Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Shah, Nilay

doi:10.20517/cdr.2019.20

Cited by 5 publications

(13 citation statements)

References 275 publications

(276 reference statements)

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“…Additionally, the development of neutralizing antibodies against therapeutic antibodies can decrease the response. In general, tumor resistance does not appear to differ between children and adults 121 .…”

Section: Immunotherapymentioning

confidence: 88%

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Epigenomics and immunotherapeutic advances in pediatric brain tumors

et al. 2021

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Brain tumors are the leading cause of childhood cancer-related deaths. Similar to adult brain tumors, pediatric brain tumors are classified based on histopathological evaluations. However, pediatric brain tumors are often histologically inconsistent with adult brain tumors. Recent research findings from molecular genetic analyses have revealed molecular and genetic changes in pediatric tumors that are necessary for appropriate classification to avoid misdiagnosis, the development of treatment modalities, and the clinical management of tumors. As many of the molecular-based therapies developed from clinical trials on adults are not always effective against pediatric brain tumors, recent advances have improved our understanding of the molecular profiles of pediatric brain tumors and have led to novel epigenetic and immunotherapeutic treatment approaches currently being evaluated in clinical trials. In this review, we focus on primary malignant brain tumors in children and genetic, epigenetic, and molecular characteristics that differentiate them from brain tumors in adults. The comparison of pediatric and adult brain tumors highlights the need for treatments designed specifically for pediatric brain tumors. We also discuss the advancements in novel molecularly targeted drugs and how they are being integrated with standard therapy to improve the classification and outcomes of pediatric brain tumors in the future.

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Section: Immunotherapymentioning

confidence: 88%

“…Multiple mechanisms are involved in resistance to immunotherapy 119 – 121 ; these include the therapeutic agent and partly the genetic, epigenetic, and immune profiles of the tumors. Cancer cells can become resistant to engineered monoclonal antibodies by losing the expression of the target antigen.…”

Section: Immunotherapymentioning

confidence: 99%

Epigenomics and immunotherapeutic advances in pediatric brain tumors

et al. 2021

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“…The antitumor potency of this prodrug and its dependence on the individual and combined effects of enhanced delivery and optimized pharmacology of the inactivation‐ and elimination‐resisting drug cargo were examined in clinically relevant models of high‐risk disease recapitulating the key features of primary and acquired multidrug resistance. Experimentally showing the effectiveness of this delivery strategy against aggressive tumor types protected from chemotherapy by different biological mechanisms is anticipated to facilitate further development and optimization of Poloxamer‐linked SN22 and analogously constructed prodrugs as novel therapeutics for refractory malignancies 2,30 …”

Section: Introductionmentioning

confidence: 99%

“…The increased rate of recurrences and a lack of significant improvement in survival rates despite aggressive multimodal therapy point to a need for novel and much more efficient therapeutic approaches for this patient group. 2 However, primary (or de novo ) and acquired forms of chemoresistance in newly diagnosed and recurrent variants of high-risk malignancies rely on different biological mechanisms. A major process governing reduced responsiveness of chemo-naïve cancer cells to a broad range of chemotherapeutics is drug efflux mediated by proteins of the ATP-binding cassette (ABC) transporter family frequently overexpressed in de novo resistant tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Experimentally showing the effectiveness of this delivery strategy against aggressive tumor types protected from chemotherapy by different biological mechanisms is anticipated to facilitate further development and optimization of Poloxamer-linked SN22 and analogously constructed prodrugs as novel therapeutics for refractory malignancies. 2 , 30 …”

Section: Introductionmentioning

confidence: 99%

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Poloxamer‐linked prodrug of a topoisomerase I inhibitor SN22 shows efficacy in models of high‐risk neuroblastoma with primary and acquired chemoresistance

et al. 2022

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High‐risk solid tumors continue to pose a tremendous therapeutic challenge due to multidrug resistance. Biological mechanisms driving chemoresistance in high‐risk primary and recurrent disease are distinct: in newly diagnosed patients, non‐response to therapy is often associated with a higher level of tumor “stemness” paralleled by overexpression of the ABCG2 drug efflux pump, whereas in tumors relapsing after non‐curative therapy, poor drug sensitivity is most commonly linked to the dysfunction of the tumor suppressor protein, p53. In this study, we used preclinical models of aggressive neuroblastoma featuring these characteristic mechanisms of primary and acquired drug resistance to experimentally evaluate a macromolecular prodrug of a structurally enhanced camptothecin analog, SN22, resisting ABCG2‐mediated export, and glucuronidation. Together with extended tumor exposure to therapeutically effective drug levels via reversible conjugation to Pluronic F‐108 (PF108), these features translated into rapid tumor regression and long‐term survival in models of both ABCG2‐overexpressing and p53‐mutant high‐risk neuroblastomas, in contrast to a marginal effect of the clinically used camptothecin derivative, irinotecan. Our results demonstrate that pharmacophore enhancement, increased tumor uptake, and optimally stable carrier‐drug association integrated into the design of the hydrolytically activatable PF108‐[SN22]2 have the potential to effectively combat multiple mechanisms governing chemoresistance in newly diagnosed (chemo‐naïve) and recurrent forms of aggressive malignancies. As a macromolecular carrier‐based delivery system exhibiting remarkable efficacy against two particularly challenging forms of high‐risk neuroblastoma, PF108‐[SN22]2 can pave the way to a robust and clinically viable therapeutic strategy urgently needed for patients with multidrug‐resistant disease presently lacking effective treatment options.

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Use of modern three‐dimensional imaging models to guide surgical planning for local control of pediatric extracranial solid tumors

Shah,

Weadock,

Williams

et al. 2024

Pediatric Blood & Cancer

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IntroductionIn complex pediatric surgical oncology, surgical planning is contingent upon data gathered from preoperative imaging. Three‐dimensional (3D) modeling and printing has been shown to be beneficial for adult presurgical planning, though pediatric literature is less robust. The study reviews our institutional experience with the use of 3D image segmentation and printed models in approaching resection of extracranial solid tumors in children.MethodsThis is a single institutional series from 2021 to 2023. Models were based on computed tomography and magnetic resonance imaging studies, optimized for 3D imaging. The feasibility and creation of the models is reviewed, including specific techniques, software, and printing materials from our institution. Clinical implications for surgical planning are also described, along with detailed preoperative and intraoperative images.Results3D modeling and printing was performed for four pediatric patients diagnosed with extracranial solid tumors. Diagnoses included Ewing sarcoma, hepatoblastoma, synovial sarcoma, and osteosarcoma. No intraoperative complications or discrepancies with the preoperative 3D‐printed model were noted. No evidence of local recurrence was identified in any patient thus far.ConclusionOur institutional series demonstrates a wide spectrum of clinical application for 3D modeling and printing technology within pediatric surgical oncology. This technology may aid in surgical planning for both resection and reconstruction, can be applied to a diverse breadth of diagnoses, and may potentially augment patient and/or family education about their condition.

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Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Cited by 5 publications

References 275 publications

Epigenomics and immunotherapeutic advances in pediatric brain tumors

Epigenomics and immunotherapeutic advances in pediatric brain tumors

Poloxamer‐linked prodrug of a topoisomerase I inhibitor SN22 shows efficacy in models of high‐risk neuroblastoma with primary and acquired chemoresistance

Use of modern three‐dimensional imaging models to guide surgical planning for local control of pediatric extracranial solid tumors

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