Challenges and Opportunities for Childhood Cancer Drug Development

Houghton, Peter J.; Kurmasheva, Raushan T.

doi:10.1124/pr.118.016972

Cited by 17 publications

(20 citation statements)

References 320 publications

(339 reference statements)

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“…HD‐MTX has been associated with hepatic toxicity with elevated serum ALT and AST values, but these laboratory findings usually have no clinical significance and require no adjustment of subsequent courses of HD‐MTX because most cases are transient and reversible 5 . However, the association of HD‐MTX with other chemotherapy agents can promote higher hepatic and renal dysfunction and can be associated with OM development.…”

Section: Discussionmentioning

confidence: 99%

Oral mucositis in childhood cancer patients receiving high‐dose methotrexate: Prevalence, relationship with other toxicities and methotrexate elimination

Valer

Curra

Gabriel

et al. 2020

Int J Paed Dentistry

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Background Oral mucositis (OM) is one of the main adverse effects of the chemotherapeutic agent methotrexate (MTX). Aim To evaluate the relationship of OM with MTX metabolism time and other toxicities in childhood, cancer patients receiving high‐dose of methotrexate (HD‐MTX). Design Seventy‐seven childhood patients receiving HD‐MTX for treatment of leukaemia, osteosarcoma or lymphoma were evaluated. MTX serum level, hepatic and renal function parameters, and presence and intensity of OM were analysed. Results The patients were submitted to 255 cycles of chemotherapy. OM was diagnosed in 191 (74.9%) cycles. Of these, 119 (46.6%) presented ulcerative lesions. Lymphoma was associated with severe OM (P = .01). OM was associated with higher serum levels of aspartate aminotransferase (P = .006), alanine aminotransferase (P = .04) and creatinine (P = .008). Increase of one unit of total bilirubin and indirect bilirubin associated, respectively, with 11% and 39% higher prevalence of OM. For each increase of one unit of creatinine serum level, it was observed a 37% higher prevalence of OM in patients with lymphoma. No association was found between delayed excretion of MTX and OM development. Conclusions OM is a prevalent complication of childhood cancer patients receiving HD‐MTX. Renal and hepatic toxicity could be considered risk factors for OM, especially in patients with lymphoma.

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Section: Discussionmentioning

confidence: 99%

Oral mucositis in childhood cancer patients receiving high‐dose methotrexate: Prevalence, relationship with other toxicities and methotrexate elimination

Valer

Curra

Gabriel

et al. 2020

Int J Paed Dentistry

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“…Although several cancer therapies except for surgery are available for patients, the drug induced toxicities and the secondary resistance remain big challenges worldwide 28 , 29 . That's mostly because we haven't really figured out the characteristics how normal cells become cancer cells 30 .…”

Section: Discussionmentioning

confidence: 99%

JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling

Cui¹,

Shu²,

Xu³

et al. 2020

Theranostics

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Background: JWA gene is known to down-regulate SP1 and reduces the expression level of Integrin αvβ3. Here, we identified a functional polypeptide (JP1) based on the active fragment of the JWA protein to suppress melanoma growth and metastasis by inhibiting the Integrin αvβ3. Methods: We conducted a series of melanoma growth and metastasis mouse models to evaluate anti-melanoma effect of JP1 peptide. 18 F-labeled JP1 ( 18 F-NFP-JP1) was detected by Micro-PET assay to demonstrate drug biodistribution. Toxicity test in cynomolgus monkeys and pharmacokinetic studies in rats were done to assess the druggability. The expression of MEK1/2, NEDD4L, SP1 and Integrin αvβ3 were detected in vitro and vivo models. Results: The peptide JP1 with the best anticancer effect was obtained. Micro-PET assay showed that JP1 specifically targeting to melanoma cells in vivo . JP1 inhibited melanoma growth, metastasis, and prolonged the survival of mouse. JP1 reduced the dosage and toxicity in combination with DTIC in melanoma xenograft and allograft mouse models. Cynomolgus monkey toxicity test showed no observed adverse effect level (NOAEL) of JP1 was 150 mg/kg. Mechanistically, JP1 was shown to activate p-MEK1/2 and triggered SP1 ubiquitination in melanoma cells. NEDD4L, an E3 ubiquitin ligase, was activated by p-MEK1/2 and to ubiquitinate SP1 at K685 site, resulting in subsequent degradation. Conclusions: JP1 was developed as a novel peptide that indicated therapeutic roles on proliferation and metastasis of melanoma through the NEDD4L-SP1-Integrin αvβ3 signaling.

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“… 92 Repurposing safe, commonly prescribed drugs is a superficially favourable approach, as the limitations of testing new agents in children exceed those for adults; known safety and toxicity profiles shorten the timeline and reduce the number of patients required—already scarce to start with—to obtain approval for a novel indication in children. 93 , 94 Ethically, these patients must receive the highest standard of care and some patients/parents are not willing to accept the safety risks involved with Phase 1 testing. 93 Together with the lack of commercial interest to develop new drugs with the sole indication of treating rare paediatric cancers, 93 , 94 these factors support repurposing atovaquone in children, although preclinical evidence must be generated to support this combination before clinical trials commence.…”

Section: Hypoxia-targeted Treatment Strategy 1: Increasing Oxygen Avamentioning

confidence: 99%

“… 93 , 94 Ethically, these patients must receive the highest standard of care and some patients/parents are not willing to accept the safety risks involved with Phase 1 testing. 93 Together with the lack of commercial interest to develop new drugs with the sole indication of treating rare paediatric cancers, 93 , 94 these factors support repurposing atovaquone in children, although preclinical evidence must be generated to support this combination before clinical trials commence.…”

Section: Hypoxia-targeted Treatment Strategy 1: Increasing Oxygen Avamentioning

confidence: 99%

Hypoxia and its therapeutic possibilities in paediatric cancers

et al. 2020

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In tumours, hypoxia—a condition in which the demand for oxygen is higher than its availability—is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.

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Challenges and Opportunities for Childhood Cancer Drug Development

Cited by 17 publications

References 320 publications

Oral mucositis in childhood cancer patients receiving high‐dose methotrexate: Prevalence, relationship with other toxicities and methotrexate elimination

Oral mucositis in childhood cancer patients receiving high‐dose methotrexate: Prevalence, relationship with other toxicities and methotrexate elimination

JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling

Hypoxia and its therapeutic possibilities in paediatric cancers

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