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 GLAD regimen[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.

The ReDO project[5] 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 {9}.

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.[6]

Two in vitro studies confirmed strong cytotoxicity to a pannel of glioblastoma cells {8, 10}.

References
  1. 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.
  2. 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.
  3. using Metronomic chemotherapy in advanced pediatric malignancies: a multicenter experience. Oncology. 2012;82(5):249-60. doi:10.1159/000336483.
  4. 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.
  5. 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.
  6. "CUSP9*, 9 nine repurposed drugs, glioblastoma, temozolomide - Anticancer Fund". anticancerfund.org.

7. 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.

8. 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.

9. 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.

10. 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.

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