we saw expressed in the models are truly expressed on the tumors that come from human patients. We then tested the drugs on the model systems.

What were some of the key findings from this research?

At the 2021 AACR Annual Meeting, [we] presented the results of the proteomic profiling, [which identified] a large number of targets on the surface of the osteosarcoma. A couple of targets had been identified previously, and it supported our view that we may be onto something.

[At this meeting, we reported information about] the first drug that nobody really thought about testing in osteosarcoma, and it is only being tested there because of the results of this research. It is the product [BT1769, which] that targets the protein MMP14. There is a company [called] Bicycle Therapeutics that makes a drug that targets this. We are reporting the testing of that drug in preclinical models. What is really nice is [that] we have identified a drug that seems to work in preclinical models. We used that to validate the system, which suggests that we may have other targets that we can look into, as well.

Is there anything else you would like to add about this agent?

[BT1769] is actually a drug that is already in human clinical trials. It has gone through phase 2 trials [and] made it through its phase 1 safety studies. We know this is a drug that is tolerable in humans. One of the things we did to find the proteins is actually after we looked at what is abundantly expressed, we looked at what is expressed on normal tissues and confirmed that there is a differential expression at a minimum between what is on the tumor and what is in normal [tissue].

From there, I would highlight that osteosarcoma is treated with chemotherapy—standard cytotoxic agents. ADCs bring the drug to cells that express a particular target, which offers a potential advantage; the cytotoxic aspects of it do not go through the whole body. Our hope is even if it is [utilizing] the same types of drugs, the adverse effects will be less. Treatment for patients with osteosarcoma is rough.

Reference

1. Wang Y, Zhang W, Zhang Z, et al. Integrative surfaceome profiling identifies immunotherapeutic targets in osteosarcoma and preclinical testing of BT1769, an MT1-MMP-targeted Bicycle^® toxin conjugate, in osteosarcoma by the Pediatric Preclinical Testing Consortium (PPTC). Presented at: 2021 AACR Annual Meeting; April 10-15, 2021; virtual. Abstract LB008.