Tinostamustine (EDO-S101)

Tinostamustine (EDO-S101) is an AK-DACi (a first-in-class alkylating deacetylase inhibiting molecule) that, in preclinical studies, has been shown to improve access to the DNA strands within cancer cells, break them and counteract damage repair.1-3

Preclinical studies suggest that these complementary and simultaneous modes of action have the potential to overcome resistance.3,4

The efficacy observed in preclinical studies suggests tinostamustine may offer a new single-agent treatment option for patients.4,5 In pre-clinical studies, tinostamustine alone has shown significant response and slowed disease progression in myeloid and lymphoid malignancies and solid tumours.1

Pre-clinical studies suggest that tinostamustine also exhibits strong synergy when given as part of combination therapy with agents such as bortezomib and dexamethasone and may enhance the efficacy, offering the possibility of improved duration and depth of response.4,5

The synergistic efficacy observed in pre-clinical studies suggests that tinostamustine administered as combination therapy, may provide healthcare professionals with a new treatment approach for patients who have relapsed and/or are resistant to treatment.1,4,5

The first clinical studies with tinostamustine are ongoing in patients with haematological malignancies and solid tumours.

1. López-Iglesias AA. The Alkylating Histone Deacetylase Inhibitor Fusion Molecule Edo-S101 Displays Full Bi-Functional Properties in Preclinical Models of Hematological Malignancies. Blood 2014; 124: (21).
2. López-Iglesias AA. preclinical antimyeloma activity of EDO-S101 (bendamustine-vorinostat fusion molecule) through DNA-damaging and HDACi effects. 15th International Myeloma Workshop. 23−26 September 2015. Rome, Italy.
3. Di Filippi R, et al. The First-In-Class Alkylating Histone Deacetylase Inhibitor (HDACi) Fusion Molecule EDO-S101 Exerts Potent Preclinical Activity Against Tumor Cells of Hodgkin Lymphoma (HL) Including Bendamustine Resistant Clones. 57th Annual Meeting and Exposition of the American Society of Hematology (ASH), 6 December 2015.
4. Yan S, Xu K, Lin J, et al. Synergistic inhibition of tumor growth and overcoming chemo-resistance by simultaneously targeting key components in DNA damage/repair, epigenetic, and putative cancer stem cell signaling pathways using novel dual-functional DNA-alkylating/HDAC inhibitor and tumor suppressor gene nanoparticles in lung cancer. Cancer Research 2012;72( Suppl 1): Abstract 2741.
5. Kraus M. EDO-S101, a New Alkylating Histone-Deacetylase Inhibitor (HDACi) Fusion Molecule, Has Superior Activity Against Myeloma and B Cell Lymphoma and Strong Synergy with Proteasome Inhibitors in Vitro. Blood 2014:124.
6. Graham RL, Cooper B and Krause JR. Proc (Bayl Univ Med Cent) 2013; 26(1): 19-21.
7. Breastcancer.org website. Last accessed June 2017.
8. National Cancer Institute Seer Factsheet Pancreatic Cancer. Last accessed June 2017.
9. National Cancer Institute SCLC Cancer Factsheet. American Cancer Society website. Updated December 2016. Last accessed July 2017.
10. O’Connor MJ. Targeting the DNA Damage Response in Cancer. Molecular Cell 2015; 60: 547-60.
11. Leoni LM, Bailey B, Reifert J, et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 2008; 14(1): 309-17.

Rationale for development

Despite significant breakthroughs in treatment, there are wide disparities in outcomes between types of cancer and many patients are still left with limited options.6-9

Traditional DNA-damaging therapies have certain limitations which can result in resistance. These include, failure to gain access to the DNA strands to break them, or an inability to counteract DNA repair mechanisms within cancer cells.10-11