Unsolved:CUSP9

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CUSP9 (Coordinated Undermining of Survival Paths) is one of several cancer treatment protocols using repurposed 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 translation-controlled tumor protein [TCTP]. These targets have been shown to be active in promoting glioblastoma growth.

The current version, CUSP9v3, uses continuous daily very low dose temozolomide with aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, ritonavir and sertraline. Of these, an exhaustive study in 2024 showed particularly strong in vitro glioblastoma cell growth inhibition by auranofin, disulfiram, itraconazole, sertraline.[3] An in vitro study in 2024 showed synergy between the "Tumor Treating Field" Optune device and the CUSP9v3 medicines.[4]

Multidrug approaches like CUSP9 may be required to target the different aspects or attributes of the common deadly cancers, including glioblastoma.[5]

Some attributes of glioblastoma that require a multi-drug approach are:

  1. Spatial and temporal heterogeneity of growth-driving dependencies [6]
  2. Existence of mutually supporting, bilaterally communicating cell communities
  3. Compensatory tumor responses to treatments
  4. Existence of multiple cross-covering, growth-driving signaling pathways functioning in parallel
  5. Metabolic flexibility reliance shifted to another energy source if one becomes inhibited
  6. Pathological engagement of multiple normally functioning body systems to facilitate growth (e.g., cytokines, trophic factors, innervation, interacting stroma, angiogenesis)
  7. A subset of tumor stem cells with the potential to enter dormancy
  8. An inverse relationship often seen between growth and invasion, where inhibiting one enhances the other[7]

Combinations of drugs to treat glioblastoma are commonly based on empirical, non-hypothesis driven data.[8] CUSP9 is related several other trials using similar repurposed multidrug conceptual approach: The COMBAT regimen [9] for treating various advanced pediatric cancers that uses two re-purposed non-cytotoxic drugs to augment two traditional cytotoxic drugs, or the GLAD regimen[10] 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 MDACT regimen for glioblastoma, cholangiocarcinoma or non-small cell lung cancer celecoxib, dapsone, disulfiram, itraconazole, pyrimethamine, and telmisartan [13]. The CLOVA Regimen uses cimetidine, lithium, olanzapine, and valproate with temozolomide in treating glioblastoma.[11] A regimen related to CUSP9v3 called AVRO has been proposed as a simpler regimen. AVRO uses aprepitant, vortioxetine, roflumilast and olanzapine. In common with CUSP9v3, aprepitant and an SSRI antidepressant related to sertraline, vortioxetine, are used in AVRO.[12]

The ReDO project[13] and many others[14][15] also follow this line of thought as in CUSP9, repurposing older drugs for their anti-cancer effect with 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.[16]

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.

Five in vitro studies confirmed strong cytotoxicity of CUSP9 to a panel of glioblastoma cells.[17][18][19][20][3]

Clinical use

Results of a phase 1 clinical trial of CUSP9v3 [NCT02770378] was reported in June 2021.[21] Although sample size was too small for statistically meaningful inferences of effectiveness, 30% remained alive and overtly disease free at 4+ years warranting a planned follow up phase 2-3 trial of CUSP9v3.

References

  1. ↑ "CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide". Oncotarget 5 (18): 8052–82. September 2014. doi:10.18632/oncotarget.2408. 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 4 (4): 502–30. April 2013. doi:10.18632/oncotarget.969. PMID 23594434. 
  3. ↑ 3.0 3.1 "Exhaustive in vitro evaluation of the 9-drug cocktail CUSP9 for treatment of glioblastoma". Comput Biol Med 178. August 2024. doi:10.1016/j.compbiomed.2024.108748. PMID 38925084. 
  4. ↑ Cao, Qiyu; Hajosch, Annika; Kast, Richard Eric et al. (3 May 2024). "Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro". British Journal of Cancer 130 (8): 1365–1376. doi:10.1038/s41416-024-02608-8. PMID 38396172. 
  5. ↑ "Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment". Biomedicines 10 (11): 2988. November 2022. doi:10.3390/biomedicines10112988. PMID 36428556. 
  6. ↑ "Functional and Molecular Heterogeneity in Glioma Stem Cells Derived from Multiregional Sampling". Cancers (Basel) 15 (24): 5826. December 2023. doi:10.3390/cancers15245826. PMID 38136371. 
  7. ↑ "MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen". Cancers (Basel) 14 (10): 2563. May 2022. doi:10.3390/cancers14102563. PMID 35626167.   This article incorporates text from this source, which is available under the CC BY 4.0 license.
  8. ↑ Johanssen T, McVeigh L, Erridge S, Higgins G, Straehla J, Frame M, Aittokallio T, Carragher NO, Ebner D (2023). "Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia". Front Oncol 12. doi:10.3389/fonc.2022.1075559. PMID 36733367. 
  9. ↑ "Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience". Oncology 82 (5): 249–60. 2012. doi:10.1159/000336483. PMID 22538363. 
  10. ↑ "Multitargeted low-dose GLAD combination chemoprevention: a novel and promising approach to combat colon carcinogenesis". Neoplasia 15 (5): 481–90. May 2013. doi:10.1593/neo.13282. PMID 23633920. 
  11. ↑ "Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma". Oncotarget 8 (14): 22811–24. April 2017. doi:10.18632/oncotarget.15206. PMID 28423558. 
  12. ↑ Kast RE, Marques Vieira B, Barros da Silva E Jr (Jun 2025). "A New Adjuvant Treatment for Glioblastoma Using Aprepitant, Vortioxetine, Roflumilast and Olanzapine: The AVRO Regimen". Int J Mol Sci 26 (13): 6158. doi:10.3390/ijms26136158. PMID 40649933. 
  13. ↑ "The Repurposing Drugs in Oncology (ReDO) Project". ecancermedicalscience 8: 442. 2014. doi:10.3332/ecancer.2014.442. PMID 25075216. 
  14. ↑ "An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs". Curr Top Med Chem 16 (19): 2156–68. 2016. doi:10.2174/1568026616666160216153618. PMID 26881715. 
  15. ↑ "Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery-A Comprehensive Review of the Literature". Biomolecules 11 (12): 1870. December 2021. doi:10.3390/biom11121870. PMID 34944514. 
  16. ↑ "Drug Repositioning in Oncology". Am J Ther 28 (1): e111–7. 2021. doi:10.1097/MJT.0000000000000906. PMID 31033488. 
  17. ↑ Cao Q, Hajosch A, Kast RE, Loehmann C, Hlavac M, Fischer-Posovszky P, Strobel H, Westhoff MA, Siegelin MD, Wirtz CR, Halatsch ME, Karpel-Massler G (May 2024). "Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro". Br J Cancer 130 (8): 1365–1376. doi:10.1038/s41416-024-02608-8. PMID 38396172. 
  18. ↑ "The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy". J Cancer Res Clin Oncol 145 (6): 1495–1507. June 2019. doi:10.1007/s00432-019-02920-4. PMID 31028540. 
  19. ↑ "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 176 (18): 3681–94. September 2019. doi:10.1111/bph.14773. PMID 31222722. 
  20. ↑ "In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma". Pharmaceuticals (Basel) 14 (12): 1241. November 2021. doi:10.3390/ph14121241. PMID 34959641. 
  21. ↑ "A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3". Neurooncol Adv 3 (1). 2021. doi:10.1093/noajnl/vdab075. PMID 34377985. 



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