2023-09-18 15:01:00
glioblastoma [이미지=서울대병원TV 캡처]
[헬스코리아뉴스 / 이충만] With the advancement of diagnostic technology, the prevalence of glioblastoma, a type of brain cancer (tumor), is rapidly increasing, and interest in developing new therapeutic drugs is also increasing.
Glioblastoma is a tumor that originates from glial cells inside the brain and spinal cord. It is also called glioma, glioma, glioma, and glioma. It is the most common brain tumor, accounting for regarding 50% of primary intracranial tumors. It mostly grows by infiltrating surrounding normal tissues and has the characteristic of rapid growth. Above all, glioblastoma is the most malignant and fatal disease, with approximately 600 patients occurring annually in Korea.
However, the exact cause of the disease has not yet been revealed, and it is only assumed that genetic factors are involved. Scientists believe that genes related to the development of brain tumors, such as EGFR, PDGF, INK4α, MDM2, PRb, CDK4/6, PTEN, P53, H3 K27M, and ALDH, are biomarkers that play an important role in the expression of glioblastoma.
As the exact cause is not known, there is no clear prevention or treatment. When screening for glioblastoma, the tumor is removed as much as possible through surgery, and then adjuvant treatments such as radiation therapy and chemotherapy are used to prolong survival.
Of course, there are approved treatments. Switzerland’s Roche’s targeted anticancer drug ‘Avastin (ingredient name: bevacizumab)’ and its generic drug have been approved by regulatory authorities as a treatment for glioblastoma. This drug is a mechanism that inhibits new blood vessels formed by cancer cells to continuously divide by receiving an unlimited supply of nutrients and oxygen from surrounding tissues.
However, since ‘Avastin’ is not a drug that fundamentally targets the cause of glioblastoma, its therapeutic effect is limited. Clinical studies have shown that Avastin improves progression-free survival (PFS), but no clinical benefit on overall survival (OS) was observed.
Therefore, the average survival period of glioblastoma patients is less than 1 year, and the survival rate within 10 years is only 5%.
As unmet medical needs increase, the pharmaceutical industry is making desperate efforts to introduce innovative new drugs for glioblastoma.
20 drug classes currently entering clinical trials
According to a 2021 count by Johns Hopkins University in the United States, there are currently approximately 20 types of drugs that have entered the clinical stage among treatments for glioblastoma. Both are approaches that expand the use of the drugs from existing approved indications to glioblastoma treatments.
[현재 개발 중인 교모세포종 치료제 현황]
drug
Existing indications
Glioblastoma treatment mechanism
Mefloquine
malaria treatment
Inducing cancer cell death by intervening in the cell cycle process
Memantine
Alzheimer’s treatment
Involves cell signaling by antagonizing NMDA receptors and inhibits cancer cell proliferation
Levetiracetam
Epilepsy treatment
Inhibits cancer cell growth and proliferation by activating autophagy, a process that decomposes unnecessary or malfunctioning organelles within cells.
Valproic Acid
Epilepsy treatment
Inhibits tumor growth by reducing PON2, which is believed to cause glioblastoma when overexpressed, within cells.
Disulfiram
alcohol addiction treatment
Inhibits glioblastoma growth by inhibiting ALDH, a presumed glioblastoma biomarker
Dimethyl Fumarate
multiple sclerosis treatment
Prevents neovascularization of cancer cells by inhibiting endothelial cell growth
Sertraline
antidepressants
Targets glioblastoma with a mechanism of action that crosses the blood brain barrier (BB)
Imipramine
antidepressants
Inhibition of glioblastoma progression by targeting YAP factor, which is presumed to be associated with glioblastoma
Metformin
diabetes medication
Preclinical results show inhibition of tumor cell growth (mechanism of action in cancer treatment unclear)
Sulfasalazine
Ulcerative colitis treatment
Reduced side effects and amplified effects when used in combination with radiation therapy (mechanism of action in cancer treatment unclear)
Aprepitant
anticancer chemotherapy drug
Induces cancer cell death by causing cytotoxicity
Lopinavir+Ritonavir (Ritonavir+Lopinavir)
HIV treatment
Prevents cancer cell metastasis by suppressing the expression of MMP, a protein enzyme that decomposes extracellular matrix in microglia or astrocytes
Valganciclovir
Cytomegalovirus (CMV) treatment
Inhibits glioblastoma progression by targeting CMV virus, known to contribute to tumor growth
Nelfinavir
HIV treatment
Inhibition of signal transduction pathways of genes presumed to be glioblastoma biomarkers such as PI3K, AKT, and MTOR
Itraconazole
antifungal agent
Inhibits glioblastoma tumor growth by redistributing intracellular cholesterol
Minocycline
Antibiotic
Reduces glioblastoma invasion and metastasis by suppressing MMP expression in microglial cells
Chloroquine+hydroxychloroquine
malaria treatment
Inhibit tumor growth by inhibiting TGF-β secretion and signaling pathways
Mebendazole
helminthic
Inhibits tumor growth by interfering with cancer cell microtubules, which are essential for cell division, through a mechanism of action that crosses the blood brain barrier (BB)
Captopril
high blood pressure medication
Prevents new blood vessel formation in cancer cells through vascular pressure action
Losartan
high blood pressure medication
Prevents new blood vessel formation in cancer cells through vascular pressure action
Representative treatments include ① ‘OKN-007’ from Korea’s HLB Therapeutics and ② ‘ONC201’ from Chimerix from the United States.
HLB Therapeutics’ ‘OKN-007’ improves the tumor microenvironment and inhibits the generation of transforming growth factor β (TGFβ), a key factor that inhibits the effectiveness of immunotherapy treatment, and HIF-1α, a hypoxia-inducing factor. It is a drug that inhibits the creation and growth of new blood vessels in cancer cells by normalizing tumor blood vessels. In terms of drug type, it is the chloroquine series.
According to the company, ‘OKN-007’ has proven to be highly effective in drug delivery, including temporarily opening the blood-brain barrier (BBB) and improving the permeability of other substances. This drug is currently undergoing phase 1 clinical trials in the United States through its U.S. subsidiary Oblato.
Chimeric’s ‘ONC201’ selectively inhibits dopamine receptor D2 (DRD2), blocking the signaling pathway of the H3 K27M gene commonly expressed in glioblastoma, thereby inducing the death of cancer cells. The drug type is psychotropic medication.
In a previously conducted clinical study, ‘ONC201’ showed an objective response rate of 96% in a 22-year-old H3K27M-positive glioblastoma patient.
In addition, Aurora Healthcare, a non-profit medical organization in the United States, is developing a combination therapy that combines disulfiram, an alcohol addiction treatment, with copper and temozolomide, a chemical anticancer drug. In 2018, this organization initiated a phase 2 clinical trial evaluating disulfiram + copper + temozolomide for glioblastoma patients who did not respond well to chemotherapy.
Trial results published last year showed that the disulfiram + copper + temozolomide combination therapy had an excellent safety profile and demonstrated preliminary antitumor activity that might cross the blood brain barrier (BB) and target glioblastoma.
However, these treatments have not yet proven to have a clear effect, so it is considered too early to raise patients’ expectations. Therefore, it appears that it will take a considerable amount of time to develop a drug that can be expected to have practical effects.
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