-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
Angela Mweempwa et al.
of the Department of Medical Oncology at Peter MacCallum Cancer Center in Melbourne, Australia, systematically reviewed the perioperative clinical trial study of glioma, with the aim of providing reference for the development of new glioma drugs
.
The review was published online in the May 2021 issue of the Journal of Clinical Neuroscience
.
- Excerpted from the article chapter
【Ref: Mweempwa A, et al.
J Clin Neurosci.
2021 Jul; 89:144-150.
doi: 10.
1016/j.
jocn.
2021.
04.
026.
Epub 2021 May 11.
】
Research background
Angela Mweempwa et al.
of the Department of Medical Oncology at Peter MacCallum Cancer Center in Melbourne, Australia, systematically reviewed the perioperative clinical trial study of glioma, with the aim of providing reference for the development of new glioma drugs
.
The review was published online in the May 2021 issue of the Journal of Clinical Neuroscience
.
Research methods
The authors believe that although glioma has undergone comprehensive treatment such as surgery, radiotherapy and chemotherapy, the efficacy is still not satisfactory, which is closely related
to tumor heterogeneity, tumor microenvironment and blood-brain barrier.
Perioperative clinical trials are necessary
to improve the efficacy of gliomas and develop targeted drugs.
Study results
Perioperative clinical trials for gliomas range widely, including phase 0, perioperative, biopsy surgery, neoadjuvant therapy, and timing (Figure 1).
Figure 1.
Perioperative clinical trials
of gliomas.
Phase 0 studies were short and had no treatment assumption; The aim is to collect pharmacokinetic (PK) and pharmacodynamic (PD) data, study opportunity windows for therapeutic doses, and typically include pre-treatment PK and PD analysis
.
Neoadjuvant therapy and perioperative studies have a therapeutic purpose and may include preoperative biopsy
.
For personalized therapies to be successful, clinically relevant biomarkers need to be identified, and complementary diagnostic tests need to be developed to assess response
to treatment.
Perioperative trials provide a unique opportunity
to study drug PK and PD and to confirm targeted effects.
Preoperative non-invasive diagnosis and grading of gliomas is the basis for
clinical decision-making.
Patients are often resected when gliomas progress, and obtaining tumor tissue can test whether the drug is working as expected and to see if the drug has a targeted effect
.
Phase 0 clinical trials may be suitable for low-grade glioma (LGG) because LGG patients are relatively young, have tumor homogeneity, often undergo biopsy to select treatment before treatment, progress relatively slowly, often have IDH1/2 mutations, and have actionable molecular targets
.
When selecting a drug in a perioperative clinical trial, it is important to determine that a reasonable target can be targeted
.
The preferred targets for gliomas are shown in Figure 2
.
Targets for
gliomas.
GBM is characterized by epidermal growth factor receptor (EGFR) amplification or mutation (including EGFRvIII) that can be treated with multiple targeted therapies, including antibody-drug conjugation
.
ONC201 is a small molecule inhibitor
of DRD2.
Activation of EGFR and other growth factor receptor pathways leads to the targeting of the downstream signaling pathways MAPK and PI3K/AKT/mTOR pathways with RTK and small molecule inhibitors
.
In glioma, the early inactivation of the P53 tumor suppression pathway can be targeted by negative regulator (MDM2) inhibitor of P53; PARP or CHK1 inhibitors may improve this response
.
Cell cycle-dependent kinase 4/6 (CDK4/6) inhibitors and WEE1 inhibitors target cell cycle dysregulation
at different stages.
Metabolic targets, including IDH and proteasome inhibitors
.
Histone deacetylase (HDAC) inhibitors are epigenetic modifiers
.
The immunosuppressive microenvironment of gliomas is a target for immune checkpoint (CTLA4, PD1) inhibitors, chimeric antigen receptor T cells (CAR-T), and bispecific T cell conjugate (BiTE) compounds
.
Phase 1 perioperative clinical trial focused on high-grade glioma (HGG).
Phase 2 clinical trials should focus on drug dose and safety
.
The use of therapeutic doses facilitates the understanding of PK and PD data collected perioperatively, the understanding of pharmacological properties of drugs such as solubility and BBB permeability, and the evaluation of combination regimens
.
Current clinical trial designs, such as the application of GBM AGILE (NCT03970447) and INSIGhT (NCT02977780) based on biomarker-based adaptability, improve clinical trial efficacy and increase the likelihood of
finding effective treatments in gliomas.
Conclusion of the study
The authors believe that significant progress has been made in the study of the glioma molecular pathway, but it has not yet been translated into effective therapies
.
Using tumor-targeting effects, drugs that can penetrate the blood-brain barrier can be identified
.
Successful perioperative clinical trials and pre- and post-treatment biopsies of gliomas are key
to the development of new drugs and drug combinations.
