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Nirmish Singla

Dr. Nirmish Singla received a 2021 Young Investigator Award for his project “Tumor evolution of brain-specific tropism in metastatic renal cell carcinoma.” Singla is based at Johns Hopkins University in Baltimore, Maryland.

We spoke with Singla about his work and what it could mean for people with kidney cancer.

Briefly describe your project. How did you develop this idea?

Why certain cancer types have the propensity to spread to specific sites, and the underlying biological drivers for site-specific metastatic colonization (organotropism) are not well understood.  Recently, we comprehensively characterized pancreatic metastases arising from renal cell carcinoma (RCC), which represents a uniquely favorable phenomenon.  We uncovered novel associations among genomic alterations, transcriptomic signatures, morphologic phenotypes, radiographic appearance, clinical prognosis, and differential response to systemic therapies.  In the proposed study, we sought to expand our findings to patients with brain metastases (BM) from RCC, since, unlike patients with pancreatic metastases, patients with BM are among the most challenging to treat with poor survival outcomes.  By leveraging a unique partnership with a neurosurgeon-scientist at Johns Hopkins, Dr. Chetan Bettegowda, we chose to focus our efforts on this understudied population given the pressing need to improve management strategies and outcomes in these patients.  Our research aims to understand what factors drive these cancers to go to the brain and uncover whether these factors may be used to monitor for disease or help direct the optimal approach to treatment.

It sounds like there hasn’t been much work to understand why or how brain metastases arise from RCC, especially compared to other cancer types – why is this the case?

Unfortunately, patients with BM are frequently excluded from prospective clinical trials in RCC and exhibit poor overall survival, making outcomes particularly difficult to assess in this population.  Furthermore, since local control with neurosurgical resection of BM is limited to selected patients, molecular studies characterizing BM from RCC are scarce, largely due to limited availability of tumor tissue from BM.

What are the current options for RCC patients with brain metastases?

Evidence regarding the efficacy of systemic therapies in treating BM arising from RCC is conflicting, although emerging data has supported the use of the angiogenic inhibitor cabozantinib and combination immune checkpoint inhibitor therapies such as ipilimumab and nivolumab.  Aside from being able to directly treat tumor clones colonizing the brain, therapies would also need to surmount the blood-brain barrier in order to be effective against BM.  Traditionally, whole brain radiotherapy was employed to treat BM, with limited effectiveness.  Local control with neurosurgical resection or stereotactic radiosurgery is limited to selected patients, and many may develop new sites of intracranial disease or succumb to progression of extracranial disease.

We are uniquely positioned to address these needs, as we have a robust, clinicopathologically-annotated institutional cohort of patients who underwent surgical resection of at least one BM with corresponding tissue available for correlative analyses. By studying the molecular underpinnings of BM, our study may help guide future biomarker discovery in bodily fluids to help monitor response to treatment in patients with BM.  Furthermore, by uncovering biological clues in BM tumors, we hope our findings may help guide clinicians decide which treatment(s) to select for patients with BM.

What motivates you?

As a surgeon-scientist, my motivation comes directly from my patients.  The ability to treat cancer in the operating room provides an instant gratification that helps patients on an individual level.  The ability to then study their tissue in the laboratory provides a unique opportunity to tackle pressing clinical and research needs in kidney cancer and give back to patients on a broader scale.  This is made possible only through collaboration with a talented, multidisciplinary team.  Clinically, I strive to provide personalized and compassionate care to my patients by integrating cutting-edge technologies and multidisciplinary approaches to treatment.  My overarching goal is to help scientific discoveries in the laboratory materialize for patients with cancer in the clinic.

What else do you want others to know about you or your work?

As the Director of Translational Research in Genitourinary Oncology and the Kidney Cancer Program at Johns Hopkins, I hope to undertake a comprehensive approach to address the complete spectrum of kidney cancer.  My translational research interests include studying the biology of kidney cancer on a molecular level, focusing on prognostication in localized and advanced disease, identifying diagnostic and therapeutic targets, understanding mechanisms of therapeutic resistance, and designing multidisciplinary clinical trials to reduce morbidity, personalize treatment, and improve outcomes in patients.  Through our rapidly expanding Kidney Cancer Program, we are fortunate to have established numerous collaborations with investigators both internally and externally to span immuno-oncology, biomarker discovery, molecular imaging, novel therapeutics, stereotactic radiation, and engineering. I am immensely grateful and indebted to the Kidney Cancer Association for its generous support in advancing our team’s research efforts.  I am excited to embark on our next project and hope to pay the investment forward!

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