Disease Information

General Information of the Disease (ID: DIS00515)

• Name: Brain cancer
• ICD: ICD-11: 2A00

Type(s) of Resistant Mechanism of This Disease

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Caffine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Sterol regulatory element binding protein 2 (SREBP2) [1]

• Metabolic Type: Lipid metabolism
• Sensitive Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Sensitive Drug: Caffine
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Terpenoid backbone biosynthesis; Activation; hsa00900
• In Vivo Model: NOD/SCID mice, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our data are consistent with a recent study in liver cancer cell lines showing that statin represses FOXM1 expression by blocking geranylgeranylation of RhoA, Rac1 or Cdc42 proteins (46). Together, these findings suggest a molecular mechanism for the long-observed connection between the mevalonate pathway and cell-cycle progression (47).

Simvastatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Forkhead box M1 (FOXM1) [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Resistant Drug: Simvastatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Terpenoid backbone biosynthesis; Activation; hsa00900
• In Vivo Model: NOD/SCID mice, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Like dipyridamole (41, 57), caffeine can block statin-induced feedback activation of SREBP2 and mevalonate pathway enzymes. Our data suggest that this action of caffeine depends on its activity as an antagonist of adenosine receptors (43, 59, 62), as evidenced by the findings that supplemental adenosine can abrogate the ability of caffeine to block statin-induced feedback activation SREBP2 and mevalonate pathway enzymes and to enhance the antigrowth effect of simvastatin.

Key Molecule: Sterol regulatory element binding protein 2 (SREBP2) [1]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Resistant Drug: Simvastatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Terpenoid backbone biosynthesis; Activation; hsa00900
• In Vivo Model: NOD/SCID mice, with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our data are consistent with a recent study in liver cancer cell lines showing that statin represses FOXM1 expression by blocking geranylgeranylation of RhoA, Rac1 or Cdc42 proteins (46). Together, these findings suggest a molecular mechanism for the long-observed connection between the mevalonate pathway and cell-cycle progression (47).

Sirolimus

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Mechanistic target of rapamycin complex 1 (mTORC1) [2]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Sensitive Drug: Sirolimus
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: The nude, athymic female mice, with IMR-32 or SK-N-DZ cells; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Besides both a block of glycolysis and OXPHOS, the HDAC/mTORC1 inhibitor combination produced significantly higher levels of reactive oxygen species (ROS) in the treated cells and in xenograft tumor samples, also a consequence of increased glycolytic block. The lead compounds were also tested for changes in the message levels of the glycolytic enzymes and their pathway activity, and HK2 and GPI glycolytic enzymes were most affected at their RNA message level.

Vorinostat

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Mechanistic target of rapamycin complex 1 (mTORC1) [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Resistant Drug: Vorinostat
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: The nude, athymic female mice, with IMR-32 or SK-N-DZ cells; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Besides both a block of glycolysis and OXPHOS, the HDAC/mTORC1 inhibitor combination produced significantly higher levels of reactive oxygen species (ROS) in the treated cells and in xenograft tumor samples, also a consequence of increased glycolytic block. The lead compounds were also tested for changes in the message levels of the glycolytic enzymes and their pathway activity, and HK2 and GPI glycolytic enzymes were most affected at their RNA message level.

Preclinical Drug(s) 1 drug(s) in total

AZD3463/Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Proto-oncogene serine/threonine-protein kinase Pim (PIM kinase) [3]

• Sensitive Disease: Neuroblastoma [ICD-11: 2AOO.11]
• Sensitive Drug: AZD3463/Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SK-N-BE cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: In the current study, we explore how PIM kinase correlates with the MRP1 drug efflux pump. We demonstrate that PIM kinase inhibition modulates the function of MRP1 mediated efflux of doxorubicin in neuroblastoma.?

References

• Ref 1: Caffeine Supplementation and FOXM1 Inhibition Enhance the Antitumor Effect of Statins in Neuroblastoma. Cancer Res. 2023 Jul 5;83(13):2248-2261.
• Ref 2: Reversing the HDAC-inhibitor mediated metabolic escape in MYCN-amplified neuroblastoma. Biomed Pharmacother. 2022 Jun;150:113032.
• Ref 3: PIM Kinase Inhibition Sensitizes Neuroblastoma to Doxorubicin. J Pediatr Surg. 2024 Jul;59(7):1334-1341.