Developing New Agents for Treatment of Childhood Cancer: Challenges and Opportunities for Preclinical Testing

Ghilu, Samson; Kurmasheva, Raushan T.; Houghton, Peter J.

doi:10.3390/jcm10071504

Cited by 4 publications

(6 citation statements)

References 54 publications

(35 reference statements)

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“…About 50% of tumors have TP53 mutations, resulting in the inactivation of its function 100 . Murine double minute 2 (MDM2) is a key negative regulator of p53 and can mediate the degradation of TP53 101 . MDM2 inhibitors can block TP53 degradation by inhibiting the function of MDM2, possibly restoring the function of TP53 protein 102 .…”

Section: The Molecular Pathways Involved In Glioma Circadian Clockmentioning

confidence: 99%

“… 100 Murine double minute 2 (MDM2) is a key negative regulator of p53 and can mediate the degradation of TP53. 101 MDM2 inhibitors can block TP53 degradation by inhibiting the function of MDM2, possibly restoring the function of TP53 protein. 102 Lowering Per2 expression reduces DNA damage response and cell death following low‐dose X‐ray irradiation.…”

Section: The Molecular Pathways Involved In Glioma Circadian Clockmentioning

confidence: 99%

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Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

Wang

Chen

2022

CNS Neurosci Ther

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Glioma is characterized as the most aggressive brain tumor that occurred in the central nervous system. The circadian rhythm is an essential cyclic change system generated by the endogenous circadian clock. Current studies found that the circadian clock affects glioma pathophysiology. It is still controversial whether the circadian rhythm disruption is a cause or an effect of tumorigenesis. This review discussed the association between cell cycle and circadian clock and provided a prominent molecular theoretical basis for tumor therapy. We illustrated the external factors affecting the circadian clock including thermodynamics, hypoxia, post‐translation, and microRNA, while the internal characteristics concerning the circadian clock in glioma involve stemness, metabolism, radiotherapy sensitivity, and chemotherapy sensitivity. We also summarized the molecular pathways and the therapeutic drugs involved in the glioma circadian rhythm. There are still many questions in this field waiting for further investigation. The results of glioma chronotherapy in sensitizing radiation therapy and chemotherapy have shown great therapeutic potential in improving clinical outcomes. These findings will help us further understand the characteristics of glioma pathophysiology.

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Section: The Molecular Pathways Involved In Glioma Circadian Clockmentioning

confidence: 99%

Section: The Molecular Pathways Involved In Glioma Circadian Clockmentioning

confidence: 99%

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

Wang

Chen

2022

CNS Neurosci Ther

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“…It was also con rmed that 34% of POs (29 of 85) focused on supporting pediatric patients (Additional File 2). Considering the current situation in which drug development for the pediatric population has not progressed regardless of the type of cancer [47][48][49], this nding suggests that there is a gap between the unmet medical needs of patients and the development strategies of IND companies. At IND sponsors, where the development of innovative drugs that meet the patient's needs are directly linked to growth, it is conceivable that patient-centered drug development that involves patients in the process will continue to be important.…”

Section: Collaborative Trends Of Posmentioning

confidence: 99%

Trends in collaboration with patient organizations on cancer-related clinical trials: Collaborative relationship with existing stakeholders and the characteristics of their co-sponsored studies in the United States

Lee

Sengoku

2022

Preprint

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Background In recent years, the importance of patient centricity in drug development has been recognized, affecting the stakeholders conducting clinical trials. In this context, end users, patients and patient organizations are becoming increasingly involved in the development process to address their unmet medical needs. However, there is a lack of research on environmental trends in which patient organizations collaborate with incumbent stakeholders in drug development. This study aimed to understand the current status of clinical trials regarding patient organization involvement as sponsors and collaboration with different types of sponsors in cancer-related clinical trials. This cross-sectional study also examined the characteristics of clinical trials involving patient organizations as new stakeholders by analyzing the environmental factors that promote collaboration with existing stakeholders. Methods A total of 14,830 interventional clinical trials registered on ClinicalTrials.gov between January 1, 2010, and December 31, 2020, were categorized and analyzed by target cancer types and five different sponsor types: 1. patient organization co-sponsored (PO-co), 2. academia (ACD), 3. governmental (GOV), and 4. industry co-sponsored (IND-co) and 5. industry only (IND). Results PO-Co studies accounted for 2% (289 of 14,830) of the total studies, ACD 5%, IND-Co 21%, GOV and IND 36%. When the 289 PO-Co studies were analyzed by cancer type and eligible study population, we found that the proportion of pediatric studies was significantly higher for PO-Co studies (30% (88 of 289)) than for total studies (9% (1,378 of 14,830); P < .001), and we also found that collaboration with PO was more common for certain cancer types compared with the total study. Regarding collaboration with POs, more than half of the PO-GOV collaborative studies were conducted at the Nation cancer center comprehensive cancer centers, and even particular investigators actively engaged in collaboration with POs. Conclusions A cross-sectional analysis of cancer-related clinical trials revealed that the involvement of patient organizations as sponsors in clinical trials did not increase significantly over time. However, some organizations have become actively engaged in certain cancers and pediatric populations that are less prioritized by incumbent sponsors. We also found that governmental sponsors and selected principal investigators played an important role in collaborating with patient organizations. These findings provide a basis for understanding the current status of patient organizations and for considering further contributions.

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“…Preclinical studies aimed at understanding resistance tend to focus on individual drugs, rather than resistance to poly-chemotherapy [7][8][9][10][11][12][13] . Further, often drug exposures used in vitro far exceed those achieved in patients, and escalating drug concentrations over time do not simulate how clinical resistance is acquired [14] .…”

Section: Introductionmentioning

confidence: 99%

Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma

Ghilu¹,

Morton²,

Vaseva³

et al. 2022

CDR

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Aim: Despite aggressive multiagent protocols, patients with metastatic rhabdomyosarcoma (RMS) have poor prognosis. In a recent high-risk trial (ARST0431), 25% of patients failed within the first year, while on therapy and 80% had tumor progression within 24 months. However, the mechanisms for tumor resistance are essentially unknown. Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431. Methods: A Single Mouse Testing (SMT) protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine, actinomycin D, cyclophosphamide (VAC) treatment. Tumor response was determined by caliper measurement, and tumor regression and event-free survival (EFS) were used as endpoints for evaluation. Treated tumors at regrowth were transplanted into recipient mice, and the treatment was repeated until tumors progressed during the treatment period (i.e., became resistant). At transplant, tumor tissue was stored for biochemical and omics analysis. Results: The sensitivity to VAC of 34 RMS models was determined. EFS varied from 3 weeks to > 20 weeks. Tumor models were classified as having intrinsic resistance, intermediate sensitivity, or high sensitivity to VAC therapy. Resistance to VAC was developed in multiple models after 2-5 cycles of therapy; however, there were examples where sensitivity remained unchanged after 3 cycles of treatment. Conclusion: The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models. As such, it provides a platform for assessing in vivo drug resistance mechanisms at a “population” level, simulating conditions in vivo that lead to clinical resistance. These VAC-resistant models represent “high-risk” tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

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Developing New Agents for Treatment of Childhood Cancer: Challenges and Opportunities for Preclinical Testing

Cited by 4 publications

References 54 publications

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

Insights about circadian clock in glioma: From molecular pathways to therapeutic drugs

Trends in collaboration with patient organizations on cancer-related clinical trials: Collaborative relationship with existing stakeholders and the characteristics of their co-sponsored studies in the United States

Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma

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