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Nature Communications May 2023Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin...
Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.
Topics: Humans; Kidney Neoplasms; Sickle Cell Trait; Carcinoma, Medullary; Ferroptosis; Carcinoma, Renal Cell; SMARCB1 Protein; Repressor Proteins; Homeodomain Proteins
PubMed: 37236926
DOI: 10.1038/s41467-023-38472-y -
Clinical and Translational Medicine May 2023Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by...
BACKGROUND
Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC.
METHODS
We evaluated the IC concentrations of the neddylation-activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat alone or in combination with platinum-based chemotherapy was evaluated in vivo in platinum-naïve and platinum-experienced patient-derived xenograft (PDX) models of RMC.
RESULTS
The RMC cell lines demonstrated IC concentrations of pevonedistat below the maximum tolerated dose in humans. When combined with carboplatin, pevonedistat demonstrated a significant in vitro synergistic effect. Treatment with carboplatin alone increased nuclear ERCC1 levels used to repair the interstrand crosslinks induced by platinum salts. Conversely, the addition of pevonedistat to carboplatin led to p53 upregulation resulting in FANCD2 suppression and reduced nuclear ERCC1 levels. The addition of pevonedistat to platinum-based chemotherapy significantly inhibited tumour growth in both platinum-naïve and platinum-experienced PDX models of RMC (p < .01).
CONCLUSIONS
Our results suggest that pevonedistat synergises with carboplatin to inhibit RMC cell and tumour growth through inhibition of DNA damage repair. These findings support the development of a clinical trial combining pevonedistat with platinum-based chemotherapy for RMC.
Topics: Humans; Carboplatin; Carcinoma, Medullary; Carcinoma, Renal Cell; Kidney Neoplasms
PubMed: 37226898
DOI: 10.1002/ctm2.1267 -
International Journal of Molecular... Jun 2022Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs... (Review)
Review
Renal medullary carcinoma (RMC) is a rare renal malignancy that has been associated with sickle hemoglobinopathies. RMC is aggressive, difficult to treat, and occurs primarily in adolescents and young adults of African ancestry. This cancer is driven by the loss of SMARCB1, a tumor suppressor seen in a number of primarily rare childhood cancers (e.g., rhabdoid tumor of the kidney and atypical teratoid rhabdoid tumor). Treatment options remain limited due in part to the limited knowledge of RMC biology. However, significant advances have been made in unraveling the biology of RMC, from genomics to therapeutic targets, over the past 5 years. In this review, we will present these advances and discuss what new questions exist in the field.
Topics: Adolescent; Carcinoma, Medullary; Carcinoma, Renal Cell; Child; Humans; Kidney Neoplasms; Neoplasms, Neuroepithelial; Rhabdoid Tumor; Young Adult
PubMed: 35806102
DOI: 10.3390/ijms23137097 -
Future Oncology (London, England) Sep 2022Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated...
Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with -mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic -mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, -mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. Key secondary objectives are to compare other efficacy outcomes (per RECIST 1.1) and tolerability of selpercatinib versus cabozantinib or vandetanib.
Topics: Anilides; Carcinoma, Neuroendocrine; Clinical Trials, Phase III as Topic; Humans; Multicenter Studies as Topic; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-ret; Pyrazoles; Pyridines; Randomized Controlled Trials as Topic; Thyroid Neoplasms
PubMed: 35969032
DOI: 10.2217/fon-2022-0657 -
Pathologica Sep 2020Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is... (Review)
Review
Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.
Topics: Adenocarcinoma; Carcinoma, Pancreatic Ductal; Humans; Pancreas; Pancreas, Exocrine; Pancreatic Neoplasms
PubMed: 33179623
DOI: 10.32074/1591-951X-167 -
Frontiers in Endocrinology 2022
PubMed: 35464069
DOI: 10.3389/fendo.2022.891903 -
Frontiers in Endocrinology 2022The treatment options that are currently available for management of metastatic, progressive radioactive iodine (RAI)-refractory differentiated thyroid cancers (DTCs),... (Review)
Review
The treatment options that are currently available for management of metastatic, progressive radioactive iodine (RAI)-refractory differentiated thyroid cancers (DTCs), and medullary thyroid cancers (MTCs) are limited. While there are several systemic targeted therapies, such as tyrosine kinase inhibitors, that are being evaluated and implemented in the treatment of these cancers, such therapies are associated with serious, sometimes life-threatening, adverse events. Peptide receptor radionuclide therapy (PRRT) has the potential to be an effective and safe modality for treating patients with somatostatin receptor (SSTR)+ RAI-refractory DTCs and MTCs. MTCs and certain sub-types of RAI-refractory DTCs, such as Hürthle cell cancers which are less responsive to conventional modalities of treatment, have demonstrated a favorable response to treatment with PRRT. While the current literature offers hope for utilization of PRRT in thyroid cancer, several areas of this field remain to be investigated further, especially head-to-head comparisons with other systemic targeted therapies. In this review, we provide a comprehensive outlook on the current translational and clinical data on the use of various PRRTs, including diagnostic utility of somatostatin analogs, theranostic properties of PRRT, and the potential areas for future research.
Topics: Carcinoma, Neuroendocrine; Humans; Iodine Radioisotopes; Receptors, Somatostatin; Thyroid Neoplasms
PubMed: 35712243
DOI: 10.3389/fendo.2022.896287