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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 -
Journal of Kidney Cancer and VHL 2017Renal medullary carcinoma (RMC) is a rare, highly aggressive tumor recognized as an independent pathological entity. African-descent adolescents and young adults with... (Review)
Review
Renal medullary carcinoma (RMC) is a rare, highly aggressive tumor recognized as an independent pathological entity. African-descent adolescents and young adults with sickle cell hemoglobinopathy are the most affected groups. This rare subtype of renal cell carcinoma has its own morphogenetic and pathological characteristics. The major clinical manifestations include gross hematuria, abdominal or flank pain, and weight loss. The prognosis is very poor, with 95% of cases diagnosed at an advanced stage of the disease. In this review, we summarize the morphologic and dynamic characteristics of RMC under various imaging modalities such as ultrasound, computed tomography, and magnetic resonance. Differential diagnosis and management strategies are also discussed.
PubMed: 28405543
DOI: 10.15586/jkcvhl.2017.62 -
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 -
Archives of Pathology & Laboratory... Sep 2021Renal malignancies can be divided into cortical- and medullary-based tumors, the latter of which classically infiltrate the renal parenchyma by extending between... (Review)
Review
CONTEXT.—
Renal malignancies can be divided into cortical- and medullary-based tumors, the latter of which classically infiltrate the renal parenchyma by extending between nonneoplastic structures. Although high-grade cortical tumors can rarely exhibit the same growth pattern, the infiltrative morphology should elicit a differential diagnosis to be considered in each case. However, these diagnoses can be challenging to distinguish, especially on small renal biopsy samples.
OBJECTIVE.—
To provide an overview of the clinical, gross, and microscopic findings; genetic and molecular alterations; and immunohistochemical evaluation of medullary-based renal tumors and other tumor types with overlapping morphologies and growth patterns.
DATA SOURCES.—
Literature review and personal observations were used to compile the information in this review.
CONCLUSIONS.—
Collecting duct carcinoma is a prototypical medullary-based tumor, and although diagnostic criteria exist, it remains a diagnosis of exclusion, especially with ancillary techniques aiding the recognition of established as well as more recently described neoplasms. Other medullary-based malignancies included in the differential diagnosis include renal medullary carcinoma/renal cell carcinoma unclassified with medullary phenotype, fumarate hydratase-deficient renal cell carcinoma, and upper tract urothelial carcinoma. Moreover, other rare entities should be excluded, including metastatic carcinoma, lymphoma, and melanoma. In addition to potential prognostic differences, accurate diagnoses can have important surgical and clinical management implications.
Topics: Diagnosis, Differential; Humans; Kidney Medulla; Kidney Neoplasms
PubMed: 33406251
DOI: 10.5858/arpa.2020-0464-RA -
Frontiers in Endocrinology 2022Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant tumor originating from parafollicular C-cells producing calcitonin. Most of cases (75%) are sporadic... (Review)
Review
Medullary thyroid carcinoma (MTC) is a neuroendocrine malignant tumor originating from parafollicular C-cells producing calcitonin. Most of cases (75%) are sporadic while the remaining (25%) are hereditary. In these latter cases medullary thyroid carcinoma can be associated (multiple endocrine neoplasia type IIA and IIB) or not (familial medullary thyroid carcinoma), with other endocrine diseases such as pheochromocytoma and/or hyperparathyroidism. RET gene point mutation is the main molecular alteration involved in MTC tumorigenesis, both in sporadic and in hereditary cases. Total thyroidectomy with prophylactic/therapeutic central compartment lymph nodes dissection is the initial treatment of choice. Further treatments are needed according to tumor burden and rate of progression. Surgical treatments and local therapies are advocated in the case of single or few local or distant metastasis and slow rate of progression. Conversely, systemic treatments should be initiated in cases with large metastatic and rapidly progressive disease. In this review, we discuss the details of systemic treatments in advanced and metastatic sporadic MTC, focusing on multikinase inhibitors, both those already used in clinical practice and under investigation, and on emerging treatments such as highly selective RET inhibitors and radionuclide therapy.
Topics: Carcinoma, Neuroendocrine; Humans; Multiple Endocrine Neoplasia Type 2a; Precision Medicine; Proto-Oncogene Proteins c-ret; Thyroid Neoplasms
PubMed: 35422765
DOI: 10.3389/fendo.2022.864253 -
Proceedings of the National Academy of... May 2023Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized...
Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor . Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.
Topics: Animals; Humans; Mice; Carcinoma, Renal Cell; Hypoxia; Kidney; Kidney Neoplasms; Sickle Cell Trait; SMARCB1 Protein
PubMed: 37186844
DOI: 10.1073/pnas.2209639120 -
Visceral Medicine Dec 2018Medullary thyroid carcinoma (MTC) represents a distinct form of thyroid cancer with a potentially aggressive behavior, early lymph node metastases, and sporadic as well... (Review)
Review
Medullary thyroid carcinoma (MTC) represents a distinct form of thyroid cancer with a potentially aggressive behavior, early lymph node metastases, and sporadic as well as hereditary forms. Only surgery with total thyroidectomy and lymph node dissection is able to achieve biochemical cure. Due to the uncommon nature of MTC, a specialization in endocrine surgery for diagnosis as well as therapy of MTC seem to be mandatory for a successful treatment. Knowledge of genotype-phenotype correlations for hereditary forms or routine calcitonin screening for sporadic forms is important to analyze preoperative findings and plan surgical procedures. Postoperative follow-up depends on biochemical cure or monitoring for patients with elevated calcitonin levels.
PubMed: 30675485
DOI: 10.1159/000493809