New Frontiers in Kidney Cancer: Translating Discovery into Opportunity

Renal cell carcinoma (RCC) continues to pose significant clinical challenges, including treatment resistance, disease heterogeneity, and a lack of robust biomarkers to guide treatment selection and predict patient outcomes (1). Addressing these gaps requires research that connects biological insight with new therapeutic opportunities. To help accelerate this progress, AACR partnered with KidneyCAN, a nationwide organization committed to accelerating cures for kidney cancer, to establish the AACR-KidneyCAN Kidney Cancer Innovation and Discovery Grant, which supports translational, mechanistically grounded research with clear potential to improve patient care.

This grant program provides one-year, $50,000 awards to support scientifically rigorous projects with clear translational goals. Since 2024, it has funded five independent investigators whose work spans therapeutic resistance, tumor biology, tumor microenvironment interactions, immunotherapy, metabolism, and novel drug discovery. In the sections that follow, AACR-KidneyCAN-supported researchers describe how this funding enabled them to build on their research and generate early data to inform future directions in kidney cancer.

HIF‑2α inhibitors are an emerging class of targeted therapies now used in advanced renal cell carcinoma and under active investigation in other disease settings. However, mechanisms of primary and acquired resistance remain poorly understood (2). At UT Southwestern Medical Center, 2024 grant recipient Qing Zhang, PhD, identified the PTGES-prostaglandin E2 signaling pathway as a potential mediator of resistance, providing insights that may inform biomarker development and combination strategies aimed at restoring responses to HIF-2α inhibitors.

Dr. Zhang notes that the award enabled his team to develop resistant renal cancer models, evaluate candidate pathways in functional studies, and generate critical early evidence for future mechanistic and translational work. He adds that the funding also supported trainees, increased visibility within the AACR and KidneyCAN communities, and provided flexibility to “follow the biology where it led. Some of our results suggest that PTGES may play a more context-dependent role than initially anticipated, which is exactly the kind of insight that is essential for building more precise therapeutic strategies.” Building on this foundation, the Zhang Lab is working to “identify rational combination approaches with HIF-2α inhibitors and to define biomarkers that can help determine which kidney cancer patients may benefit from targeting the PTGES/prostaglandin pathway.”

Also focused on improving existing treatment approaches, 2024 grantee Edus “Hootie” Warren, MD, PhD, a professor at Fred Hutchinson Cancer Center, is investigating new opportunities in immunotherapy for kidney cancer. Surprisingly, renal cancer patients have been responsive to immune checkpoint inhibitors despite a relatively low tumor mutation burden (3). This responsiveness has been attributed, at least in part, to human endogenous retroviral (hERV) antigen expression (4).  Dr. Warren hypothesized that promiscuous expression of antigenic hERV loci elicits spontaneous CD8+ T cell immunity.  As Dr. Warren explains, “Confirmation of this hypothesis could lead to antigen-specific therapy for renal cell carcinoma based on T-cell transfer or vaccination.” He shared that “AACR-supported research confirms that CD8+ T cells reactive with hERV peptide/MHC class I multimers can be found infiltrating clear cell renal cell carcinoma,” and his team is now characterizing these cells and their T-cell receptors to enable more precise, personalized immunotherapy approaches.

Focusing on a rare and aggressive subtype of kidney cancer, translocation renal cell carcinoma (tRCC), 2025 grantee Srinivas Viswanathan, MD, PhD, at Dana-Farber Cancer Institute, is using an innovative phenotypic chromatin displacement screening approach to target TFE3 fusion proteins, the key oncogenic driver of tRCC (5). As Dr. Viswanathan explains, “Our work identifies a new way to target the TFE3 fusion, which has been difficult to drug directly. Using a cell-based screen, we found a compound that inhibits TFE3 activity by trapping it on chromatin, suggesting a promising new therapeutic strategy for tRCC and potentially other transcription factor–driven cancers.” He shared that AACR-KidneyCAN support has been instrumental in building and validating the screening platform and generating early proof-of-concept data that positions the project for larger-scale screening and future drug development approaches. Looking ahead, his team plans to further define the compound’s mechanism of action and expand screening to identify additional drug candidates.

In Wilms tumors (WT), the most common pediatric kidney cancer, Astgik Petrosyan, PhD, and her team at Children’s Hospital Los Angeles are investigating how the tumor microenvironment influences disease behavior and therapy response. They found that the extracellular matrix (ECM) protein COL2A1 can drive chemoresistance in WT and that blocking COL2A1 can enhance chemotherapy response. Their findings point to the potential of ECM-directed strategies as a novel therapeutic approach in WT (6). She noted that “AACR support has been critical in enabling me to pursue bold, high-risk questions and giving me the flexibility to explore underappreciated mechanisms while generating the preliminary data needed to advance this work forward.”Further, she says that the grant has provided visibility, mentorship, and access to a strong and collaborative network of investigators, which has “opened doors for collaboration, strengthened my research program, and played a key role in my growth as an independent scientist.” Her group is now building on these findings through expanded mechanistic and translational studies, manuscript preparation, and efforts to secure larger-scale funding, including NIH R01 support.

Completing the profile of funded projects, 2025 grant recipient Ralph J. DeBerardinis, MD, PhD, also at UT Southwestern Medical Center, is building on the discovery that metastatic clear cell renal cell carcinoma (ccRCC) relies on a shift toward mitochondrial metabolism. His team is repurposing ONC201, an orally available small molecule that reduces oxygen consumption in cancer cells with minimal toxicity, to selectively disrupt this process. In parallel, they are developing an innovative deuterium MRI platform to noninvasively measure glucose metabolism and TCA cycle-related metabolites in real time. Together, these efforts integrate metabolic targeting with functional imaging to better understand tumor biology. Ultimately, this approach aims to identify high-risk tumors earlier, guide treatment decisions, and expand therapeutic options for metastatic disease.

Looking forward, three new grantees will be supported in 2026, continuing the program’s commitment to advancing high-impact kidney cancer research. As new findings emerge and promising approaches move closer to clinical application, the AACR-KidneyCAN Kidney Cancer Innovation and Discovery Grant will continue to support investigators as they translate early-stage discoveries into advances with the potential to improve patient care.

References

1. Lyskjær I, Iisager L, Axelsen CT, Nielsen TK, Dyrskjøt L, Fristrup N. Management of Renal Cell Carcinoma: Promising Biomarkers and the Challenges to Reach the Clinic. Clin Cancer Res 2024;30:663-672. doi: 10.1158/1078-0432.CCR-23-1892.
2. Saad E, Machaalani M, McDermott DF, Choueiri T. The clinical landscape of HIF2α inhibitors in oncology. Nat Rev Clin Oncol 2026; 23:501-519. doi: 10.1038/s41571-026-01145-y.
3. Kazama A, Bilim V, Tasaki M, Anraku T, Kuroki H, Shirono, Y, et al. Tumor-infiltrating immune cell status predicts successful response to immune checkpoint inhibitors in renal cell carcinoma. Scientific Reports 2022; 12: 20386. Doi: 10.1038/s41598-022-24437-6
4. Gessner KH, Zhou M, Rose TL, Milowsky MI, Kim WY, Bjurlin MA. Current perspective on the impact of endogenous retroviruses in clear cell renal cell carcinoma. Kidney Cancer J 2022;21:88–94. doi: 10.52733/kcj21n3-r2
5. Garinet S, Semaan K, Li J, Zhang Z, Konda P, Sadagopan A, et al. Cell-free DNA epigenomic profiling enables noninvasive detection and monitoring of translocation renal cell carcinoma. J Clin Invest. 2026 Feb 2;136(3):e195725. doi: 10.1172/JCI195725.
6. Yeung W, Chomoyan H, Thornton ME, Koos DS, Villani V, Sunwoo J, et al. Targeting the extracellular matrix in Wilms tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7478.