Six Papers from 2023 that Improved our Understanding of Renal Medullary Carcinoma
- January 11, 2024
Blog post from Kidney Cancer Association.
This is a guest post by Dr. Pavlos Msaouel, a medical oncologist and researcher at MD Anderson Cancer Center, renal medullary carcinoma expert, and member of the KCA’s Medical Steering Committee. Dr. Msaouel has also received multiple KCA grants to further research in kidney cancer.
Six papers published in 2023 improved our understanding of renal medullary carcinoma (RMC), a rare and aggressive type of kidney cancer that impacts primarily young people of African descent. Until recently, people diagnosed with RMC, who make up less than 1% of everyone with a kidney cancer diagnosis, have had extremely poor outcomes and no treatment options, including no opportunities to enroll in clinical trials. That has changed in the last few years, thanks to tireless work from patient advocates and fellow researchers and the result is an increased output of new research that explains some of the ways that RMC develops and what might be effective in treating it.
SMARCB1 regulates the hypoxic stress response in sickle cell trait
Journal: Proceedings of the National Academy of Sciences
This study connected hypoxia, in which the oxygen levels in the cellular environment are lower than normal, and loss of the tumor suppressor gene SMARCB1 in people with sickle cell trait. SMARCB1 loss, which is a molecular hallmark of RMC, is actually protective for renal cells when the oxygen in the environment is low due to decreased blood vessels. Drugs such as the antibody bevacizumab and the tyrosine kinase inhibitors cabozantinib, lenvatinib, axitinib, sunitinib, pazopanib, and tivozanib, were developed to target the blood vessels that provide oxygen in more common kidney cancers such as clear cell renal cell carcinoma. However, the loss of SMARCB1 protects RMC from these therapies.
Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24)
Journal: European Journal of Cancer
Consistent with the results of the Proceedings of the National Academy of Sciences study in animal models and human tissues, this prospective phase II clinical trial found that adding bevacizumab to platinum-based chemotherapy, which is the current first-line treatment recommendation for RMC, does not improve outcomes in patients with RMC.
SMARCB1 regulates a TFCP2L1-MYC transcriptional switch promoting renal medullary carcinoma transformation and ferroptosis resistance
Journal: Nature Communications
In addition to hypoxia, this Nature Communications study showed that another key protective role of SMARCB1 loss in RMC is resistance to ferroptosis, which is a form of cell death that happens when cells have too much iron. The sickling of red blood cells in the renal medulla of individuals with sickle hemoglobinopathies, such as the sickle cell trait, leads to both hypoxia (low oxygen levels) and release of iron contained in the red blood cells. And we now know that the loss of SMARCB1 protects RMC cells from both hypoxia and excess iron. This research also provides additional evidence that RMC arises from specific cells in the kidneys called “thick ascending limb cells”.
Neddylation inhibition sensitises renal medullary carcinoma tumours to platinum chemotherapy
Journal: Clinical Translational Medicine
Conversely, SMARCB1 loss can make RMC cells sensitive to toxicity related to mis-folded protein molecules (known as “proteotoxic stress”) and to toxicity due to incomplete or faulty DNA replication (known as “replication stress”). Therefore, we now know that while the loss of SMARCB1 can protect RMC cells from some processes such as hypoxia and ferroptosis, it can also make them vulnerable to other processes such as proteotoxic stress and replication stress. This study showed in RMC cell lines and animal models that inhibiting a process known as “neddylation” which cells use to protect themselves from proteotoxic and replication stress can be particularly effective as a therapy for RMC.
Renal Cell Carcinoma Unclassified with Medullary Phenotype in a Patient with Neurofibromatosis Type 2
Journal: Current Oncology
Interestingly, genetic factors other than sickle hemoglobinopathies may occasionally be associated with RMC, as suggested by one patient reported in this study who had the tumor-causing syndrome known as neurofibromatosis Type 2, caused by a mutation in the NF2 gene. The NF2 gene happens to be positioned on the chromosome right beside SMARCB1 and is often lost in RMC. Thanks to the therapies we have pioneered for patients with RMC, this patient’s metastatic RMC is now in complete remission. By understanding the molecular pathways involved in patients with such excellent responses, we hope to one day be able to reproduce these results in all patients with RMC.
A Phase II Clinical Trial of Pembrolizumab Efficacy and Safety in Advanced Renal Medullary Carcinoma
Journal: Cancers
We also now have the first prospective data showing that RMC can rapidly progress in response to standard immunotherapy using agents such as pembrolizumab (Keytruda). Stay tuned on upcoming work on why and how to reverse this progression and harness the power of immunotherapy.
Overall, 2023 was a landmark year for RMC research and 2024 promises even more. I’m grateful to our patients, advocates, clinicians, and researchers, all of whom are working tirelessly to support efforts to end RMC.