Supporting the Future of Kidney Cancer Research

Research Summary

The Incidence of renal cell carcinoma (RCC) continues to increase in the United States, ranking among the ten most frequently diagnosed cancers in men and women. Unfortunately, resistance to existing treatments remain a major obstacle, driving the need for identification of clinically relevant biomarkers and therapeutic targets. TNF-related apoptosis inducing ligand (TRAIL) is a promising cancer therapy that selectively induces apoptosis in malignant cells while sparing normal cells. TRAIL exerts its cytotoxic effects through binding death receptors DR4 and DR5, initiating caspase dependent programmed cell death. However, intrinsic and acquired resistance mechanisms have limited TRAIL’s efficacy as anti-cancer strategy. We have identified a link between the overexpression of oncogenic PIM kinases and regulation of DR5 expression and sensitivity to TRAIL apoptosis in RCC. PIM1 is emerging as a clinically relevant biomarker and therapeutic target in RCC. Nuvisertib (TP-3654) is a selective PIM1 kinase inhibitor currently being evaluated in Phase 1/2 clinical trials for patients with myelofibrosis and has received FDA fast track designation. We find that treatment of RCC cells with low dose (2.5 µM) of Nuvisertinib over 24 hours induces a 5.75-fold (p<0.01) increased mean membrane expression of DR5 compared to vehicle control assessed by flow cytometry. We also investigated synergism between Nuvisertib and Dordaviprone, a newly FDA approved imipridone and TRAIL inducer. We evaluated combinations of Nuvisertib and Dordaviprone via Cell Titer Glo in RCC cells and find that combination indices indicate synergism which significantly reduce RCC cell viability more potently than either agent alone. Our findings highlight actionable novel candidate targets and strategies for therapeutic intervention in RCC. Ongoing studies are aimed to uncover mechanistic insights of these treatments in RCC and guide the development of optimal treatment strategies.

Personal Statement

My long-term goal is to become an independent cancer biology research investigator. I am currently a 6th-year PhD student at Brown University mentored by Dr. Wafik El-Deiry, director of the Legorreta Cancer Center. My thesis focuses on identifying dysregulated signaling pathways in renal cell carcinoma (RCC) to validate novel biomarkers and develop more efficient anti-cancer strategies. My research has found that the emerging biomarker oncogenic PIM-1 kinase is regulated via an actionable IL-6/JAK/STAT3 axis in ccRCC. Presented at a previous AACR meeting, this work is now in revision for publication. I am now evaluating the inhibition of PIM kinases to re-sensitize RCC cells to TRAIL apoptosis. I have identified and submitted an abstract describing a potent synergism between TP-3654, an FDA fast-tracked PIM1 inhibitor, and ONC201, a newly FDA-approved imipridone TRAIL inducer discovered by Dr. El-Deiry. The targeting of PIM1 and reactivation of TRAIL apoptosis in RCC is a novel combination strategy that could address therapy resistance in RCC and be developed as a more accessible treatment with FDA designations. The AACR-Kidney Cancer Collaborative Scholar-In-Training award is clearly aligned with my goals and would allow me to i) disseminate my doctoral research, ii) expose me to novel research, and iii) empower me to network with peer and senior leaders at AACR. It would be my honor and privilege to be selected for this award and gain access to a distinguished network.

Research Summary

The presence of sarcomatoid (Sarc) and rhabdoid (Rhab) dedifferentiation in renal cell carcinoma (RCC) is linked to poor clinical outcomes and higher risk of metastatic disease. Previous molecular studies on renal tumors with these dedifferentiated features lacked spatial resolution to distinguish these aggressive regions from classical RCC histology, leaving the biology underlying these aggressive phenotypes poorly understood. We applied spatial whole transcriptome profiling (GeoMx DSP) to 370 regions exhibiting Sarc, Rhab, clear cell, papillary, or benign kidney from 54 RCC tumors. We combined these spatial transcriptome profiles with our single-cell RNA-sequencing atlas consisting of different RCC subtypes to investigate Sarc/Rhab biology and verified clinical significance of our findings using public databases such as The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Deconvolution of the spatially resolved transcriptome data revealed substantial gene expression reprogramming in Sarc/Rhab regions. Notably, Sarc/Rhab areas featured a high fibroblast-like gene expression pattern and a loss of cytokeratin expression as a defining hallmark of Sarc and Rhab dedifferentiation, reflecting their histological nature. We established cancer cell-intrinsic gene expression signatures of Sarc and Rhab tumors and found they are highly correlated with higher tumor grade in the ccRCC cohorts from both TCGA (n=485) and CPTAC (n=103). Importantly, these signatures significantly predicted poor disease-free survival in clinically low-risk (Stage 1-2) ccRCC patients. In the ccRCC cohort of TCGA, tumors with high Sarc gene signature levels were enriched for mutations in SETD2, PTEN, MTOR, and KDM5C, as well as specific copy-number variations, notably loss of 14q, 9, 18, and 6p and gain of 20, 12, and 8q, compared to other tumors. Pathway enrichment analyses suggested that genes related to extracellular matrix organization, coagulation, and epithelial-mesenchymal transition were highly enriched in Sarc/Rhab regions compared to classical ccRCC regions, while pathways for oxidative phosphorylation, adipogenesis, and amino acid metabolism were decreased.These findings provide novel insights into the biology of Sarc/Rhab dedifferentiation in RCC, paving the way for the development of improved prognostic markers and targeted therapeutic strategies.

Personal Statement

My thesis leverages single-cell and spatial transcriptomics to dissect the biology of aggressive renal cell carcinoma (RCC) subtypes, specifically sarcomatoid (Sarc) and rhabdoid (Rhab) dedifferentiation. My research addresses a critical gap: translating specific histopathological changes into molecular profiles. The submitted research is highly relevant to scientific and clinical advances in these aggressive phenotypes. By presenting novel findings such as the fibroblast-like genetic shift and a gene signature predictive of progression in early-stage RCC cases, I provide crucial insights for developing quantitative, unbiased diagnosis and identifying potential therapeutic targets co-targeting the tumor and its microenvironment. Presenting at the AACR is vital for knowledge mobilization. I aim to share progress on this clinically unmet need with leading colleagues and pharmaceutical companies interested in novel targets for aggressive RCC. I also expect to meet potential collaborators in AI-based digital pathology to develop spatial transcriptomics-guided AI models capable of detecting subtle micro-dedifferentiations in minimally invasive biopsy samples. My long-term career goal is to become an independent Investigator dedicated to translational genomics in oncology. Drawing on my biotech co-founder experience and academic research, I aim to bridge advanced computational data (like spatial multi-omics) with clinical pathology to develop next-generation precision medicine.

Research Summary

SMARCB1-deficient renal medullary carcinoma (RMC) is a highly aggressive kidney cancer characterized by replication stress and proteotoxic vulnerabilities, yet the molecular determinants of therapy response remain poorly understood. To delineate the mechanisms of response and resistance, we performed integrative single-cell and bulk multi-omic profiling of tumor samples from patients with RMC treated with a combination of the proteasome inhibitor ixazomib, gemcitabine, and doxorubicin. Analysis of 33,410 single cells from 11 patients revealed pronounced intratumoral and microenvironmental heterogeneity. Responding tumors displayed immune-inflamed microenvironments enriched for CD8⁺ cytotoxic T cells, effector-like and Tfh CD4⁺ T cells, NK cells, plasmacytoid (pDC) and conventional dendritic cells (cDC1/cDC2), and S100A8⁺ monocytes, consistent with enhanced antigen presentation and effector activation. In contrast, non-responders exhibited abundant macrophages, regulatory T cells, plasma cells, and inflammatory and myofibroblastic cancer-associated fibroblasts (iCAFs/mCAFs), forming immunosuppressive stromal-myeloid circuits that impeded cytotoxic infiltration and response. Malignant cells segregated into six transcriptional states, including proliferative, hypoxia-responsive, epithelial-mesenchymal, and neuroendocrine-squamous hybrid lineages. A proliferative state marked by replication stress, unfolded-protein-response activation, and proteasome component upregulation was enriched in non-responders and persisted at progression, suggesting adaptive proteostasis-driven resistance. Copy-number analyses identified focal gains in BAG4, UBE4B, and UBE2W that may enhance apoptosis evasion and p53 degradation, reinforcing proteotoxic resilience. In contrast, well-differentiated and immune-mimicry tumor states correlated with improved survival. Integrative cell-cell communication analysis highlighted stromal-immune signaling through BMP4/5 and WNT4/6 as a hallmark of resistant tumors, whereas BMP6 expression associated with dendritic-cell activation and favorable immune remodeling. Together, these findings define molecular and cellular programs underlying therapeutic response in RMC and nominate actionable stress-adaptation and stromal-immune circuits as potential targets for future biomarker-guided combination strategies.

Personal Statement

My research focuses on understanding how intrinsic tumor programs and microenvironmental ecosystems shape therapeutic response and resistance in aggressive cancers. As a postdoctoral fellow at MD Anderson Cancer Center, I integrate multi-omic data to dissect cellular heterogeneity, lineage plasticity, proteotoxic stress responses, and stromal-immune interactions. In my current work on SMARCB1-deficient renal medullary carcinoma, I use high-resolution single-cell profiling to define immune and malignant cell states associated with response to ixazomib-based therapy, and to identify stress-adaptation circuits that drive resistance. Attending this conference will allow me to present these findings, receive feedback from leaders in tumor immunology and systems oncology, and build collaborative networks essential for translating mechanistic insights into biomarker-guided precision medicine. Exposure to cutting-edge approaches in single-cell analytics, tumor microenvironment biology, and therapeutic resistance will directly strengthen my ongoing research. My long-term goal is to lead an independent laboratory dedicated to mapping the tumor ecosystem at single-cell resolution, identifying predictive biomarkers of treatment response, and developing combination strategies that overcome resistance in cancers. I am committed to advancing translational cancer research that bridges computational modeling, multi-omic profiling, and therapeutic development to improve patient outcomes.

Proposed Work

Tumor metastasis is the major cause of death in kidney cancer patients. Dr. DeBerardinis and his team aim to identify the metabolic pathways required for metastasis. They developed techniques to compare metabolism between primary and metastatic kidney tumors in patients. The group previously observed that oxidative mitochondrial metabolism was activated in metastatic tumors. In mice, mitochondrial metabolism was necessary and sufficient to induce metastasis from the kidney.

In this project, Dr. DeBerardinis proposes to test the effect of ONC201, which blocks mitochondrial activity by activating the protease ClpP, on kidney cancer growth and metastasis in mice. He also proposes to use deuterium MRI (dMRI) to non-invasively assess  mitochondrial activity and assess the effect of ONC201 on these pathways.

Anticipated Impact

ONC201 is well-tolerated in patients, and dMRI can be used in humans. If successful, this study may lay the groundwork for future clinical trials in kidney cancer. 

“I am grateful for the AACR-KidneyCAN Innovation and Discovery Grant. It comes at a pivotal time in our efforts to understand kidney cancer progression and translate this knowledge into practice. We believe this proposal will provide foundational data for imaging and therapeutic clinical trials in kidney cancer.”

Proposed Work

High-risk and relapsed Wilms tumors remain a major clinical challenge with poor outcomes. Dr. Petrosyan’s team has identified COL2A1, an extracellular matrix (ECM) protein absent in normal kidney but upregulated in aggressive tumors, as a potential driver of cancer stem cell (CSC) plasticity and chemoresistance. Their findings indicate that COL2A1 negatively regulates the tumor suppressor KLF4, facilitates epithelial-mesenchymal transition (EMT), and drives therapeutic resistance. Targeted inhibition of COL2A1 restores KLF4 expression, reverses EMT, and re-sensitizes CSCs to chemotherapy.

Using CSC organoid cultures, patient-derived decellularized ECM scaffolds, and in vivo xenograft models, Dr. Petrosyan aims to elucidate the molecular mechanisms behind COL2A1-mediated KLF4 suppression and evaluate pharmacological KLF4 activation as a therapeutic approach in high-risk Wilms tumor.

Anticipated Impact

This work aims to explore whether combining ECM-targeted strategies with pharmacological interventions could offer therapeutic benefits and potentially improve treatment outcomes in high-risk Wilms tumors.

“The ECM actively regulates tumor progression, therapy resistance, and cellular crosstalk within the tumor microenvironment. This AACR-KidneyCAN Innovation and Discovery Grant will support research into ECM-driven mechanisms in kidney cancer and foster interdisciplinary efforts to develop tumor microenvironment–targeted therapies with translational potential.”

Proposed Work

Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer that affects both adults and children and is driven by gene fusions of the TFE3 transcription factor. While TFE3 fusions create critical oncogenic dependencies in tRCC, direct targeting of TFE3 is challenging because it is a transcription factor with many disordered regions..

Dr. Viswanathan’s team has developed a phenotypic screening strategy to identify small molecules that disrupt TFE3-chromatin interactions essential for oncogenesis. Screening of 25,000 compounds identified 62 hits, acting through two complementary mechanisms: retention/trapping of TFE3 on chromatin or displacement of TFE3 from chromatin.

Dr. Viswanathan will focus on further functional validation of these hits and mechanistic characterization via a suite of cell-based and biochemical deconvolution assays.

Anticipated Impact

This effort aims to establish a robust pipeline for screening for TFE3 inhibitors, which may enable future large-scale screens and enable the development of a first-in-class targeted therapy for tRCC.

“This award will help establish foundational data to support efforts in discovering inhibitors of TFE3 fusions for translocation renal cell carcinoma, a kidney cancer of great unmet needs that currently lacks specifically approved therapies.”