Combination treatment of cancer
Inventors
Brünner, Nils Aage • Christophersen, Palle • Stenvang, Jan • Lichtenberg, Jens • Thougaard, Annemette
Assignees
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Publication Number
US-11903927-B2
Publication Date
2024-02-20
Expiration Date
Abstract
The present invention relates to treatment of cancer, in particular to methods of sensitising cancer cells to an anti-cancer therapy by administering an effective amount of a modulator of Volume Regulated Anion Channels, i.e. a VRAC modulator.
Core Innovation
The invention provides a method of sensitizing cancer cells of a cancer to an anti-cancer agent or potentiating the therapeutic effect of an anti-cancer agent by administering, to a subject in need thereof, an effective amount of a VRAC modulator together with an effective amount of an anti-cancer agent. The cancer is selected from a specified group of cancer types including colorectal cancer, breast cancer, lung cancer, glioblastomas, head and neck cancers, and malignant melanomas. The disclosure defines VRAC and VRAC blockers/modulators and connects VRAC activity with apoptosis and drug response in the context of cancer cell sensitivity.
The core includes using specific VRAC modulators, including VRAC blockers/inhibitors described by general formula I and/or general formula II, including pharmaceutically acceptable salts. The disclosure further includes example VRAC blocker structures based on urea derivatives under general formula I, with IC50 ranges stated for the VRAC blockers. The concept is that modulating VRAC changes how cancer cells respond to anti-cancer agents, enabling sensitization or re-sensitisation to therapeutic agents.
The document also describes cancer combination treatment regimens in which VRAC modulators are combined with anti-cancer agents to enhance anti-tumor efficacy. It specifically reports preclinical observations that NS3728 (Endovion/SCO-101) combined with temozolomide produces enhanced anti-tumor effects in glioblastoma xenografts, and that combining NS3728 with paclitaxel or 5-fluorouracil (5-FU) potentiates inhibition of HT29 colorectal tumors. It further reports re-sensitisation in resistant cancer models using NS3728 in combination with docetaxel, SN-38, and anti-estrogen therapy including tamoxifen and fulvestrant.
Claims Coverage
The document contains one independent claim directed to sensitizing or potentiating an anti-cancer agent effect using a VRAC modulator plus the anti-cancer agent, with the cancer limited to a specified list. The dependent claims then refine the structural definition of the VRAC modulator and the timing and/or classes of anti-cancer agents, including treatment in resistant cancers.
Sensitizing or potentiating using a VRAC modulator with an anti-cancer agent
Administering to a subject an effective amount of a VRAC modulator and an effective amount of an anti-cancer agent to sensitize cancer cells to an anti-cancer agent or potentiate the therapeutic effect of the anti-cancer agent, wherein the cancer is selected from a specified group of cancer types.
VRAC modulator defined by general formula I
A method wherein the VRAC modulator is a compound of general formula I, or a pharmaceutically acceptable salt thereof, with specified substituent definitions and ring constraints.
VRAC modulator defined by formula II
A method wherein the VRAC modulator is a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula II.
Timing of VRAC modulator relative to the anti-cancer agent
Administering the VRAC modulator by co-administration, administration before the anti-cancer agent, or administration after the anti-cancer agent.
Anti-cancer agent restricted to specified therapeutic categories
Using an anti-cancer agent that is a chemotherapeutic agent selected from specified classes including topoisomerase inhibitors, anti-hormone agents, alkylating agents, mitotic inhibitors, antimetabolites, anti-tumour antibiotics, corticosteroids, targeted anti-cancer therapy, differentiating agents, and immunotherapy.
Targeting cancer that is resistant to the anti-cancer agent
A method directed to cancer that is resistant to an anti-cancer agent.
Overall claim coverage centers on combining a VRAC modulator with an anti-cancer agent to sensitize or potentiate anti-cancer effects across a specified range of cancer types. Dependent claim refinements focus on defining VRAC modulators by general formula I and/or formula II, setting timing relative to the anti-cancer agent, restricting the anti-cancer agent to specified therapeutic categories, and applying the method to anti-cancer agent-resistant cancers.
Stated Advantages
Sensitizing cancer cells to an anti-cancer agent.
Potentiating the therapeutic effect of an anti-cancer agent.
Re-sensitisation of resistant cancer models to anti-cancer agents is described in the document context.
Documented Applications
Preclinical use of NS3728 (Endovion/SCO-101) with temozolomide in glioblastoma xenografts.
Preclinical use of NS3728 with paclitaxel or 5-fluorouracil (5-FU) to potentiate inhibition of HT29 colorectal tumors.
Re-sensitisation in resistant cancer models, including NS3728 with docetaxel in docetaxel-resistant breast lines, NS3728 with SN-38 in SN-38 resistant colorectal cancer models, and NS3728 with tamoxifen or fulvestrant in anti-estrogen resistant breast models.
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