المؤلفون: Matilde Simoni, Chiara Menegazzi, Cristina Fracassi, Claudia C Biffi, Francesca Genova, Nazario Pio Tenace, Roberta Lucianò, Andrea Raimondi, Carlo Tacchetti, James Brugarolas, Davide Mazza, Rosa Bernardi

المصدر: EMBO Molecular Medicine, Vol 16, Iss 6, Pp 1324-1351 (2024)

مصطلحات موضوعية: PML, ccRCC, p53, Senescence, Arsenic Trioxide, Medicine (General), R5-920, Genetics, QH426-470

الوصف: Abstract Clear-cell renal cell carcinoma (ccRCC), the major subtype of RCC, is frequently diagnosed at late/metastatic stage with 13% 5-year disease-free survival. Functional inactivation of the wild-type p53 protein is implicated in ccRCC therapy resistance, but the detailed mechanisms of p53 malfunction are still poorly characterized. Thus, a better understanding of the mechanisms of disease progression and therapy resistance is required. Here, we report a novel ccRCC dependence on the promyelocytic leukemia (PML) protein. We show that PML is overexpressed in ccRCC and that PML depletion inhibits cell proliferation and relieves pathologic features of anaplastic disease in vivo. Mechanistically, PML loss unleashed p53-dependent cellular senescence thus depicting a novel regulatory axis to limit p53 activity and senescence in ccRCC. Treatment with the FDA-approved PML inhibitor arsenic trioxide induced PML degradation and p53 accumulation and inhibited ccRCC expansion in vitro and in vivo. Therefore, by defining non-oncogene addiction to the PML gene, our work uncovers a novel ccRCC vulnerability and lays the foundation for repurposing an available pharmacological intervention to restore p53 function and chemosensitivity.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1757-4684Test

الوصول الحر: https://doaj.org/article/943d98c6d7a140ae919de5ddf5a741fdTest

المؤلفون: Sari Khaleel, Christopher Ricketts, W. Marston Linehan, Mark Ball, Brandon Manley, Samra Turajilic, James Brugarolas, Ari Hakimi

المصدر: Société Internationale d’Urologie Journal, Vol 3, Iss 6, Pp 386-396 (2022)

مصطلحات موضوعية: renal cell carcinoma, clear cell carcinoma, non-clear cell renal cell carcinoma, genetics, tumor microenvironment, Diseases of the genitourinary system. Urology, RC870-923

الوصف: Renal cell carcinoma is a diverse group of diseases that can be distinguished by distinct histopathologic and genomic features. In this comprehensive review, we highlight recent advancements in our understanding of the genetic and microenvironmental hallmarks of kidney cancer. We begin with clear cell renal cell carcinoma (ccRCC), the most common subtype of this disease. We review the chromosomal and genetic alterations that drive initiation and progression of ccRCC, which has recently been shown to follow multiple highly conserved evolutionary trajectories that in turn impact disease progression and prognosis. We also review the diverse genetic events that define the many recently recognized rare subtypes within non-clear cell RCC. Finally, we discuss our evolving understanding of the ccRCC microenvironment, which has been revolutionized by recent bulk and single-cell transcriptomic analyses, suggesting potential biomarkers for guiding systemic therapy in the management of advanced ccRCC.

وصف الملف: electronic resource

العلاقة: https://siuj.org/index.php/siuj/article/download/217/170Test; https://doaj.org/toc/2563-6499Test

الوصول الحر: https://doaj.org/article/fa6da6e015554c299dd8748de96a5f1fTest

المؤلفون: Divya Bezwada, James Brugarolas

المصدر: The Journal of Clinical Investigation, Vol 133, Iss 11 (2023)

مصطلحات موضوعية: Medicine

الوصف: Fumarate hydratase–deficient (FH-deficient) renal cell carcinoma (RCC) represents a particularly aggressive form of kidney cancer. FH-deficient RCC arises in the setting of germline, or solely somatic, mutations in the FH gene, a two-hit tumor suppressor gene. Early detection can be curative, but there are no biomarkers, and in the sporadic setting, establishing a diagnosis of FH-deficient RCC is challenging. In this issue of the JCI, Zheng, Zhu, and co-authors report untargeted plasma metabolomic analyses to identify putative biomarkers. They discovered two plasma metabolites directly linked to fumarate overproduction by tumor cells, succinyl-adenosine and succinic-cysteine, which correlate with tumor burden. The identification of circulating biomarkers of FH-deficient RCC may aid in the diagnosis of FH-deficient RCC and provide a means for longitudinal follow-up.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/1558-8238Test

الوصول الحر: https://doaj.org/article/e2431da534d14526803f43e30070088fTest

المؤلفون: Cassandra Duarte, Junxiao Hu, Benoit Beuselinck, Justine Panian, Nicole Weise, Nazli Dizman, Katharine A. Collier, Nityam Rathi, Haoran Li, Roy Elias, Nieves Martinez-Chanza, Tracy L. Rose, Lauren C. Harshman, Dharmesh Gopalakrishnan, Ulka Vaishampayan, Yousef Zakharia, Vivek Narayan, Benedito A. Carneiro, Anthony Mega, Nirmish Singla, Cheryl Meguid, Saby George, James Brugarolas, Neeraj Agarwal, Amir Mortazavi, Sumanta Pal, Rana R. McKay, Elaine T. Lam

المصدر: EClinicalMedicine, Vol 60, Iss , Pp 102018- (2023)

مصطلحات موضوعية: Metastatic renal cell carcinoma, Pancreatic metastases, VEGFR, Immunotherapy, Medicine (General), R5-920

الوصف: Summary: Background: Metastatic renal cell carcinoma (mRCC) is a heterogenous disease with poor 5-year overall survival (OS) at 14%. Patients with mRCC to endocrine organs historically have prolonged OS. Pancreatic metastases are uncommon overall, with mRCC being the most common etiology of pancreatic metastases. In this study, we report the long-term outcomes of patients with mRCC to the pancreas in two separate cohorts. Methods: We performed a multicenter, international retrospective cohort study of patients with mRCC to the pancreas at 15 academic centers. Cohort 1 included 91 patients with oligometastatic disease to the pancreas. Cohort 2 included 229 patients with multiples organ sites of metastases including the pancreas. The primary endpoint for Cohorts 1 and 2 was median OS from time of metastatic disease in the pancreas until death or last follow up. Findings: In Cohort 1, the median OS (mOS) was 121 months with a median follow up time of 42 months. Patients who underwent surgical resection of oligometastatic disease had mOS of 100 months with a median follow-up time of 52.5 months. The mOS for patients treated with systemic therapy was not reached. In Cohort 2, the mOS was 90.77 months. Patients treated with first-line (1L) VEGFR therapy had mOS of 90.77 months; patients treated with IL immunotherapy (IO) had mOS of 92 months; patients on 1L combination VEGFR/IO had mOS of 74.9 months. Interpretations: This is the largest retrospective cohort of mRCC involving the pancreas. We confirmed the previously reported long-term outcomes in patients with oligometastatic pancreas disease and demonstrated prolonged survival in patients with multiple RCC metastases that included the pancreas. In this retrospective study with heterogeneous population treated over 2 decades, mOS was similar when stratified by first-line therapy. Future research will be needed to determine whether mRCC patients with pancreatic metastases require a different initial treatment strategy. Funding: Statistical analyses for this study were supported in part by the University of Colorado Cancer Center Support Grant from the NIH/NCI, P30CA046934-30.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2589537023001955Test; https://doaj.org/toc/2589-5370Test

الوصول الحر: https://doaj.org/article/153c01ff313644d0bf2fd30f76560d5dTest

المؤلفون: James Brugarolas, Michael B Atkins, Brian I Rini

المصدر: Journal for ImmunoTherapy of Cancer, Vol 11, Iss 3 (2023)

مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Advanced renal cell carcinoma is a biologically heterogeneous disease with multiple treatment options that largely involve immunotherapy and/or anti-angiogenic therapies. The choice of initial and subsequent therapy depends on both clinical and biological considerations. Here, we describe the application of recent data to clinical practice.

وصف الملف: electronic resource

العلاقة: https://jitc.bmj.com/content/11/3/e006361.fullTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/4cba60273fac488aabdf0ef591f21807Test

المؤلفون: Payal Kapur, James Brugarolas, Kiril Trpkov

المصدر: Cancers, Vol 15, Iss 16, p 4043 (2023)

مصطلحات موضوعية: kidney cancer, tuberin, hamartin, PTEN, ccRCC, clear cell renal cell carcinoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: A spectrum of renal tumors associated with frequent TSC/mTOR (tuberous sclerosis complex/mechanistic target of rapamycin) pathway gene alterations (in both the germline and sporadic settings) have recently been described. These include renal cell carcinoma with fibromyomatous stroma (RCC FMS), eosinophilic solid and cystic renal cell carcinoma (ESC RCC), eosinophilic vacuolated tumor (EVT), and low-grade oncocytic tumor (LOT). Most of these entities have characteristic morphologic and immunohistochemical features that enable their recognition without the need for molecular studies. In this report, we summarize recent advances and discuss their evolving complexity.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/2072-6694/15/16/4043Test; https://doaj.org/toc/2072-6694Test

الوصول الحر: https://doaj.org/article/abee8474f3634bf1baef0c4d9c667e8bTest

المؤلفون: Kangsan Kim, Qinbo Zhou, Alana Christie, Christina Stevens, Yuanqing Ma, Oreoluwa Onabolu, Suneetha Chintalapati, Tiffani Mckenzie, Vanina Toffessi Tcheuyap, Layton Woolford, He Zhang, Nirmish Singla, Pravat Kumar Parida, Mauricio Marquez-Palencia, Ivan Pedrosa, Vitaly Margulis, Arthur Sagalowsky, Zhiqun Xie, Tao Wang, Steffen Durinck, Zora Modrusan, Somasekar Seshagiri, Payal Kapur, James Brugarolas, Srinivas Malladi

المصدر: Nature Communications, Vol 12, Iss 1, Pp 1-12 (2021)

مصطلحات موضوعية: Science

الوصف: Tumour thrombi (TT) are intravascular extensions of renal cell carcinomas (RCC) which often lead to distant metastases. Here the authors examine the determinants of vascular invasion and metastasis in a unique cohort of RCC patients with TT using multi-region genomics and in vivo models.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2041-1723Test

الوصول الحر: https://doaj.org/article/3266527d43244260bdb0306af8f05a4dTest

المؤلفون: Vandana Panwar, Jay Jasti, Vitaly Margulis, James Brugarolas, Payal Kapur, Satwik Rajaram

المصدر: Journal of Pathology Informatics, Vol 13, Iss , Pp 100083- (2022)

مصطلحات موضوعية: Computer applications to medicine. Medical informatics, R858-859.7, Pathology, RB1-214

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2153353922000839Test; https://doaj.org/toc/2153-3539Test

الوصول الحر: https://doaj.org/article/3c81c7ffa9fd48feba8c5f708137fe56Test

المؤلفون: Jonathan E. Schoenhals, BS, Osama Mohamad, MD, PhD, Alana Christie, MS, Yuanyuan Zhang, MD, PhD, Daniel Li, MD, Nirmish Singla, MD, MSCS, Isaac Bowman, MD, Waddah Arafat, MD, Hans Hammers, MD, Kevin Courtney, MD, PhD, Suzanne Cole, MD, Aditya Bagrodia, MD, Vitaly Margulis, MD, Neil Desai, MD, Aurelie Garant, MD, Hak Choy, MD, Robert Timmerman, MD, James Brugarolas, MD, PhD, Raquibul Hannan, MD, PhD

المصدر: Advances in Radiation Oncology, Vol 6, Iss 5, Pp 100692- (2021)

مصطلحات موضوعية: Medical physics. Medical radiology. Nuclear medicine, R895-920, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Purpose: Oligoprogression, defined as limited sites of progression on systemic therapy, in patients with metastatic renal cell carcinoma (mRCC) is not uncommon, possibly because of inter- and intratumoral heterogeneity. We evaluated the effect of stereotactic ablative radiation therapy (SAbR) for longitudinal control of oligoprogressive mRCC. Methods and Materials: Patients with extracranial mRCC were included in this retrospective analysis if they progressed in ≤3 sites on systemic therapy while demonstrating response/stability at other sites and received SAbR to all progressing sites without switching systemic therapy. Our primary endpoint was modified progression-free survival (mPFS), which we calculated from the start of SAbR to the start of a subsequent systemic therapy, death, or loss to follow-up. Results: We identified 36 patients with a median follow-up of 20.4 months (interquartile range, 10.9-29.4). Forty-three sites were treated with SAbR with a median dose of 36 Gy (range, 18-50) in 3 fractions (range, 1-5). Median time to SAbR from the start of systemic therapy was 11.4 months (interquartile range, 6.1-17.1). Median mPFS was 9.2 months (95% confidence interval [CI], 5.9-13.2). Patients receiving SAbR while on immunotherapy exhibited a longer median mPFS (>28.4 months, log-rank P = .0001) than patients not on immunotherapy (9.2 months). Median overall survival from SAbR administration was 43.4 months (95% CI, 21.5-not Reached). The 1-year local control rate was 93% (95% CI, 78.7-97.5). Most SAbR-related toxicities were grade 1 to 2 (33% of patients), with one grade 5 hemoptysis event possibly related to SAbR or disease progression. Conclusions: SAbR has the potential to extend the the duration of current systemic therapy for selected patients with mRCC, preserving subsequent therapies for later administration possibly enabling longer treatment duration.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S2452109421000506Test; https://doaj.org/toc/2452-1094Test

الوصول الحر: https://doaj.org/article/d3d6725df09840e68eee2bfa7aa552b3Test

المؤلفون: Joseph Vento, Aditi Mulgaonkar, Layton Woolford, Kien Nham, Alana Christie, Aditya Bagrodia, Alberto Diaz de Leon, Raquibul Hannan, Isaac Bowman, Renee M. McKay, Payal Kapur, Guiyang Hao, Xiankai Sun, James Brugarolas

المصدر: Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-6 (2019)

مصطلحات موضوعية: Kidney cancer, Renal cancer, Immuno-PET, PD-L1, PD-1, PDX, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282

الوصف: Abstract Background Programmed death-ligand 1 (PD-L1) expression in metastatic renal cell carcinoma (RCC) correlates with a worse prognosis, but whether it also predicts responsiveness to anti-PD-1/PD-L1 therapy remains unclear. Most studies of PD-L1 are limited by evaluation in primary rather than metastatic sites, and in biopsy samples, which may not be representative. These limitations may be overcome with immuno–positron emission tomography (iPET), an emerging tool allowing the detection of cell surface proteins with radiolabeled antibodies. Here, we report iPET studies of PD-L1 in a preclinical tumorgraft model of clear cell RCC (ccRCC) from a patient who had a favorable response to anti-PD-1 therapy. Case presentation A 49-year-old man underwent a cytoreductive nephrectomy in 2017 of a right kidney tumor invading into the adrenal gland that was metastatic to the lungs and a rib. Histological analyses revealed a ccRCC of ISUP grade 4 with extensive sarcomatoid features. IMDC risk group was poor. Within two hours of surgery, a tumor sample was implanted orthotopically into NOD/SCID mice. Consistent with an aggressive tumor, a renal mass was detected 18 days post-implantation. Histologically, the tumorgraft showed sarcomatoid differentiation and high levels of PD-L1, similar to the patient’s tumor. PD-L1 was evaluated in subsequently transplanted mice using iPET and the results were compared to control mice implanted with a PD-L1-negative tumor. We labeled atezolizumab, an anti-PD-L1 antibody with a mutant Fc, with zirconium-89. iPET revealed significantly higher 89Zr-atezolizumab uptake in index than control tumorgrafts. The patient was treated with high-dose IL2 initially, and subsequently with pazopanib, with rapidly progressive disease, but had a durable response with nivolumab. Conclusions To our knowledge, this is the first report of non-invasive detection of PD-L1 in renal cancer using molecular imaging. This study supports clinical evaluation of iPET to identify RCC patients with tumors deploying the PD-L1 checkpoint pathway who may be most likely to benefit from PD-1/PD-L1 disrupting drugs.

وصف الملف: electronic resource

العلاقة: http://link.springer.com/article/10.1186/s40425-019-0607-zTest; https://doaj.org/toc/2051-1426Test

الوصول الحر: https://doaj.org/article/8c4fd226b847427c8134b2fba28b7121Test