Background

Metastasis is the deadliest cancer stage, and there is no universal treatment. Different tumors have distinct tissue-specific signatures, but as cancer progresses, they follow a common evolutionary trajectory toward invasiveness and metastasis. Targeting this shared vulnerability in metastatic tumors holds significant translational potential. Recent insights from kidney cancer reveal a novel metastatic mechanism, leading to the discovery of small-molecule drugs, SIMs, that selectively inhibit metastasis across cancers. By understanding SIMs, we aimed to create safer, more effective treatments, potentially saving over 500,000 lives annually in the U.S.

Method & Results

1) New concept: Metastasis requires cooperation between VHL+ and VHL- cells, with VHL- cells driving growth and migration in VHL+ cells.

2) SIM candidates: In high-throughput screening of 2,530 FDA-approved drugs, drugs selectively inhibiting VHL cells were identified, with fluvastatin being the most potent (“SIM-1”). Subsequent SAR studies identified SIM-2, four times more potent than fluvastatin (IC₅₀ 92nM).

3) Older statins (fluvastatin, simvastatin) were more cytotoxic than newer statins (e.g., atorvastatin and rosuvastatin) despite a lower affinity for their known target, HMG-CoA reductase (HMGCR). Thus, SIMs target a pathway distinct from cholesterol-lowering or HMGCR.

4) Transcriptomics and proteomics analyses suggest that older statins may target a non-HMGCR molecule in their anti-metastatic activities, possibly explaining mixed clinical trial results regarding statin use as antineoplastics.

5) SIMs are effective in treating various cancers, including kidney, breast (TNBC), and prostate (NEPC).

Conclusions

Critical steps to advancing SIM development toward clinical translation are (i) target identification and (ii) target and therapeutic validation. While our focus is on metastatic renal cell carcinoma (mRCC) to identify SIM’s drug target, strategic findings from this project will be directly relevant to other high-risk urological cancers. By investigating this further, we could develop a novel pan-cancer anti-metastatic drug.

Personal Statement

Cancer research has advanced significantly, revealing new vulnerabilities in cancer cells and developing new treatments such as immune checkpoint inhibitors. However, it’s still far away from curative therapy, especially against metastatic diseases. That is why I am here at UCLA Pharmacology, investigating the metastatic mechanism with a focus on heterogeneity. The primary goal of my project is to develop a new drug that can target intratumoral communication that drives distant metastases. Our effort has led to promising discoveries, such as statins’ selective toxicity against the metastatic driver. This is especially exciting because 1) statins are already FDA-approved and widely used in the clinic, but 2) their mechanism of action, as well as indications for metastatic diseases, are unknown. I am so eager to share these findings at the AACR Annual Meeting with world-renowned scientists in the field to gain valuable feedback and potentially facilitate new collaborations that could further propel this project. My long-term career aspirations include becoming a scientific expert on metastatic cancer who also understands the business side of biotech. The more I know about the drug development process, the more I realize the importance of having well-strategized financial and IP plans. To maximize the commercial potential of academic research, I will put myself on both sides of the world and bridge the two so that biotech continues to flourish for the better future of patients.

Research Summary

Clear cell renal cell carcinoma (ccRCC) is the most common malignancy originated from the kidney, with bone and lungs as the main sites of distant spread in vast majority of patients. A key feature of ccRCC is the loss of function of the von Hippel-Lindau (VHL) protein leading to enhanced angiogenesis; in addition, ccRCC exhibits a rich and heterogeneous immune infiltrate. Consequently, different anti-angiogenic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)have emerged as standard of care for these patients, as single agents or in combination. Yet, limited data are available ontheir efficacy in different metastatic sites, and their impact on the immune infiltrate is unclear. We hypothesized thatmodulation of the microenvironment with a TKI provides an additive impact on ICI, and the outcome of combinational treatments depends on metastatic sites, treatment doses and tumor size.To this purpose, we implanted a luciferase-GFP-positive RENCA-VHL- cell line in the tibia of immunocompetent mice, resulting in synchronous bone and lung metastases. Cabozantinib (C), as one of the most potent TKIs, anti-programmed celldeath protein 1 (Anti-PD1) and anti-CTLA4 antibodies, were used as single agents or in combination. The outcomes weremonitored by macroscopic bioluminescence detection in vivo, and 3D multiparametric spatial analysis of bones and lungs, ex vivo. Compared to control-treated mice, all agents significantly reduced tumor progression at both tumor sites. Although all these treatments are clinically applied at stage IV of disease development, differences in their efficacy were noted once treatment was withdrawn. Spatial analysis of tumor cells, immune infiltrate and blood vessels revealed significant changes dependent on treatment, tumor site and time, with potential synergistic mechanism by TKIs when used in combination with ICI. We proved the efficacy of standard of care for bone and lung lesions of ccRCC in an immunocompetent mouse model and identified differences between treatments at the cellular level in the tumor microenvironment. We believe our studies may provide important insights and efficacy predictions for therapeutic applications in metastatic ccRCC patients.

Personal Statement

The most commonly applied drugs for metastatic kidney cancer, antiangiogenic tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICI), have not been specifically studied in any metastatic site.

Hence, there is no data about determinants of response or resistance in these tumor niches. Up to date, nobody has defined the biology of clear cell renal cell carcinoma in bone or lungs, neither the role of the immune infiltrate nor its changes by treatment. Therefore, I developed first immunocompetent mouse model with these two metastatic sites in order to study standard of care and their influence on tissue microenvironment. By attending AACR25 I would broaden my prospective on spatial biology and learn how to apply current knowledge and techniques to level up our research. As a physician, I strongly believe that the future of oncology and medicine relies on physicians who can translate highly relevant clinical questions to the lab bench and contribute to unmet needs in curing cancer. Therefore, as a fourth-year postgraduate fellow while applying for medical residency programs to become physician-scientis, my end goal is to dedicate my lifetime to bone metastases in genitourinary malignancies and patients affected with this unfavorable course of cancer. I am convinced that nothing of these would have sense if we do not share our knowledge among scientists from the rest of the world at the conferences like AACR25.

Research Summary

Renal medullary carcinoma (RMC) is defined by the loss of the SMARCB1 tumor suppressor and represents one of the most aggressive kidney cancers, predominantly affecting young individuals of African descent with the sickle cell trait. RMC exhibits rapid progression, and poor response to standard therapies, with a median survival of only 13 months following diagnosis. In pursuit of more effective treatments, we launched two clinical trials specifically for patients with RMC evaluating anti-PD1 + anti-CTLA4 immune checkpoint therapy (ICT) with nivolumab + ipilimumab (ClinicalTrials.gov identifier: NCT03274258) and anti-PD1 + anti-LAG3 ICT using nivolumab + relatlimab (ClinicalTrials.gov identifier: NCT05347212). However, both trials were terminated early for futility due to resistance and hyperprogression by the established consensus Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 radiological criteria in Matos et al. Clin Cancer Res. 2020 (PMID: 31757877). Co-clinical experiments testing the same ICT regimens in our immunocompetent somatic mosaic genetically engineered mouse model (GEMM) of RMC demonstrated similar patterns of resistance and hyperprogression with ICT compared with IgG control. The combination of anti-PD1 with either anti-CTLA4 or anti-LAG3 significantly accelerated primary tumor progression and markedly increased metastatic burdens in the lung and liver of RMC mice. Comprehensive analyses, including longitudinally collected single-cell RNA sequencing from human RMC patient samples and RNA sequencing of GEMM RMC tumors revealed significant transcriptional reprogramming, enhanced tumor proliferation, activation of oncogenic pathways, and a shift toward myeloid-specific gene expression by RMC tumor cells in response to ICT. In our RMC mouse models, tumor cells have been engineered to express green fluorescent protein (GFP), enabling us to distinguish them from non-malignant mouse cells. Accordingly, multiplex immunofluorescence (mIF) revealed that tumor tissues from mice treated with ICT showed a significant increase of tumor cells co-expressing GFP and myeloid markers such as CD68, F4/80 and S100A9. Differential patterns of resistance and hyperprogression when RMC mice were treated with monotherapies targeting PD1, CTLA4, or LAG3. To counteract ICT-induced hyperprogression, we tested the CEBPB/p300 complex inhibitor IACS16898 which successfully induced tumor responses when combined with ICT in our RMC GEMM. IACS16898 treatment significantly reduced the expression of myeloid-associated markers on GFP+ tumor cells. Our study not only elucidates a novel mechanism of resistance and hyperprogression to PD1 plus either CTLA4 or LAG3 inhibition in SMARCB1-deficient cancers but also provides a foundation for targeting oncogenic and resistance pathways in RMC treated with distinct immunotherapy regimens. 

Personal Statement

My long-term research interests focus on identifying novel therapeutic targets for aggressive cancers with limited treatment options. Losing a close family member to lymphoma at a young age fueled my passion to pursue cancer research. As a medical doctor with a Ph.D. in cancer biology, I bring a unique perspective to addressing clinical needs through basic research. My Ph.D. work under Dr. Powel Brown at MD Anderson focused on triple-negative breast cancer (TNBC), where I identified NUDT5 as a phosphatase that maintains TNBC growth by preventing oxidative DNA damage. I demonstrated the efficacy of a NUDT5 inhibitor in suppressing tumor growth, leading to a first-author publication in Breast Cancer Research and presentations at prestigious conferences like the San Antonio Breast Cancer Symposium. My postdoctoral research builds on this foundation, addressing immunotherapy resistance in renal medullary carcinoma (RMC), a rare, aggressive kidney cancer affecting young individuals. My work has already contributed to a manuscript under revision Nature Cancer. My goal is to become a physician-scientist who bridges patient care and research, addressing real-life challenges in oncology. Attending the AACR meeting will provide an invaluable platform to present my findings, gain expert feedback, and foster collaborations to advance cancer treatment. The AACR Scholar-in-Training Award will help me further my mission to develop effective therapies for aggressive cancers.