Challenges and Recent Advances in Medulloblastoma Therapy

Kumar, Vinod; Kumar, Virender; McGuire, Timothy R.; Coulter, Donald W.; Sharp, John; Mahato, Ram I.

doi:10.1016/j.tips.2017.09.002

Cited by 65 publications

(65 citation statements)

References 154 publications

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“…Most current chemotherapies used to treat MB are genotoxic agents. 1 These compounds target all the proliferative cells and are not selective towards cancer cells. This accounts for major side this study as well as other models mostly rely on LAT1 ( Figure 1B).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the amino‐acid transporter LAT1 demonstrates anti‐neoplastic activity in medulloblastoma

Cormerais

Pagnuzzi‐Boncompagni

Schrötter

et al. 2019

J Cellular Molecular Medi

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Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo‐ and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L‐type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1‐specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD‐MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long‐term treatment with JPH203 does not lead to resistance in MB cells. Therefore, this study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the amino‐acid transporter LAT1 demonstrates anti‐neoplastic activity in medulloblastoma

Cormerais

Pagnuzzi‐Boncompagni

Schrötter

et al. 2019

J Cellular Molecular Medi

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show abstract

“…Most current chemotherapies used to treat MB are genotoxic agents [1]. These compounds target all the proliferative cells and are not selective towards cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…This may represent an important advantage as compared to the aforementioned genotoxic treatments. Finally, these effects should be weighed against current therapies for MB, generally involving radio-and chemotherapy combinations which are showed to cause major cognitive side effects [1].…”

Section: Discussionmentioning

confidence: 99%

“…Medulloblastoma (MB) is the most prevalent pediatric brain tumor [1]. Recent advances in genetic characterization of the disease have led to an international consensus classification of MB into four biologically and clinically relevant subtypes: the wingless (Wnt), the sonic hedgehog (Shh), and the more similar though molecularly distinguishable groups 3 and 4 [2,3].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the amino-acid transporter LAT1 demonstrates anti-neoplastic activity in medulloblastoma

Cormerais

Pagnuzzi‐Boncompagni

Schrötter

et al. 2018

Preprint

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Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo-and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L-type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1-specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD-MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long-term treatment with JPH203 does not lead to resistance in MB cells. Therefore, the present study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment. KEYWORDS

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“…More recent advancements in deep transcriptional and methylation profiling of 763 primary MB samples revealed new subtypes within each of the four subgroups and further classified MB into 12 subtypes: two Wnt, four Shh, three group 3, and three group 4 subgroups (Cavalli et al, 2017). Current treatment is based in risk stratification and despite significant advances in surgery, radiotherapy, and drug therapy, effective treatment to MB remains a challenge (Kumar et al, 2017;Northcott et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

Thomaz

Pinheiro

Souza

et al. 2019

Preprint

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Neurotrophins are critically involved in regulating normal neural development and plasticity. Brain-derived neurotrophic factor (BDNF), a neurotrophin that acts by binding to the tropomyosin receptor kinase B (TrkB) receptor, has also been implicated in the progression of several types of cancer. However, its role in medulloblastoma (MB), the most common type of malignant brain tumor afflicting children, remains unclear. Here we show that selective TrkB inhibition with the small molecule compound ANA-12 impaired proliferation and viability of human UW228 and D283 MB cells, and slowed the growth of MB tumors xenografted into nude mice. These effects were accompanied by increased apoptosis, reduced extracellular-regulated kinase (ERK) activity, increased expression of signal transducer and activator of transcription 3 (STAT3), and differential modulation of p21 expression dependent on the cell line. In addition, MB cells treated with ANA-12 showed morphological alterations consistent with differentiation, increased levels of the neural differentiation marker β-III Tubulin (TUBB3), and reduced expression of the stemness marker Nestin. These findings are consistent with the possibility that selective TrkB inhibition can display consistent anticancer effects in MB, possibly by modulating intracellular signaling and gene expression related to tumor progression, apoptosis, and differentiation.

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Challenges and Recent Advances in Medulloblastoma Therapy

Cited by 65 publications

References 154 publications

Inhibition of the amino‐acid transporter LAT1 demonstrates anti‐neoplastic activity in medulloblastoma

Inhibition of the amino‐acid transporter LAT1 demonstrates anti‐neoplastic activity in medulloblastoma

Inhibition of the amino-acid transporter LAT1 demonstrates anti-neoplastic activity in medulloblastoma

Antitumor Activities and Cellular Changes Induced by TrkB Inhibition in Medulloblastoma

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