Selinexor, a drug approved recently for pretreated multiple myeloma and lymphoma patients seems capable of benefiting patients with GBM, even if they are neither methylating nor have an IDH-1 mutation.
Glioblastoma Multiforme or GBM is a terrible disease. Some patients are given a prognosis of just 5 months. The average survival is approximately 15 months. In 1986 a drug called Temozolomide was approved. It was known then that it only ‘worked’ with people whose tumours were methylating. In fact, at first the FDA turned it down, but approved it as long as patients were tested. Rather like Herceptin in breast cancer, with GBM just 20% of patients have the appropriate condition. Herceptin is not used on every lady with breast cancer, just those who are HER2+ve, but Temozolomide is used on everyone, even though it is doomed to failure with the 80% of GBM patients who are not methylating.
This is why it is often given at the outset of treatment with radiotherapy for 6 weeks. At least the radiotherapy may achieve something. There is research that cutting blood sugar using metformin and/or berberine can make it slightly more effective and for more people (those who are methylating slightly). Phase II Clinical trials in the Lancet suggest Lomustine can improve its performance. And the Optune System - where you live with an electric field generating cap on your head, is also proven to extend survival times. Various other ‘drugs’ from Chlomipramine, to Celebrex and even hydroxychloroquine seem to help a little.
The key issue then is what is the best orthodox protocol for non-methylators; the 80%? Does one even exist?
Selinexor (KPT-330) and GBM
Selinexor is an FDA-approved chemotherapy for multiple myeloma and diffuse large B-cell lymphoma patients who have been heavily pretreated with other medicines. It was given Fast Track approval by the FDA in 2018/9.
Selinexor is a first-in-class, oral, Selective Inhibitor of Nuclear Export (SINE) drug, which functions by binding to and blocking the nuclear export protein XPO1. This results in an accumulation of tumor suppressor proteins in the cell nucleus, which in turn provides stronger tumour suppression leading to apoptosis of cancer cells, while having minimal effect on healthy cells.
In 2019, neurologist Dr. Andrew Lassman presented Phase II results of a clinical trial at the American Society of Clinical Oncology on Selinexor with GBM (1, 2). The initial interest was because increased XPO1 expression is also seen in GBM especially those that are more aggressive.
The researchers presented findings from 30 patients with recurrent GBM who had received an average of two prior cancer treatments, although some had received up to seven. The overall response rate was 10% even though some patients had been heavily pretreated, 19% of patients survived 6 months without cancer progression and Selinexor-treated patients survived 9.4 months on average. Lassman said that even where there was no IDH mutation or other biomarkers the responses were noted, with stable and durable responses; one patient had been stable on the trial for 3 years.
More is needed to be known about the relationship between the cancer characteristics and the drug.
Worldwide enrollment is currently taking place (3) to test Selinexor’s effects in combination with other treatments including standard current treatments.
Go to: Brain cancer overview
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References
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Lassman AB, et al. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
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https://news.cancerconnect.com/brain-cancer/certain-patients-with-glioblastoma-appear-to-respond-to-selinexor
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Lassman et al; Presented at ASCO Annual Meeting 2021 - https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.TPS2071?expanded=undefined