Accelerating chromophobe research promises a brighter future for this rare kidney cancer

This is a guest post by Katie Coleman, a patient, advocate, and the founder of the Chromophobe and Oncocytic Tumor Alliance, a KCA Affiliate Partner.

“ChRCC research, therefore, appears to be at an inflection point, with the potential for the first specific therapeutic strategies on the near horizon.”

This exciting excerpt from a recently published paper on chromophobe renal cell carcinoma (ChRCC) inspires hope for future treatments and shows just how far ChRCC has come in recent years. This comprehensive review released earlier this month in the journal Cancer Cell summarizes the current state of treatment and understanding of ChRCC and dives deep into everything from the biology and mutations to treatments and potential therapeutic targets. So, let’s unpack a few of its highlights.

ChRCC is a rare type of kidney cancer, making up approximately 5% of cases diagnosed each year. While it’s typically less likely to spread than other types of kidney cancer, it does become metastatic in about 5% of cases. This rarity has, in the past, limited the research dedicated to ChRCC, leaving a gap in treatment options.

What sets ChRCC apart and causes this gap? Genetically, genomically, and metabolically, it’s almost entirely distinct from clear cell RCC (ccRCC) and other types of kidney cancer. Notably, ChRCC is the most common non-clear type found in young women with 46% of ChRCC patients being female compared to 34% for ccRCC and it’s associated with two hereditary cancer syndromes: Birt-Hogg-Dube (BHD) syndrome and tuberous sclerosis complex (TSC). ChRCC also has a unique cell of origin (intercalated cell) and responds differently to targeted therapies and immune checkpoint inhibitors.

This presents a challenge, as ChRCC’s unique biology makes it less responsive to existing treatments. For instance, while some response has been seen with targeted tyrosine kinase inhibitor (TKI) therapies and everolimus (an mTOR inhibitor), ChRCC has a notably low response rate to immunotherapy, with under 10%. A recent study published in The Lancet showed a 28% response with the combination of pembrolizumab (an immunotherapy) and lenvatinib (a TKI). However, a previous study using pembrolizumab alone only had a 9% response rate, suggesting that the response might be primarily driven by the TKI (that study used lenvatinib). Phew, say that three times fast – why do they make drug names so difficult to pronounce?

One way to think about treating ChRCC is like a puzzle. Currently, doctors use treatments known to be effective in clear cell RCC to treat ChRCC, like fitting puzzle pieces from one puzzle into a different puzzle with a similar landscape. We get the idea of the image, but the pieces don’t quite fit or work the way we need them to. 

Recent research, however, has identified potential new pieces (targetable pathways) with edges that match the ChRCC puzzle to help fill in the gaps. One such piece would be ChRCC’s high sensitivity to an iron-dependent type of cell death (ferroptosis) highlighted in a Proceedings of the National Academy of Sciences paper published last year by a large team along with one of the leading experts on chromophobe kidney cancer Dr. Lisa Henske, a medical oncologist at the Dana-Farber Cancer Institute and Director of the Center for LAM Research and Clinical Care at Brigham and Women’s Hospital  in Boston, Massachusetts. Another of those tailored pieces may be a novel IL-15 based immunotherapy. 

Historically, ChRCC has been seen as a “cold” tumor, often described as an immune desert, without many immune cells to put up a fight against the cancer. This has been proposed as part of the reason for the lower response rates to current immunotherapies, such as nivolumab and pembrolizumab which are PD-1 inhibitors. However, research for IL-15 based immunotherapies is currently showing promise, offering a potential solution based on the unique microenvironment and immune cells found in ChRCC.

The horizon looks promising. While there are no ChRCC-specific trials available yet, there are Phase 1 trials for some of these targets, like IL-15 open to a broad range of solid tumors including RCC. With the current momentum, this will hopefully mean ChRCC-specific clinical trials might soon be a reality in the next few years.

The full paper summarizing what is known about ChRCC is packed with information and it dives deep into the science assembling the pieces to the puzzle. Elsevier, which publishes Cancer Cell, has a patient access program that offers access to papers at no cost for patients who may want to dive in deeper to learn more.

More information on Chromophobe RCC can also be found through the Chromophobe and Oncocytic Tumor Alliance (COA) as well as through a newly created resource that consolidates the latest research and information on ChRCC.