CUSP9 explained

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 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]

Multidrug approaches like CUSP9 may be required to target the different aspects or attributes of the common deadly cancers, including glioblastoma. Some of these aspects are:

1. Spatial and temporal heterogeneity of growth-driving dependencies
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^[4]

CUSP9 is related several other trials using similar repurposed multidrug conceptual approach: The COMBAT regimen ^[5] for treating various advanced pediatric cancers that uses two re-purposed non-cytotoxic drugs to augment two traditional cytotoxic drugs, or the GLAD regimen^[6] 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.^[7]

The ReDO project^[8] and many others^[9] 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.^[10]

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.

Three in vitro studies confirmed strong cytotoxicity of CUSP9 to a pannel of glioblastoma cells.^{[11] [12] [13]}

Clinical Use

Results of a phase 1 clinical trial of CUSP9v3 [NCT02770378] was reported in June 2021.^[14] 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.

Notes and 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. .
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. ; .
3. Chantzi E, Hammerling U, Gustafsson MG. Exhaustive in vitro evaluation of the 9-drug cocktail CUSP9 for treatment of glioblastoma. Comput Biol Med. 2024;178:108748. doi: 10.1016/j.compbiomed.2024.108748. PMID: 38925084.
4. Kast RE, Alfieri A, Assi HI, Burns TC, Elyamany AM, Gonzalez-Cao M, Karpel-Massler G, Marosi C, Salacz ME, Sardi I, Van Vlierberghe P, Zaghloul MS, Halatsch ME. MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen. Cancers (Basel). 2022;14(10):2563. doi:10.3390/cancers14102563.
5. using Metronomic chemotherapy in advanced pediatric malignancies: a multicenter experience. Oncology. 2012;82(5):249-60. .
6. Multitargeted low-dose GLAD combination chemoprevention: a novel and promising approach to combat colon carcinogenesis. Neoplasia. 2013;15(5):481-90. ; .
7. 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.
8. Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP, Vikas P. The Repurposing Drugs in Oncology (ReDO) Project. ecancermedicalscience. 2014;8:442. .
9. 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.
10. 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.
11. 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.
12. 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;176(18):3681-3694. doi:10.1111/bph.14773.
13. Halatsch ME, Dwucet A, Schmidt CJ, Mühlnickel J, Heiland T, Zeiler K, Siegelin MD, Kast RE, Karpel-Massler G. In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma. Pharmaceuticals (Basel). 2021;14(12):1241. doi:10.3390/ph14121241.
14. 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.