Dr. Scott Haake is a medical oncologist and PhD candidate in cancer biology at Vanderbilt University Medical Center.
Dr. Haake received a 2019 Young Investigator Award for research that will investigate endogenous retrovirus (ERV) expression in papillary renal cell carcinoma (RCC), both type 1 and 2, and how ERV expression impacts anti-tumor response in this understudied RCC subtype.
We spoke to Dr. Haake about his work and what it means for patients.
Endogenous retroviruses are relics of ancestral retroviruses that got incorporated into our germline DNA many years ago… Many are defunct [but] for reasons we don’t understand portions of the old broken viruses are expressed more in cancer cells than other cells, which may be important for triggering an immune response against those cancer cells. About 5% of the genome is ERV – a huge proportion of our genome.
We know that patients whose tumors express ERVs respond better to immunotherapy in the context of kidney cancer. Does ERV expression change in type 1 vs type 2 papillary kidney cancer and if so, would that potentially contribute to different outcome and eventually influence what treatments we choose for patients with papillary type 1 versus type 2. We want to understand the biology of papillary type 1 and 2 and tailor therapies for patients with these unique subtypes.
A guiding principle of my work has been to prove the assumption that not all kidney cancers are the same and that the distinctive biology is important for clinical care.
We had already observed that ERVs were highly expressed in clear cell renal cell carcinoma and those patients had increased benefit with new immunotherapies. We wanted to explore whether these viruses were expressed in papillary as well and whether they were equally expressed in papillary type 1 and papillary type 2.
Let’s take a step back. Thirty years ago, there was no clear cell kidney cancer versus papillary type 1 kidney cancer versus papillary type 2 kidney cancer. They were all lumped into one big bucket and all got treated the same and all entered clinical trials together. Over the years we started appreciating the distinctions more.
It’s tough for the papillary kidney cancer patient because so much of the field is driven by the clear cell subtype. Everything that occurs in the papillary kidney cancer research field is piggybacking off what is undertaken within the clear cell field.
It’s important for papillary kidney cancer patients to understand that their disease is unlike clear cell, it’s a distinct disease. It’s really important for providers and patients to get as much information as they can about their cancer and what category it falls in because that could influence treatment choices.
If the story holds up that ERV expression is important to tumor response to immunotherapy, and if our preliminary data holds up, which shows that ERV expression is very low in papillary type 2 kidney cancer relative to type 1, then we need to be focusing on immunotherapy in combination with other types of therapies or other therapies altogether in the type 2 subset. I would urge colleagues to remain cognizant of the distinct biologies and to make sure we understand how these drugs are working in the context of these distinct subtypes. While there are exciting therapies, we need to understand where they’re active and where they’re not.
These sorts of translational studies are exciting for two reasons. One, there’s a huge unmet clinical need for biomarkers of immunotherapy response. We have exciting drugs but we don’t know who’s going to respond to them… and they do have side effects. The better we can tailor our therapy choices to the individual biology of individual patient tumors, the better.
Second, if we know ERV expression correlates with drug response, the next logical step is can we do things to increase ERV expression and is that going to improve the efficacy of these drugs. That opens up a new line of research… getting patients who would not normally respond to these immunotherapy drugs to respond.
As we make these biological inferences, it can be exciting from a biomarker perspective but also in terms of learning how to make non-responders into responders.
It’s frustrating as a physician when you’re in the clinic and you have certain tools in your toolbelt and you have patients suffering and all of your tools don’t work and you’re left shrugging your shoulders and saying “I can’t help you”. I think any kidney cancer clinician would acknowledge that there is not enough tools in our toolbelt and we need to push the envelope for discovery to create new therapies and strategies for this really deadly disease.