CUSP9* off-label drugs to improve GBM outcomes?

CUSP9* off-label drugs to improve GBM outcomes?

CUSP9* is nine off-label drugs - aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir - packaged to improve the effectiveness of Temozolomide in treating Glioblastoma multiforme. 

Researchers from Ulm University in Germany and the IIAIGC study centre in Burlington, Vermont have been exploring ways of using off-label, or repurposed, drugs to help extend survival times in patients with Glioblastoma (1). The current orthodox treatment protocol since 2005 has been surgery to remove as much of the tumour as possible, followed by 6 weeks of combined Temozolomide (TMZ) and simultaneous radiotherapy. Survival time is then usually 15-24 months.

Temozolomide itself is only effective with methylating tumours, found in only 20 per cent of all patients. CUSP9* (Coordinated Undermining of Survival Paths) is an updated group of repurposed, off-label (i.e. outside of their original licensed designation) drugs to augment the cytoxic properties of Temozolomide by adding a programme of interfering with the cancer’s signalling and growth pathways.

This is a theoretical protocol based on research into each drug’s effects. No clinical trial data seems available although trial data was due to be completed in 2019 from ULM. 

The researchers expect this group of drugs to block factors present in GBM 

  • aprepitant blocks NK-1, 

  • auranofin inhibits thioredoxin reductase, 

  • captopril inhibits angiotensin converting enzyme,

  • celecoxib blocks cyclooxygenase-2, 

  • disulfiram blocks aldehyde dehydrogenase, 

  • itraconazole blocks Hedgehog signalling, 

  • minocycline inhibits metalloproteinase-2 and -9, 

  • quetiapine inhibits RANKL, 

  • sertraline inhibits Tissue Factor

Two in vitro studies showed significant cancer cell destruction in GBM with the protocol alone, or better with TMZ (2). The researcher from the USA reviewed the benefits of starting celecoxib alone, 600 to 800 mg twice daily before surgery and continuing it through the combined chemo-irradiation phase of treatment and believed it would be a low-risk intervention with sound rationale.

Theoretical protocols need testing or they remain theory. However, research (3) has shown the diabetes drug Metformin can improve the effectiveness and block chemoresistance to TMZ, and arguably better is the herb berberine (4), and in 2021 a review of a number of studies showed the benefit of using Atorvastatin (5).

 

At CANCERactive, we've been building off-label drug protocols varying by cancer since 2017, with early research of drugs such as Low Dose Naltrexone, antihistamines (e.g. Cimetidine, Loratadine), and Metformin and Atorvastatin. We have a constantly updated overview of useful off-label or repurposed drugs.

Perhaps the pioneer of off-label drugs with GBM was Professor Ben Williams who cured his own GBM back in 1998 by using a mix of diet, supplements (like cancer stem cell killers genistein, PSK and EGCG), orthodox medicine, and off-label drugs - his protocol included Melatonin, Accutane, Cimetidine and Tamoxifen. Care Oncology use Metformin, Mebendazole, Atorvastatin and Doxycycline.

Go to: Building an anti-brain cancer protocol

 

References

 

  1. CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide; Ocotarget 2014; Richard E. Kast et al - https://pubmed.ncbi.nlm.nih.gov/25211298/ 

  2. Halatsch ME, Kast RE, Dwucet A, Hlavac M, Heiland T, Westhoff MA, Debatin KM, Wirtz CR, Siegelin MD, Karpel-Massler G. Bcl-2/Bcl-xL inhibition predominantly synergistically enhances the anti-neoplastic activity of a low-dose CUSP9 repurposed drug regime against glioblastoma. Br J Pharmacol. 2019 Jun 21. doi: 10.1111/bph.14773. 

  3. Metformin treatment reduces temozolomide resistance of glioblastoma cells; Oncotarget 2016; Nov 29; Sueng Ho Yang, Uni Texas; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346677/ 

  4.  Berberine reduces temozolomide resistance by inducing autophagy via the ERK1/2 signaling pathway in glioblastoma; Canc Cell Int; 2020; Dec 9, 20; Huiling Qu et al - https://pubmed.ncbi.nlm.nih.gov/33298057/

  5. Effects of statins on brain tumors: a review - Semin Canc Biol; 2021 Aug;73:116-133.Amir R Afshari et al - https://pubmed.ncbi.nlm.nih.gov/32814114/

 


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