Research Efforts Seek to Understand Biology, Genomic Driver of Translocation RCC

Partner | Cancer Centers | <b>Dana Farber</b>

Ziad Bakouny, MD, MSc, discusses recent ongoing research into the genomic drivers and biology of tRCC that could lead to improved outcomes for patients.

Due to the rareness of the disease, investigators have made few developments in the treatment of patients with translocation renal cell carcinoma (tRCC). Current therapeutic options often involve therapies that have shown efficacy in other forms of kidney cancer, but often do not yield positive outcomes in this patient population, said Ziad Bakouny, MD, MSc.

“If we do not understand the biology [of the disease], we are not going to be able to target it correctly,” Bakouny said. “Currently, extrapolating treatments from clear cell RCC has not yielded optimal outcomes. Because of this, we want to understand the biology more to be able to target the disease better, treat patients better, and ultimately get them better clinical outcomes.”

In an interview with OncLive® during the 2021 Kidney Cancer Research Summit, Bakouny, a research associate at Dana-Farber Cancer Institute and resident in internal medicine at Brigham and Women’s Hospital, discussed recent ongoing research into the genomic drivers and biology of tRCC that could lead to improved outcomes for patients.

OncLive®: Could you provide some background on the treatment of tRCC?

Bakouny: tRCC is a very rare disease that affects primarily young patients, and interestingly, females more than males. It is thought to account for 1% to 5% of all RCCs in adults, and in children, it accounts for 20% to 50% of kidney cancers. The disease is aggressive, and what we know about is actually that we do not know that much. There have been large studies on more frequent forms of kidney cancer, including clear cell RCC and papillary RCC, and because of these efforts, there is quite a bit understood about the genomic drivers of this disease.

However, rarer forms, like tRCC, have not been studied as extensively, and we do not know much about them. This contributes to the fact that we do not have many therapies that work for them. All the therapies currently used for tRCC are extrapolated from clear cell RCC, as well as from other forms of kidney cancer.

The reason it is important to understand the biology of tRCC is because it is aggressive, and patients, unfortunately, often have poor outcomes, Additionally, it disproportionately affects young patients, and there is a significant burden of disease for these young patients, particularly young women.

What were the key takeaways from this research? Did investigators identify any clinical molecular features of the disease?

Because of how rare this disease is, we realized that we could not do this on our own, in the sense that no one center anywhere across the world would have been able to get enough samples to study the molecular characteristics of the disease, in addition to the clinical characteristics. What we did was pull data from approximately 10 different data sets that were publicly available, including some of our own. We put it all together and we analyzed it, using some unorthodox methods, to be able to ask the questions about what the molecular characteristics of these tumors are, what is driving these tumors, and what therapies might work for them.

To do this, we pulled the data together and included genomic data such as DNA level analyses and mutations. We also looked at fusions because these tumors are known to be driven by a characteristic fusion involving the TFE family of genes. Then we looked at was transcriptomic data, as well, and wanted to know what the transcriptomic characteristics of these tumors are. Finally, we looked at clinical responses to therapies.

In the DNA-level analyses of data, we found that these tumors have a silent genome—they do not have a lot of mutations, they do not have a lot of copy number alterations. Despite that, they do seem to have some recurrent alterations that we have identified, primarily 9p21.3 deletion, which is the CDK2NA locus that seems to be deleted in up to 20% of these tumors, as well as a few mutations that we detected in DNA damage response genes and SWI/SNF genes. That was the mutational bucket, in fusion bucket, it is known that these tumors evolve TFE3, TFEB, and MITF genes. What we noticed is that the pattern of how these fusions form, what they conserve as part of these genes, differs between fusions. These genes seem to conserve the C-terminal domain, the DNA binding domain, of these proteins well, but depending on the actual gene itself, there are different parts of the protein domains that are conserved in the fusion product between them, so we that was characterized.

On the transcriptomic side of things, what we found is that these tumors seem to have a distinct transcriptional signature that is different from all other forms of RCC. This is characterized by genes that are known to be targets of TFE3. We then used cell lines to transfect the fusion into this alliance [and were then able to] deduct that the transcriptional program of these tumors appears to be induced by the fusion itself. We then asked, what is this transcriptional program and what is it characterized by? What we found is that it is characterized by activation of the NRF2 transcriptional program, and that is a program that has been known to be activated across several malignancies.

Now that we know what the genomic characteristics are, we know what the fusion looks like, and we know what the transcriptomics look like for these tumors, we are left with the clinical response. What we found is that, as expected, these NRF2-expressing tumors do not seem to respond well to targeted therapies, which explains the usually poor outcomes seen in this patient population. We used to treat clear cell RCC with targeted therapies like mTOR inhibitors and VEGF inhibitors, and because of the NRF2 activation, we see poor responses to those with tRCC. However, they [do seem to] respond well to immune checkpoint inhibitors. We used our own data, as well as data from tRCCs that were identified post hoc in the phase 3 IMmotion151 trial (NCT02420821) to show that these tumors respond well to immune checkpoint inhibitors. This is still preliminary data, but given how rare this disease is, we believe they are convincing data that patients with these tumors may do well on immune checkpoint inhibitors or immune checkpoint inhibitor-based combinations.

What are some next steps for this research?

I am excited that through our study, and from multiple other studies that have been done in this space, we now have a firmer grasp on what the genomics of these tumors are and what the drivers are. What remains to be understood is how these interplay with each other. For instance, what is the fusion doing with the CDKN2A loss? How are they cooperating to drive the pathogenesis of these tumors?

The next step that I am excited about is figuring out the underlying biology and following up on some of the signals that we have seen on how [these factors] interact with each other to drive tumor pathogenesis. The hope is that with a more granular understanding of these tumors, we will be able to develop specific therapies that target the pathogenic processes and be able to improve the outcomes of these patients, which is still a huge unmet clinical need.

Are there any recent therapeutic developments in tRCC, that should be highlighted that you want to discuss?

Unfortunately, the main therapeutic developments are the ones I previously mentioned as part of our study and others. These therapeutic developments are using the treatments we already have for RCC and seeing how they do in tRCC. This alludes to some of our own work that was just mentioned about how immune checkpoint inhibitors might do well in these tumors. There is corroborating data from other studies that have shown similar things, and right now, that is the most exciting space, in terms something that is clinically actionable. That said, the next steps are targeting the underlying biology of disease. That is what may drive improvement in the outcomes of patients with these tumors.