A renal cell carcinoma tumorgraft platform to advance precision medicine

Elias, Roy; Tcheuyap, Vanina Toffessi; Kaushik, Akash; Singla, Nirmish; Gao, Ming; Torras, Oscar Reig; Christie, Alana; Mulgaonkar, Aditi; Woolford, Layton; Stevens, Christina; Kettimuthu, Kavitha Priya; Pavía-Jiménez, Andrea; Boroughs, Lindsey K.; Joyce, Allison; Notgrass, Hollis; Margulis, Vitaly; Cadeddu, Jeffrey A.; Pedrosa, Iván; Williams, Noelle S.; Sun, Xiankai; DeBerardinis, Ralph J.; Öz, Orhan K.; Zhong, Hua; Seshagiri, Somasekar; Modrušan, Zora; Cantarel, Brandi L.; Kapur, Payal; Brugarolas, James

doi:10.1016/j.celrep.2021.110055

Cited by 22 publications

(32 citation statements)

References 101 publications

(212 reference statements)

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“…In contrast to previously published RCC PDX cohorts (40), our panel consists of a larger number of models, predominantly from untreated primary tumors and metastases of distinct localizations, and enables the evaluation of ITH on treatment response by multiregional RCC PDX models. To the best of our knowledge, this was only reported once very recently for RCC PDX models (45) and is a special feature of our RCC PDX panel. As ITH was recently reported to help predict the patient response against PD-1 blockade, and metabolic differences in distinct tumor areas may account for heterogeneity in drug sensitivity, this aspect will gain importance in future anti-cancer therapy (46,47).…”

Section: Discussionmentioning

confidence: 73%

“…However, no PDX model could be established from the twenty-one patients with disclosed neoadjuvant treatment history (10% sunitinib, 90% everolimus). Nevertheless, our methodology with s.c. tumor fragment transplantation was superior in terms of take rate compared to orthotopic RCC patient-derived tumor graft models ( 45 ). A very similar effect of reduced take rates was reported during the establishment of PDX models from breast cancer patients after neoadjuvant therapy ( 48 , 49 ).…”

Section: Discussionmentioning

confidence: 99%

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A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies

Gürgen

Becker²,

Dahlmann³

et al. 2022

Front. Oncol.

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Renal cell carcinoma (RCC) is a kidney cancer with an onset mainly during the sixth or seventh decade of the patient’s life. Patients with advanced, metastasized RCC have a poor prognosis. The majority of patients develop treatment resistance towards Standard of Care (SoC) drugs within months. Tyrosine kinase inhibitors (TKIs) are the backbone of first-line therapy and have been partnered with an immune checkpoint inhibitor (ICI) recently. Despite the most recent progress, the development of novel therapies targeting acquired TKI resistance mechanisms in advanced and metastatic RCC remains a high medical need. Preclinical models with high translational relevance can significantly support the development of novel personalized therapies. It has been demonstrated that patient-derived xenograft (PDX) models represent an essential tool for the preclinical evaluation of novel targeted therapies and their combinations. In the present project, we established and molecularly characterized a comprehensive panel of subcutaneous RCC PDX models with well-conserved molecular and pathological features over multiple passages. Drug screening towards four SoC drugs targeting the vascular endothelial growth factor (VEGF) and PI3K/mTOR pathway revealed individual and heterogeneous response profiles in those models, very similar to observations in patients. As unique features, our cohort includes PDX models from metastatic disease and multi-tumor regions from one patient, allowing extended studies on intra-tumor heterogeneity (ITH). The PDX models are further used as basis for developing corresponding in vitro cell culture models enabling advanced high-throughput drug screening in a personalized context. PDX models were subjected to next-generation sequencing (NGS). Characterization of cancer-relevant features including driver mutations or cellular processes was performed using mutational and gene expression data in order to identify potential biomarker or treatment targets in RCC. In summary, we report a newly established and molecularly characterized panel of RCC PDX models with high relevance for translational preclinical research.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies

Gürgen

Becker²,

Dahlmann³

et al. 2022

Front. Oncol.

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“…In one large study that included over 400 samples, ∼15% of ccRCC metastases harbored TP53 mutations ( 37 ). Another study found that 12% of ccRCC patient-derived xenografts (PDXs) bore TP53 mutations, suggesting that TP53 mutations increase ccRCC fitness and successful PDX propagation, both of which might correlate with more aggressive clinical disease ( 38 ). Moreover, other genes in the p53 pathway, such as ATM and MDM2 , are also mutated, albeit infrequently, in ccRCC ( 1 , 4 , 32 – 35 ), and TP53 loss cooperates with VHL loss to promote murine ccRCC ( 39 , 40 ).…”

Section: Resultsmentioning

confidence: 99%

Sensitivity ofVHLmutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway

Stransky

Vigeant

Huang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance VHL tumor suppressor gene inactivation is a hallmark of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and promotes tumor growth by stabilizing the hypoxia-inducible factor 2 (HIF2) transcription factor. HIF2 inhibitors appear to be helpful for some, but not all, ccRCC patients in clinical trials. Previous preclinical and clinical data suggested that only ccRCCs that can activate the p53 tumor suppressor in response to DNA damage would respond to HIF2 inhibitors. Here, we show that an intact p53 pathway is neither necessary nor sufficient for the sensitivity of ccRCCs to HIF2 inhibitors, suggesting that it would be premature to use p53 status to determine which ccRCC patients should be treated with a HIF2 inhibitor.

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“…TAK-243 is a first-in-class UBA1 inhibitor that displays preclinical efficacy in a broad spectrum of solid and hematologic malignancies including colorectal cancer 29 , glioblastoma 44 , renal cell carcinoma 45 , small-cell lung cancer 46 , acute myeloid leukemia 22 , multiple myeloma 47 , B-cell lymphoma 48 , and chronic lymphocytic leukemia 49 . Additionally, it has been advanced to phase 1 clinical trials in advanced malignancies and acute myeloid leukemia 30 .…”

Section: Discussionmentioning

confidence: 99%

A combinatorial anticancer drug screen identifies off-target effects of epigenetic chemical probes

Barghout

Mann

et al. 2022

Preprint

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Anticancer drug response is determined by genetic and epigenetic mechanisms. To identify the epigenetic regulators of anticancer drug response, we conducted a chemical epigenetics screen using chemical probes that target different epigenetic modulators. In this screen, we tested 31 epigenetic probes in combination with 14 mechanistically diverse anticancer agents and identified 8 epigenetic probes that significantly potentiate the cytotoxicity of TAK-243, a first-in-class ubiquitin-activating enzyme (UBA1) inhibitor evaluated in several solid and hematologic malignancies. These probes are TP-472, GSK-864, A-196, UNC1999, SGC-CBP30 and PFI-4 (and its related analogs GSK6853 and GSK5959), and they target BRD9/7, mutant IDH1, SUV420H1/2, EZH2/1, p300/CBP and BRPF1B, respectively. In contrast to epigenetic probes, negative control compounds did not have a significant impact on TAK-243 cytotoxicity. Potentiation of TAK-243 cytotoxicity was associated with reduced ubiquitylation and induction of apoptosis. Mechanistically, epigenetic probes exerted their potentiation by inhibiting the efflux transporter ABCG2 without inducing significant changes in the ubiquitylation pathways or ABCG2 expression levels. The identified probes shared chemical scaffold similarities with TAK-243 and could potentially interact with ABCG2 as assessed by docking analysis. Based on these data, we have developed a cell-based assay that can quantitatively evaluate ABCG2 inhibition by drug candidates. In conclusion, our study identifies epigenetic chemical probes that profoundly potentiate TAK-243 cytotoxicity through off-target ABCG2 inhibition. We also provide experimental evidence that several negative control compounds cannot exclude a subset of off-target effects of chemical probes. Finally, potentiation of TAK-243 cytotoxicity can serve as a quantitative measure of ABCG2-inhibitory activity.

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A renal cell carcinoma tumorgraft platform to advance precision medicine

Cited by 22 publications

References 101 publications

A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies

A Molecularly Characterized Preclinical Platform of Subcutaneous Renal Cell Carcinoma (RCC) Patient-Derived Xenograft Models to Evaluate Novel Treatment Strategies

Sensitivity ofVHLmutant kidney cancers to HIF2 inhibitors does not require an intact p53 pathway

A combinatorial anticancer drug screen identifies off-target effects of epigenetic chemical probes

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