CUSP9

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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 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.

Related Research Articles

<span class="mw-page-title-main">Glioma</span> Tumour of the glial cells of the brain or spine

A glioma is a type of primary tumor that starts in the glial cells of the brain or spinal cord. They are cancerous but some are extremely slow to develop. Gliomas comprise about 30 percent of all brain tumors and central nervous system tumours, and 80 percent of all malignant brain tumours.

<span class="mw-page-title-main">Celecoxib</span> Nonsteroidal anti-inflammatory medication

Celecoxib, sold under the brand name Celebrex among others, is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug (NSAID). It is used to treat the pain and inflammation in osteoarthritis, acute pain in adults, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, painful menstruation, and juvenile rheumatoid arthritis. It may also be used to decrease the risk of colorectal adenomas in people with familial adenomatous polyposis. It is taken by mouth. Benefits are typically seen within an hour.

<span class="mw-page-title-main">Glioblastoma</span> Aggressive type of brain cancer

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.

<span class="mw-page-title-main">Epirubicin</span> Chemical compound

Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in the US and Pharmorubicin or Epirubicin Ebewe elsewhere.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

<span class="mw-page-title-main">Auranofin</span> Chemical compound

Auranofin is a gold salt classified by the World Health Organization as an antirheumatic agent. It has the brand name Ridaura.

<span class="mw-page-title-main">PAC-1</span> Chemical compound

PAC-1 is a synthesized chemical compound that selectively induces apoptosis, in cancerous cells. It was granted orphan drug status by the FDA in 2016.

<span class="mw-page-title-main">Cediranib</span> Chemical compound

Cediranib is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases.

<span class="mw-page-title-main">Cilengitide</span> Chemical compound

Cilengitide is a molecule designed and synthesized at the Technical University Munich in collaboration with Merck KGaA in Darmstadt. It is based on the cyclic peptide cyclo(-RGDfV-), which is selective for αv integrins, which are important in angiogenesis, and other aspects of tumor biology. Hence, it is under investigation for the treatment of glioblastoma, where it may act by inhibiting angiogenesis, and influencing tumor invasion and proliferation.

<span class="mw-page-title-main">Mitotic inhibitor</span> Cell division inhibitor

A mitotic inhibitor, microtubule inhibitor, or tubulin inhibitor, is a drug that inhibits mitosis, or cell division, and is used in treating cancer, gout, and nail fungus. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow through continuous division that eventually spread through the body (metastasize). Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics, where they stop cell division at a stage where chromosomes can be easily examined.

<span class="mw-page-title-main">Taurolidine</span> Antimicrobial compound

Taurolidine is an antimicrobial that is used to prevent infections in catheters. Side effects and the induction of bacterial resistance is uncommon. It is also being studied as a treatment for cancer.

<span class="mw-page-title-main">Carmofur</span> Chemical compound

Carmofur (INN) or HCFU (1-hexylcarbamoyl-5-fluorouracil) is a pyrimidine analogue used as an antineoplastic agent. It is a derivative of fluorouracil, being a lipophilic-masked analog of 5-FU that can be administered orally.

<span class="mw-page-title-main">Lonidamine</span> Chemical compound

Lonidamine is a derivative of indazole-3-carboxylic acid, which for a long time, has been known to inhibit aerobic glycolysis in cancer cells. It seems to enhance aerobic glycolysis in normal cells, but suppress glycolysis in cancer cells. This is most likely through the inhibition of the mitochondrially bound hexokinase. Later studies in Ehrlich ascites tumor cells showed that lonidamine inhibits both respiration and glycolysis leading to a decrease in cellular ATP.

<span class="mw-page-title-main">Phosphoinositide 3-kinase inhibitor</span>

Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

<span class="mw-page-title-main">Temozolomide</span> Cancer medication

Temozolomide, sold under the brand name Temodar among others, is an anticancer medication used to treat brain tumors such as glioblastoma and anaplastic astrocytoma. It is taken by mouth or via intravenous infusion.

Chemotherapy-induced nausea and vomiting (CINV) is a common side-effect of many cancer treatments. Nausea and vomiting are two of the most feared cancer treatment-related side effects for cancer patients and their families. In 1983, Coates et al. found that patients receiving chemotherapy ranked nausea and vomiting as the first and second most severe side effects, respectively. Up to 20% of patients receiving highly emetogenic agents in this era postponed, or even refused, potentially curative treatments. Since the 1990s, several novel classes of antiemetics have been developed and commercialized, becoming a nearly universal standard in chemotherapy regimens, and helping to better manage these symptoms in a large portion of patients. Efficient mediation of these unpleasant and sometimes debilitating symptoms results in increased quality of life for the patient, and better overall health of the patient, and, due to better patient tolerance, more effective treatment cycles.

Alternating electric field therapy, sometimes called tumor treating fields (TTFields), is a type of electromagnetic field therapy using low-intensity, intermediate frequency electrical fields to treat cancer. TTFields disrupt cell division by disrupting dipole alignment and inducing dielectrophoresis of critical molecules and organelles during mitosis. These anti-mitotic effects lead to cell death, slowing cancer growth. A TTField-treatment device manufactured by the Israeli company Novocure is approved in the United States and Europe for the treatment of newly diagnosed and recurrent glioblastoma, malignant pleural mesothelioma (MPM), and is undergoing clinical trials for several other tumor types. Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.

mTOR inhibitors Class of pharmaceutical drugs

mTOR inhibitors are a class of drugs used to treat several human diseases, including cancer, autoimmune diseases, and neurodegeneration. They function by inhibiting the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs). mTOR regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes, mTORC1 and mTORC2. The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

<span class="mw-page-title-main">OSU-03012</span> Chemical compound

OSU-03012 (AR-12) is a celecoxib derivative with anticancer and anti-microbial activity. Unlike celecoxib, OSU-03012 does not inhibit COX, but inhibits several other important enzymes instead which may be useful in the treatment of some forms of cancer, When combined with PDE5 inhibitors such as sildenafil or tadalafil, OSU-03012 was found to show enhanced anti-tumour effects in cell culture.

<span class="mw-page-title-main">Sonidegib</span> Chemical compound

Sonidegib (INN), sold under the brand name Odomzo, is a medication used to treat cancer.

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. ↑ 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. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
  5. ↑ using Metronomic chemotherapy in advanced pediatric malignancies: a multicenter experience. Oncology. 2012;82(5):249-60. doi : 10.1159/000336483.
  6. ↑ 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.
  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. doi : 10.3332/ecancer.2014.442.
  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.
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