CUSP9

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.{{cite journal |vauthors=Kast RE, Karpel-Massler G, Halatsch ME |title=CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide |journal=Oncotarget |volume=5 |issue=18 |pages=8052–82 |date=September 2014 |pmid=25211298 |pmc=4226667 |doi=10.18632/oncotarget.2408 }}{{cite journal |vauthors=Kast RE, Boockvar JA, Brüning A, Cappello F, Chang WW, Cvek B, Dou QP, Duenas-Gonzalez A, Efferth T, Focosi D, Ghaffari SH, Karpel-Massler G, Ketola K, Khoshnevisan A, Keizman D, Magné N, Marosi C, McDonald K, Muñoz M, Paranjpe A, Pourgholami MH, Sardi I, Sella A, Srivenugopal KS, Tuccori M, Wang W, Wirtz CR, Halatsch ME |title=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 |journal=Oncotarget |volume=4 |issue=4 |pages=502–30 |date=April 2013 |pmid=23594434 |pmc=3720600 |doi=10.18632/oncotarget.969 }} 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.{{cite journal |vauthors=Chantzi E, Hammerling U, Gustafsson MG |title=Exhaustive in vitro evaluation of the 9-drug cocktail CUSP9 for treatment of glioblastoma |journal=Comput Biol Med |volume=178 |issue= |pages=108748 |date=August 2024 |pmid=38925084 |doi=10.1016/j.compbiomed.2024.108748 |doi-access=free }} An in vitro study in 2024 showed synergy between the "Tumor Treating Field" Optune device and the CUSP9v3 medicines.{{cite journal |last1=Cao |first1=Qiyu |last2=Hajosch |first2=Annika |last3=Kast |first3=Richard Eric |last4=Loehmann |first4=Christopher |last5=Hlavac |first5=Michal |last6=Fischer-Posovszky |first6=Pamela |last7=Strobel |first7=Hannah |last8=Westhoff |first8=Mike-Andrew |last9=Siegelin |first9=Markus D. |last10=Wirtz |first10=Christian Rainer |last11=Halatsch |first11=Marc-Eric |last12=Karpel-Massler |first12=Georg |display-authors=3 |title=Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro |journal=British Journal of Cancer |date=3 May 2024 |volume=130 |issue=8 |pages=1365–1376 |doi=10.1038/s41416-024-02608-8|pmc=11015043 }}

Multidrug approaches like CUSP9 may be required to target the different aspects or attributes of the common deadly cancers, including glioblastoma.{{cite journal |vauthors=Kilmister EJ, Koh SP, Weth FR, Gray C, Tan ST |title=Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment |journal=Biomedicines |volume=10 |issue=11 |pages= |date=November 2022 |pmid=36428556 |pmc=9687343 |doi=10.3390/biomedicines10112988 |doi-access=free}}

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

1. Spatial and temporal heterogeneity of growth-driving dependencies {{cite journal |vauthors=Brynjulvsen M, Solli E, Walewska M, Zucknick M, Djirackor L, Langmoen IA, Mughal AA, Skaga E, Vik-Mo EO, Sandberg CJ |title=Functional and Molecular Heterogeneity in Glioma Stem Cells Derived from Multiregional Sampling |journal=Cancers (Basel) |volume=15 |issue=24 |pages=5826 |date=December 2023 |pmid=38136371 |pmc=10741477 |doi=10.3390/cancers15245826 |doi-access=free}}
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{{cite journal |vauthors=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 |title=MDACT: A New Principle of Adjunctive Cancer Treatment Using Combinations of Multiple Repurposed Drugs, with an Example Regimen |journal=Cancers (Basel) |volume=14 |issue=10 |pages=2563 |date=May 2022 |pmid=35626167 |pmc=9140192 |doi=10.3390/cancers14102563 |doi-access=free}}

{{Creative Commons text attribution notice|cc=by4|from this source=yes}}

Combinations of drugs to treat glioblastoma are commonly based on empirical, non-hypothesis driven data Johanssen T, McVeigh L, Erridge S, Higgins G, Straehla J, Frame M, Aittokallio T, Carragher NO, Ebner D. Glioblastoma and the search for non-hypothesis driven combination therapeutics in academia. Front Oncol. 2023;12:1075559. doi: 10.3389/fonc.2022.1075559. .

CUSP9 is related several other trials using similar repurposed multidrug conceptual approach: The COMBAT regimen {{cite journal |vauthors=Zapletalova D, André N, Deak L, Kyr M, Bajciova V, Mudry P, Dubska L, Demlova R, Pavelka Z, Zitterbart K, Skotakova J, Husek K, Martincekova A, Mazanek P, Kepak T, Doubek M, Kutnikova L, Valik D, Sterba J |title=Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: a multicenter experience |journal=Oncology |volume=82 |issue=5 |pages=249–60 |date=2012 |pmid=22538363 |doi=10.1159/000336483 }} for treating various advanced pediatric cancers that uses two re-purposed non-cytotoxic drugs to augment two traditional cytotoxic drugs, or the GLAD regimen{{cite journal |vauthors=Mohammed A, Janakiram NB, Brewer M, Vedala K, Steele VE, Rao CV |title=Multitargeted low-dose GLAD combination chemoprevention: a novel and promising approach to combat colon carcinogenesis |journal=Neoplasia |volume=15 |issue=5 |pages=481–90 |date=May 2013 |pmid=23633920 |pmc=3638351 |doi=10.1593/neo.13282 }} 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.{{cite journal |vauthors=Furuta T, Sabit H, Dong Y, Miyashita K, Kinoshita M, Uchiyama N, Hayashi Y, Hayashi Y, Minamoto T, Nakada M |title=Biological basis and clinical study of glycogen synthase kinase- 3β-targeted therapy by drug repositioning for glioblastoma |journal=Oncotarget |volume=8 |issue=14 |pages=22811–24 |date=April 2017 |pmid=28423558 |pmc=5410264 |doi=10.18632/oncotarget.15206 }}

The ReDO project{{cite journal |vauthors=Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP, Vikas P |title=The Repurposing Drugs in Oncology (ReDO) Project |journal=Ecancermedicalscience |volume=8 |issue= |pages=442 |date=2014 |pmid=25075216 |doi=10.3332/ecancer.2014.442 }} and many others{{cite journal |vauthors=Bhattarai D, Singh S, Jang Y, Hyeon Han S, Lee K, Choi Y |title=An Insight into Drug Repositioning for the Development of Novel Anti-Cancer Drugs |journal=Curr Top Med Chem |volume=16 |issue=19 |pages=2156–68 |date=2016 |pmid=26881715 |doi=10.2174/1568026616666160216153618 }}{{cite journal |vauthors=Alomari S, Zhang I, Hernandez A, Kraft CY, Raj D, Kedda J, Tyler B |title=Drug Repurposing for Glioblastoma and Current Advances in Drug Delivery-A Comprehensive Review of the Literature |journal=Biomolecules |volume=11 |issue=12 |pages= |date=December 2021 |pmid=34944514 |pmc=8699739 |doi=10.3390/biom11121870 |doi-access=free}} 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.{{cite journal |vauthors=Serafin MB, Bottega A, da Rosa TF, Machado CS, Foletto VS, Coelho SS, da Mota AD, Hörner R |title=Drug Repositioning in Oncology |journal=Am J Ther |volume=28 |issue=1 |pages=e111–7 |date=2021 |pmid=31033488 |doi=10.1097/MJT.0000000000000906 }}

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 panel of glioblastoma cells.{{cite journal |vauthors=Skaga E, Skaga IØ, Grieg Z, Sandberg CJ, Langmoen IA, Vik-Mo EO |title=The efficacy of a coordinated pharmacological blockade in glioblastoma stem cells with nine repurposed drugs using the CUSP9 strategy |journal=J Cancer Res Clin Oncol |volume=145 |issue=6 |pages=1495–1507 |date=June 2019 |pmid=31028540 |pmc=6527541 |doi=10.1007/s00432-019-02920-4 }}{{cite journal |vauthors=Halatsch ME, Kast RE, Dwucet A, Hlavac M, Heiland T, Westhoff MA, Debatin KM, Wirtz CR, Siegelin MD, Karpel-Massler G |title=Bcl-2/Bcl-xL inhibition predominantly synergistically enhances the anti-neoplastic activity of a low-dose CUSP9 repurposed drug regime against glioblastoma |journal=Br J Pharmacol |volume=176 |issue=18 |pages=3681–94 |date=September 2019 |pmid=31222722 |pmc=6715605 |doi=10.1111/bph.14773 }}{{cite journal |vauthors=Halatsch ME, Dwucet A, Schmidt CJ, Mühlnickel J, Heiland T, Zeiler K, Siegelin MD, Kast RE, Karpel-Massler G |title=In Vitro and Clinical Compassionate Use Experiences with the Drug-Repurposing Approach CUSP9v3 in Glioblastoma |journal=Pharmaceuticals (Basel) |volume=14 |issue=12 |pages=1241 |date=November 2021 |pmid=34959641 |pmc=8708851 |doi=10.3390/ph14121241 |doi-access=free}}