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1.
Clin Transl Med ; 14(9): e70012, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39210542

RESUMEN

Ovarian cancer ecosystems are exceedingly complex, consisting of a high heterogeneity of cancer cells. Development of drugs such as poly ADP-ribose polymerase (PARP) inhibitors, targeted therapies and immunotherapies offer more options for sequential or combined treatments. Nevertheless, mortality in metastatic ovarian cancer patients remains high because cancer cells consistently develop resistance to single and combination therapies, urging a need for treatment designs that target the evolvability of cancer cells. The evolutionary dynamics that lead to resistance emerge from the complex tumour microenvironment, the heterogeneous populations, and the individual cancer cell's plasticity. We propose that successful management of ovarian cancer requires consideration of the ecological and evolutionary dynamics of the disease. Here, we review current options and challenges in ovarian cancer treatment and discuss principles of tumour evolution. We conclude by proposing evolutionarily designed strategies for ovarian cancer, with the goal of integrating such principles with longitudinal, quantitative data to improve the treatment design and management of drug resistance. KEY POINTS/HIGHLIGHTS: Tumours are ecosystems in which cancer and non-cancer cells interact and evolve in complex and dynamic ways. Conventional therapies for ovarian cancer inevitably lead to the development of resistance because they fail to consider tumours' heterogeneity and cellular plasticity. Eco-evolutionarily designed therapies should consider cancer cell plasticity and patient-specific characteristics to improve clinical outcome and prevent relapse.


Asunto(s)
Neoplasias Ováricas , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Neoplasias Ováricas/genética , Femenino , Microambiente Tumoral/efectos de los fármacos
2.
Nat Commun ; 14(1): 2290, 2023 04 21.
Artículo en Inglés | MEDLINE | ID: mdl-37085479

RESUMEN

Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.


Asunto(s)
Células Madre Hematopoyéticas , Ribonucleoproteínas Nucleares Heterogéneas , Proteostasis , Animales , Ratones , Regulación de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Ratones Noqueados , Proteostasis/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
3.
Cancer Cell ; 41(4): 726-739.e11, 2023 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-36898380

RESUMEN

Acute myeloid leukemia (AML) is a hematologic malignancy for which several epigenetic regulators have been identified as therapeutic targets. Here we report the development of cereblon-dependent degraders of IKZF2 and casein kinase 1α (CK1α), termed DEG-35 and DEG-77. We utilized a structure-guided approach to develop DEG-35 as a nanomolar degrader of IKZF2, a hematopoietic-specific transcription factor that contributes to myeloid leukemogenesis. DEG-35 possesses additional substrate specificity for the therapeutically relevant target CK1α, which was identified through unbiased proteomics and a PRISM screen assay. Degradation of IKZF2 and CK1α blocks cell growth and induces myeloid differentiation in AML cells through CK1α-p53- and IKZF2-dependent pathways. Target degradation by DEG-35 or a more soluble analog, DEG-77, delays leukemia progression in murine and human AML mouse models. Overall, we provide a strategy for multitargeted degradation of IKZF2 and CK1α to enhance efficacy against AML that may be expanded to additional targets and indications.


Asunto(s)
Caseína Quinasa Ialfa , Leucemia Mieloide Aguda , Animales , Humanos , Ratones , Caseína Quinasa Ialfa/genética , Caseína Quinasa Ialfa/metabolismo , Hematopoyesis , Factor de Transcripción Ikaros/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Factores de Transcripción
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