CUSP9
CUSP9 [Coordinated Undermining of Survival Paths] is one of several cancer treatment protocols using re-purposed older drugs to interfere with cancer cell's growth signaling rather than directly killing them with cytotoxic drugs.[1][2] CUSP9 is a treatment specifically targeted to glioblastoma that adds to a traditional cancer cell killing drug, temozolomide, nine older, non-cytotoxic drugs to block growth factors that enhance or drive glioblastoma growth [aprepitant blocks NK-1, auranofin inhibits thioredoxin reductase, captopril inhibits angiotensin converting enzyme, celecoxib blocks cyclooxygenase-2, disulfiram blocks aldehyde dehydrogenase, itraconazole blocks Hedgehog signaling, minocycline inhibits metalloproteinase-2 and -9, quetiapine inhibits RANKL, sertraline inhibits Tissue Factor]. These targets have been shown to be active in glioblastoma.
CUSP9 is related several other trials using a similar conceptual approach: The COMBAT regimen [3] for treating various advanced pediatric cancers that uses two re-purposed non-cytotoxic drugs to augment two traditional cytotoxic drugs, or the [4] that uses one traditional anti-cancer drug, gefitinib, with three re-purposed non-cancer drugs. Or the MEMMAT regimen, in a current trial of A.Peyrl et al. using a 7 drug cocktail, (ClinicalTrials.gov Identifier: NCT01356290)- non-cytotoxic drugs bevacizumab, thalidomide, celecoxib, and fenofibric acid to augment traditional cytotoxic drugs etoposide, cyclophosphamide, and cytarabine to treat progressive medulloblastoma. Also the CLOVA Regimen that uses cimetidine, lithium, olanzapine, and valproate with temozolomide in treating glioblastoma.[5]
The ReDO project[6] and many others[7] also follow this line of thought as in CUSP9 - repurposing older drugs for their anti-cancer effect and simultaneous use of several of them] in cancer treatment. The drug repurposing movement uses the central or ancillary attributes of a drug normally used for non-cancer indications but that may constructively interact with a cancer's growth mechanisms to slow that cancer's growth.[8]
None of these treatment regimens have been proven to be safe or effective in human cancers but are occasionally tried on compassionate-use basis in patients who have exhausted all other options. A formal trial of the CUSP9 protocol in recurrent glioblastoma [ClinicalTrials.gov Identifier: NCT02770378] in Ulm Germany was completed, results to be announced in mid-2019.[9]
Two in vitro studies confirmed strong cytotoxicity of CUSP9 to a pannel of glioblastoma cells.[10][11]
Clinical Use[]
Results of the above-mentioned clinical trial of CUSP9v3 [NCT02770378] were reported in June 2021.[12] Although sample size was too small for statistically meaningful inferences, that 30% remained alive and overtly disease free at 4+ years warranted a planned follow up phase 2-3 trial of CUSP9v3.
References[]
- ^ CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide. Oncotarget. 2014;5(18):8052-82. PMID 25211298.
- ^ A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget. 2013;4(4):502-30. PMID 23594434; PMC 3720600.
- ^ using Metronomic chemotherapy in advanced pediatric malignancies: a multicenter experience. Oncology. 2012;82(5):249-60. doi:10.1159/000336483.
- ^ Multitargeted low-dose GLAD combination chemoprevention: a novel and promising approach to combat colon carcinogenesis. Neoplasia. 2013;15(5):481-90. PMID 23633920; PMC 3638351.
- ^ Furuta T, Sabit H, Dong Y, Miyashita K, Kinoshita M, Uchiyama N, Hayashi Y, Hayashi Y, Minamoto T, Nakada M. Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma. Oncotarget. 2017;8(14):22811-22824. doi:10.18632/oncotarget.15206.
- ^ Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP, Vikas P. The Repurposing Drugs in Oncology (ReDO) Project. ecancermedicalscience. 2014;8:442. doi:10.3332/ecancer.2014.442.
- ^ Bhattarai D, Singh S, Jang Y, Hyeon Han S, Lee K, Choi Y. An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs. Curr Top Med Chem. 2016;16(19):2156-68.
- ^ Serafin MB, Bottega A, da Rosa TF, Machado CS, Foletto VS, Coelho SS, da Mota AD, Hörner R. Drug Repositioning in Oncology. Am J Ther. 2019 Jun 5. doi:10.1097/MJT.0000000000000906.
- ^ "CUSP9*, 9 nine repurposed drugs, glioblastoma, temozolomide - Anticancer Fund". anticancerfund.org.
- ^ Skaga E, Skaga IØ, Grieg Z, Sandberg CJ, Langmoen IA, Vik-Mo EO. The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy. J Cancer Res Clin Oncol. 2019;145(6):1495-1507. doi:10.1007/s00432-019-02920-4.
- ^ 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. [Epub ahead of print] PubMed PMID 31222722.
- ^ Halatsch ME, Kast RE, Karpel-Massler G, Mayer B, Zolk O, Schmitz B, Scheuerle A, Maier L, Bullinger L, Mayer-Steinacker R, Schmidt C, Zeiler K, Elshaer Z, Panther P, Schmelzle B, Hallmen A, Dwucet A, Siegelin MD, Westhoff MA, Beckers K, Bouche G, Heiland T. A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3. Neurooncol Adv. 2021;3(1):vdab075. doi:10.1093/noajnl/vdab075.
- Alternative cancer treatments