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Cancer Research Jun 2024The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict...
The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet. Despite its importance in oncogenesis, SCD underwent monoallelic co-deletion along with PTEN on chromosome 10q in about 47.5% of melanoma, and the other SCD allele was methylated, resulting in very low SCD expression. While this SCD deficient subset was refractory to SCD inhibitors, the subset of PTEN wildtype melanoma that retained SCD was sensitive. As dietary oleic acid could potentially blunt the effect of SCD inhibitors, a low-oleic acid custom diet was combined with SCD inhibitor. The combination reduced monounsaturated fatty acids and increased saturated fatty acids, inducing robust apoptosis and growth suppression and inhibiting lung metastasis with minimal toxicity in preclinical mouse models of PTEN wildtype melanoma. When combined with anti-PD1 immunotherapy, the SCD inhibitor improved T cell functionality and further constrained melanoma growth in mice. Collectively, these results suggest that optimizing SCD inhibitors with diets low in oleic acid may offer a viable and efficacious therapeutic approach for improving melanoma treatment.
PubMed: 38885087
DOI: 10.1158/0008-5472.CAN-23-1635 -
Gan To Kagaku Ryoho. Cancer &... May 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous; Adult; Hematopoietic Stem Cell Transplantation; Philadelphia Chromosome
PubMed: 38881062
DOI: No ID Found -
Gan To Kagaku Ryoho. Cancer &... May 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Adult; Philadelphia Chromosome; Antineoplastic Agents
PubMed: 38881060
DOI: No ID Found -
Gan To Kagaku Ryoho. Cancer &... May 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Adult; Philadelphia Chromosome; Antineoplastic Agents
PubMed: 38881059
DOI: No ID Found -
ELife Jun 2024Philadelphia chromosome-positive (Ph) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved...
Philadelphia chromosome-positive (Ph) leukemia is a fatal hematological malignancy. Although standard treatments with tyrosine kinase inhibitors (TKIs) have achieved remarkable success in prolonging patient survival, intolerance, relapse, and TKI resistance remain serious issues for patients with Ph leukemia. Here, we report a new leukemogenic process in which RAPSYN and BCR-ABL co-occur in Ph leukemia, and RAPSYN mediates the neddylation of BCR-ABL. Consequently, neddylated BCR-ABL enhances the stability by competing its c-CBL-mediated degradation. Furthermore, SRC phosphorylates RAPSYN to activate its NEDD8 E3 ligase activity, promoting BCR-ABL stabilization and disease progression. Moreover, in contrast to in vivo ineffectiveness of PROTAC-based degraders, depletion of RAPSYN expression, or its ligase activity decreased BCR-ABL stability and, in turn, inhibited tumor formation and growth. Collectively, these findings represent an alternative to tyrosine kinase activity for the oncoprotein and leukemogenic cells and generate a rationale of targeting RAPSYN-mediated BCR-ABL neddylation for the treatment of Ph leukemia.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Fusion Proteins, bcr-abl; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; NEDD8 Protein; Ubiquitin-Protein Ligases; Muscle Proteins
PubMed: 38865175
DOI: 10.7554/eLife.88375 -
Cell Reports Jun 2024Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells...
Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory PGCs; however, it exhibits enhanced germline and pluripotency programs and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister-Killian syndrome patients mosaic for i(12p), we model seminoma and identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular, and signaling programs driving seminoma transformation, and the in vitro platform developed herein permits evaluation of additional signals required for seminoma tumorigenesis.
PubMed: 38861385
DOI: 10.1016/j.celrep.2024.114323 -
Molecular Carcinogenesis Jun 2024Mixed phenotype acute leukemia (MPAL) is a type of acute leukemia in which encompasses mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation....
Mixed phenotype acute leukemia (MPAL) is a type of acute leukemia in which encompasses mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. Philadelphia chromosome-positive (Ph) MPAL is a rare subgroup with a poor prognosis and accounts for <1% of adult acute leukemia. Until now, there is still no consensus on how to best treat Ph MPAL. Here, we report a 62-year-old male with Ph (atypical e13a2 BCR-ABL1 fusion protein) MPAL. This patient presented with recurrent and intense bone pain due to bone marrow necrosis (BMN). Besides, he did not achieve a complete remission for the first two chemotherapies, until he received flumatinib combined with hyper-CVAD (B) (a dose-intensive regimen include methotrexate and cytarabine). To our knowledge, this is the first report to describe the coexistence of BMN and atypical e13a2 BCR-ABL1 transcripts in patients with MPAL. This finding will bring new understandings in the diagnosis and treatment of Ph MPAL.
PubMed: 38860593
DOI: 10.1002/mc.23742 -
Blood Reviews Jul 2024Since the discovery of the Philadelphia chromosome in 1960, cytogenetic studies have been instrumental in detecting chromosomal abnormalities that can inform cancer... (Review)
Review
Since the discovery of the Philadelphia chromosome in 1960, cytogenetic studies have been instrumental in detecting chromosomal abnormalities that can inform cancer diagnosis, treatment, and risk assessment efforts. The initial expansion of cancer cytogenetics was with fluorescence in situ hybridization (FISH) to assess submicroscopic alterations in dividing or non-dividing cells and has grown into the incorporation of chromosomal microarrays (CMA), and next generation sequencing (NGS). These molecular technologies add additional dimensions to the genomic assessment of cancers by uncovering cytogenetically invisible molecular markers. Rapid technological and bioinformatic advances in NGS are so promising that the idea of performing whole genome sequencing as part of routine patient care may soon become economically and logistically feasible. However, for now cytogenetic studies continue to play a major role in the diagnostic testing and subsequent assessments in leukemia with other genomic studies serving as complementary testing options for detection of actionable genomic abnormalities. In this review, we discuss the role of conventional cytogenetics (karyotyping, chromosome analysis) and FISH studies in hematological malignancies, highlighting the continued clinical utility of these techniques, the subtleties and complexities that are relevant to treating physicians and the unique strengths of cytogenetics that cannot yet be paralleled by the current high-throughput molecular technologies. Additionally, we describe how CMA, optical genome mapping (OGM), and NGS detect abnormalities that were beyond the capacity of cytogenetic studies and how an integrated approach (broad molecular testing) can contribute to the detection of actionable targets and variants in malignancies. Finally, we discuss advances in the field of genomic testing that are bridging the advantages of individual (single) cell based cytogenetic testing and broad genomic testing.
Topics: Humans; Genomics; Neoplasms; Chromosome Aberrations; Cytogenetic Analysis; Cytogenetics; In Situ Hybridization, Fluorescence; High-Throughput Nucleotide Sequencing
PubMed: 38852016
DOI: 10.1016/j.blre.2024.101209 -
Leukemia & Lymphoma Jun 2024Blinatumomab and inotuzumab ozogamicin (INO) are both active in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and improve outcomes compared with... (Review)
Review
Blinatumomab and inotuzumab ozogamicin (INO) are both active in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and improve outcomes compared with conventional chemotherapy in this setting. Several prospective clinical trials have explored the use of these agents in adults with newly diagnosed B-cell ALL, with promising outcomes observed in younger and older adults and in both Philadelphia chromosome (Ph)-positive and Ph-negative ALL. These novel regimens result in high rates of deep measurable residual disease (MRD) negativity and may improve survival compared with chemotherapy-only approaches, allowing for less reliance on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). This review discusses novel approaches to integrating INO and/or blinatumomab into frontline ALL regimens, including the potential role of chemotherapy-free regimens in some subgroups. The role of MRD monitoring is also discussed, including how this can inform decisions for consolidative allogeneic HSCT or investigational approaches with CD19 CAR T-cells.
PubMed: 38850572
DOI: 10.1080/10428194.2024.2364043