Q & A: Dr. Kaushal Asrani, KCA Trailblazer Award winner

Dr. Kaushal Asrani received a 2024 Kidney Cancer Association Trailblazer Award in partnership with Joey’s Wings Foundation for research on “Therapeutic Targeting of EGFR and HER2 in Translocation Renal Cell Carcinoma”. Dr. Asrani is a research associate at the Johns Hopkins School of Medicine in Baltimore, Maryland. We spoke with him about his research and the impact it could have on people with kidney cancer.

What do we currently understand about translocation renal cell carcinoma (tRCC)?

Translocation RCC (tRCC) is a rare and aggressive subtype of non-clear cell, sporadic kidney cancer with a predominance in females, children and young adults, and also demonstrates racial differences, with prevalence and mortality increased in Black and Asian populations, compared to White patients. tRCC arises from chromosomal translocations or gene fusions in the MiT/TFE family of transcription factors [primarily TFE3 and rarely TFEB], that also drive a subset of potentially aggressive mesenchymal tumors called perivascular epithelioid cell tumors (PEComas). These genes regulate fundamental processes like autophagy and lysosomal biogenesis in normal cells, but their unregulated activity in tRCC drives tumor formation, although the mechanisms are not clearly defined. tRCC tumors show a great degree of morphologic and clinical overlap with the major RCC subtypes (ccRCC and pRCC), and are often misclassified, making diagnosis challenging. There is also considerable heterogeneity or variation in kidney tumors driven by different TFE3-fusion proteins, in part due to varying functions of the fusion partners [the most common being ASPSCR1, PRCC and SFPQ], underscoring a need to develop fusion-specific models to study the disease. The rarity of tRCC patients and biospecimens has necessitated the use of alternate models (such as patient-derived xenografts [PDX] or organoids or novel transgenic mice) to study the disease.

Tell us about your research project and how you developed the idea.

While targeting the fusion oncoproteins themselves would be the most durable strategy, targeting oncogenes that are co-expressed on the surfaces of these tumors represents a highly effective and viable approach for their diagnosis and/ or treatment. EGFR and HER2 are oncogenes that belong to the family of proteins called receptor tyrosine kinases (RTKs). These proteins are commonly overexpressed and have been successfully targeted in many solid organ tumors, using multiple approaches (including highly specific kinase inhibitors, among others). There is some limited evidence from previous studies indicating that EGFR activity is also increased in human and mouse tRCC tumors. We also observed this in a mouse model of SFPQ-TFE3 kidney tumors generated in our lab. Working along with Dr. Ravi Anchoori, (Founder and Chief Scientific Officer of Up Therapeutics LLC), our goal in this project is to leverage our novel mouse model to test both, novel and FDA-approved anti-EGFR/HER2-directed therapies.

What is the potential in researching rare cancer types?

My work on kidney cancer began by studying renal tumors in Tuberous Sclerosis Complex (TSC), another rare kidney cancer subtype that is also prevalent in children. Loss of the TSC tumor suppressor complex is a major driver of mTORC1 activation- that has widespread impacts on cancer, metabolism and aging. In this way, TSC is often considered a “linchpin” disease–one that can potentially unlock new treatments to a wide array of disorders. Similarly, the MiT/TFE factors have widespread roles in autophagy, metabolism and cancer and are believed to drive pathogenesis in a number of diseases. Thus, work on MiT/TFE driven tumors has the potential to impact many fields, and this is a major advantage of researching rare tumors like TSC and tRCC.

What about your research could be most exciting for patients and families?

Transgenic mouse models are very effective at recapitulating human diseases, including cancer, and can serve as a useful pre-clinical tool to test targeted therapeutics. While the management of tRCC continues to be challenging, targeting well-studied tumor proteins such as EGFR or HER2 (or other similar biomarkers) via a combination of novel and/or FDA-approved repurposing agents (such as EGFR/HER2 kinase inhibitors), represents a potentially viable approach for the treatment of tRCC.

Do you have a particular interest in tRCC or pediatric kidney cancer?

My work in cancer, for the last many years, has focused on basic and translational research on rare pediatric kidney tumors (including tRCC and TSC). Additionally, engagement by the kidney cancer community, including patients, advocacy groups, researchers and clinicians provides a major impetus in my work in this field.

What motivates you?

Finding effective biomarkers for early diagnosis, and durable treatment options for tRCC are my primary motivating factors. I am also driven by the prospect of advancing studies of the basic biology of the MiT/TFE proteins and mTOR in other fields, through my work. I am fortunate to be able to work with an amazingly dedicated mentor, research team and collaborators, that has made this work possible!