Preclinical Data Highlight YAP1 and KRAS as Drivers in Soft Tissue Sarcomas

R. Lor Randall, MD, FACS, sat down for an interview with OncLive® to discuss preclinical research aimed at identifying therapeutic vulnerabilities in soft tissue sarcomas.

In the interview, he detailed collaborative efforts to develop murine models for sarcoma subtypes, highlighted the identification of key genetic drivers such as YAP1 and KRAS in pleomorphic and myxofibrosarcomas, and outlined the translational potential of targeting these pathways with commercially available inhibitors.

“These preclinical mirroring mouse models are exciting because they take us to a new frontier away from conventional cytotoxic therapy," Randall said.

Randall currently serves as the David Linn Endowed Chair for Orthopedic Surgery, chair of the Department of Orthopedic Surgery, and a professor at the University of California (UC) Davis Comprehensive Cancer Center in Sacramento, California.

OncLive: What are the current preclinical research efforts in identifying therapeutic vulnerabilities in soft tissue sarcomas, particularly regarding genetic drivers?

Randall: Some of the lab work that's going on in our group is collaborative with other centers as well, looking at preclinical models of sarcoma development as defined by genetic drivers. We are trying to figure out therapeutic vulnerabilities for these soft tissue sarcomas.

The background here is that there are basically 2 categories of sarcomas. There are translocation, and derivative sarcomas, where there's a translocation event that is pathogenic and leads to a cascade of downstream events that lead to a sarcoma. Examples include synovial or Ewing sarcomas, and there are many [other examples]. The other batch is the shattered genome sarcomas, where they don't have a molecular signature and the genome itself is quite chaotic. This pathogenic event has not [yet] been clearly defined.

What progress has been made in utilizing murine models to identify genetic drivers and therapeutic targets for pleomorphic and myxofibrosarcomas?

Janai R. Carr-Ascher, MD, PhD, who is our lead medical oncologist for our sarcoma program [at UC Davis], has a robust lab-based effort and [treats] our adult patients with sarcoma from a medical oncology vantage point. Dr Carr-Ascher has built these murine mouse models for soft tissue sarcoma, looking at the more pleomorphic types of sarcomas—the non-translocation derived sarcomas.

Recently, she and [colleagues] published work in Clinical Cancer Research, a foremost translational cancer mechanistic journal, on their genetic screening of these murine models to look at the drivers that generate these pleomorphic sarcomas. Interestingly, what they found after screening the Cancer Genome Atlas is that YAP1 and wild-type KRAS were significant drivers, and they validated that it transformed human mesenchymal stem cells into 2 distinct sarcoma subtypes: the undifferentiated pleomorphic sarcoma—which is the most common soft tissue sarcoma in adults—and myxofibrosarcoma, respectively. Therefore, YAP1 [was associated] with the pleomorphic and KRAS [was linked with] myxofibrosarcoma.

What's exciting about this and the fact that these are pathogenic is that there are YAP1 inhibitors and KRAS inhibitors that are commercially available.

The next steps will be to see if we can find a therapeutic effect in these models. There may be these commercially available drugs that can have an impact on patients with pleomorphic and myxofibrosarcoma.

What advantages do mouse models offer in the preclinical development pipeline?

Mouse models are advantageous, particularly in sarcoma, [primarily] because the fidelity is has shown to be pretty good. These are not genetically engineered mouse models. We have [used] genetically engineered mouse models in translocation-derived sarcomas, but these are basically immune-incompetent or nude mice, where we transform these cells and put them into the mouse model to see how they behave clinically.

There is the disadvantage of the immune system, and there's a lot of excitement appropriately around immunomodulation, so that is a downside to this model. The upside is that you can, with great fidelity, look mechanistically at the pathogenic process and elucidate mechanisms and vulnerabilities. [These models are beneficial] in sarcomas because they are so rare, and it's hard to have robust clinical trials; there are not enough patients to be able to congregate into a specific disease type. Therefore, [it is hoped that the] preclinical models will give us some better insights into vulnerabilities.

What are the implications of this preclinical research?

For medical oncologists, this [research] demonstrates that there are potential pathways that could be targeted [such as] YAP1 in pleomorphic sarcoma and KRAS in myxofibrosarcoma, where there are commercially available agents that could lead to an impactful improvement in outcomes for patients with advanced or metastatic soft tissue sarcomas. We need that because the overall survival rate with chemotherapy for advanced soft tissue sarcomas [is poor], and it is less when you talk about metastatic disease.

Particularly in rare diseases, such as sarcoma, [mouse models] afford us an ability to elucidate targets and vulnerabilities because we don't have the ability to amass large patient cohorts from a clinical trial standpoint. [However], the next steps for this—once we put the drugs into the mice—will be to do some phase 1/2 studies.

Reference

Freeland J, Muñoz M, O'Donnell E 3rd, et al. Genetic Screen in a Preclinical Model of Sarcoma Development Defines Drivers and Therapeutic Vulnerabilities. Clin Cancer Res. 2024;30(21):4957-4973. doi:10.1158/1078-0432.CCR-24-1238