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EP-4739311-A1 - CSE INHIBITOR FOR USE IN THE TREATMENT OF A TUMOR IN COMBINATION WITH A MAPK INHIBITOR

EP4739311A1EP 4739311 A1EP4739311 A1EP 4739311A1EP-4739311-A1

Abstract

The invention relates to cystathionine-γ-lyase (CSE) inhibitor for use in the treatment of a cancer, preferably a tumor in a patient, in combination with a (one or more) MAPK inhibitor, in particular an inhibitor of a BRAF V600 mutant, preferably for use in the prevention or delaying the onset or development of resistance of said patient to a treatment of said cancer with the MAPK inhibitor, in particular the inhibitor of the BRAF V600 mutant. The invention also relates to combination treatments, if desired with diagnosis, as well as pharmaceutical compositions, combinations and kits for such therapies.

Inventors

  • NAGY, Péter
  • ERDÉlYI, Katalin
  • BORBÉNYI-GALAMBOS, Klaudia

Assignees

  • Országos Onkológiai Intézet

Dates

Publication Date
20260513
Application Date
20240703

Claims (16)

  1. 1. A cystathionine-y-lyase (CSE) inhibitor for use in the treatment of a BRAF V600 mutation positive cancer in a patient, in combination with one or more MAPK inhibitor, for use in the prevention or delaying the onset or development of acquired resistance of said patient to a treatment of said cancer with the one or more MAPK inhibitor, wherein the MAPK inhibitor comprises a BRAF V600 mutant inhibitor.
  2. 2. The CSE inhibitor for use according to claim 1, wherein the CSE inhibitor is selective for CSE.
  3. 3. The CSE inhibitor for use according to any of claims 1 and 2, for use in the prevention of or delaying the development of acquired resistance of said patient to a treatment of said cancer with the one or more MAPK inhibitor, wherein the cancer is a BRAF V600 mutation positive melanoma, and the MAPK inhibitor comprises a BRAF V600 inhibitor, wherein preferably the mutation in the BRAF V600 mutant inhibitor is selected from the group consisting of V600D, V600K, V600R or V600E; more preferably V600K or V600E; more preferably V600E, and wherein preferably the patient is a mammalian patient, preferably a human patient.
  4. 4. The CSE inhibitor for use according to claim 3, wherein said MAPK inhibitor comprises a BRAF inhibitor and preferably a MEK inhibitor.
  5. 5. The CSE inhibitor for use according to any of claims 1 to 4, for use in the prevention or delaying the onset of acquired resistance of said patient to said tumor, wherein the tumor is a BRAF V600 mutation positive cancer with BRAF V600D, V600K, V600R or V600E mutation.
  6. 6. The CSE inhibitor for use according to any of claims 3 to 5, wherein the BRAF inhibitor is selected from vemurafenib, dabrafenib or encorafenib.
  7. 7. The CSE inhibitor for use according to any of claims 3 to 6, wherein the MEK inhibitor is selected from trametinib, cobimetinib, binimetinib or selumetinib, more preferably selected from trametinib, cobimetinib or binimetinib, more preferably the MEK inhibitor is trametinib.
  8. 8. The CSE inhibitor for use according to any of claims 3 to 7, wherein the MAPK inhibitor comprises a BRAF V600 inhibitor selected from vemurafenib, dabrafenib and encorafenib, and a MEK inhibitor selected from cobimetinib, trametinib, binimetinib, wherein preferably the combination of BRAF inhibitor and MEK inhibitor is dabrafenib + trametinib, vemurafenib + cobimetinib, or encorafenib + binimetinib; more preferably dabrafenib + trametinib.
  9. 9. The CSE inhibitor for use according to any of claims 3 to 8, for use in the prevention or delaying the onset of acquired resistance to BRAF V600E and MEK inhibitors in BRAF V600E mutant cancer, wherein the inhibitor is specific to CSE.
  10. 10. The CSE inhibitor for use according to claim 9, wherein the CSE inhibitor is selected from propargylglycine (PAG), P-cyanoalanine (BCA), L-aminoethoxyvinylglycine (AVG), hydroxylamine, 1194496, 1157172, S-3-carboxpropyl-L-cysteine (CPC), NSC4056 (aurintricarboxylic acid), L-aminoethoxyvinylglycine, 2- arylidene-hydrazinecarbodithioates or cystathionine-y-lyase-IN-1 (CAS No. 2165706-30-7), preferably p-cyanoalanine (BCA), L-aminoethoxyvinylglycine (AVG) and propargylglycine (PAG), more preferably D,L-propargylglycine (2-aminopent-4-ynoic acid or H-DL-Pra-OH) or N-Propargylglycine (2-propyn- l-ylamino)acetic acid), highly preferably propargylglycine (PAG).
  11. 11. The CSE inhibitor for use according to any of claims 1 to 10, wherein the development of resistance is delayed by at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or more.
  12. 12. The CSE inhibitor for use according to any of claims 1 to 11, wherein wherein the CSE inhibitor is administered prior to the administration of the MAPK inhibitor, or wherein the CSE inhibitor is administered concurrendy with the MAPK inhibitor, or wherein the CSE inhibitor is administered after the administration of the MAPK inhibitor, orwherein the CSE inhibitor and the MAPK inhibitor is administered in a sequential, intermittent or continuous therapy.
  13. 13. A pharmaceutical kit comprising a cystathionine-y-lyase (CSE) inhibitor and a MAPK inhibitor for use in the treatment of a BRAF V600 mutation positive cancer in a patient, in combination with a (one or more) MAPK inhibitor, preferably for use in the prevention or delaying the onset/development of resistance of said patient to a treatment of said cancer with the MAPK inhibitor, wherein the MAPK inhibitor comprises a BRAF V600 mutant inhibitor.
  14. 14. A pharmaceutical composition comprising a cystathionine-y-lyase (CSE) inhibitor and a MAPK inhibitor, and a pharmaceutically acceptable excipient, for use in the treatment of a BRAF V600 mutation positive cancer in a patient.
  15. 15. The kit for use according to claim 13 or the pharmaceutical composition for use according to claim 14 wherein said CSE-inhibitor is defined in claim 9 and/or the MAPK inhibitor is defined in claim 6 to 8.
  16. 16. The CSE inhibitor for use according to any of claims 1 or 2, the kit according to claim 13 or the pharmaceutical composition according to claim 14 wherein the cancer, preferably a tumor, is selected from the group consisting of melanoma, skin cancer, epithelial cancer, colorectal cancer, cancer of the colon, cancer of the rectum, lung cancer, thyroid cancer, breast cancer, ovarian cancer, brain cancer, pancreatic cancer, gastrointestinal neuroendocrine tumor, neuroblastoma, glioma, astrocytoma, leukemia, hairy cell leukemia, hepatobiliary cancer, nephroblastoma (Wilms tumor), histiocytosis, Langerhans cell histiocytosis and Erdheim-Chester disease; preferably melanoma, colorectal cancer, cancer of the colon, cancer of the rectum, lung cancer; particularly melanoma.

Description

CSE inhibitor for use in the treatment of a tumor in combination with a MAPK inhibitor FIELD OF THE INVENTION The invention relates to cystathionine-y-lyase (CSE) inhibitor for use in the treatment of a cancer, preferably a tumor in a patient, in particular a melanoma, in combination with a (one or more) MAPK inhibitor, in particular an inhibitor of a BRAF V600 mutant, preferably for use in the prevention or delaying the onset or development of resistance of said patient to a treatment of said cancer with the MAPK inhibitor. The invention also relates to combination treatments, if desired with diagnosis, as well as pharmaceutical compositions, combinations and kits for such therapies. TECHNICAL BACKGROUND Cutaneous melanoma is the deadliest form of skin cancer. Although early diagnosis increases the chance of survival, the overall poor prognosis is due to rapid progression of the disease and frequent appearance of distant metastases. The most common oncogenic mutations that drive tumor development occur in the BRAF, NRAS and NF1 genes. Approximately 50% of skin melanoma patients carry the V600E activating mutation of the Serine/threonine-protein kinase B-raf (Braf) oncogene, which leads to overactivation of the MAPK/ERK pathway and therefore to uncontrolled cancer cell proliferation (Davies et al., 2002). Vemurafenib (V-treatment), the first FDA-approved targeted therapy for BrafV 600E mutant melanoma, has a high response rate, but unfortunately tumors rapidly acquire resistance (Sosman et al., 2012). Combined inhibition of V600E mutant Braf with dabrafenib and the downstream Dual specificity mitogen-activated protein kinase kinase 1/2 (MEK1/2, also known as MAP2K1/2) with trametinib (DT-treatment) prolong progression-free survival and overall survival, but resistance to this combination therapy is also mostly inevitable (Manzano et al., 2016; Prahallad et al., 2012; Robert et al., 2015; Sosman et al., 2012; Sun et al., 2014). It is increasingly recognized that therapy resistance in various cancers is associated with extensive reprogramming of metabolic pathways in cancer cells (Luis et al., 2020; Yoo and Han, 2022). The ability of melanoma cells to proliferate rapidly is supported by increased aerobic glycolysis (Hall et al., 2013), which is promoted by BRAFV600E mutation-induced activation of the Braf/MEK/ERK pathway (Haq et al., 2013). On the other hand, BrafV600E inhibition induces major metabolic changes in melanoma cells. This includes a shift from aerobic glycolysis towards increased mitochondrial respiration (Corazao-Rozas et al., 2016), which triggers the production of reactive oxygen species (ROS) and leads to an altered redox environment (Khamari et al., 2018; Wang et al., 2018). The aim of the current work was to uncover potential mechanistic aspects that may link this elevated ROS production to the development of resistance to dabrafenib/trametinib (DT) and vemurafenib (V) therapies. The present inventors found that the transsulfuration pathway, which is dedicated to produce cysteine from methionine, plays a major role in this process. Apart from their canonical functions to produce cysteine, the transsulfuration enzymes cystathionine- -synthase (CBS) and cystathionine-y-lyase (CSE) are key players in the biogenesis of small signaling molecules including hydrogen sulfide and cysteine persulfide (Ida et al., 2014; Kumar and Banerjee, 2021). Recently uncovered vital functions of these reactive sulfur species (RSS) in human physiology and pathology places them in the focus of redox biomedical research (Cirino et al., 2023; Cortese-Krott et al., 2017; Wallace and Wang, 2015; Wang et al., 2021). Among others, their oncogenic functions are increasingly recognized (Coletta et al., 2012; Czikora et al., 2022; Erdelyi et al., 2021; Pavlova et al., 2022; Szabo, 2016). In most targeted therapies that block a driver oncogene (such as BRAF V600E), cancer cells can develop acquired resistance with continuous dosing (Sosman et al., 2012). In cancer, for example in melanoma, acquired resistance to treatment is still an unsolved problem, and solutions that can overcome or prevent such a resistance is critical to further advances in the treatment of melanoma and other tumors. EP3563870A1 discloses a PD-1 axis binding antagonist for use in treating or delaying progression of melanoma that is resistant to a BRAF antagonist, wherein the PD-1 axis binding antagonist is administered in combination with a MEK inhibitor. However, this combination treatment does not prevent development of resistance to BRAF inhibitors. W02015004636A1 discloses a method of treating melanoma comprising administering a subject in need thereof a CDK (cyclin dependent kinase) inhibitor and a BRAF inhibitor and/or MEK inhibitor. The melanoma being treated may be a resistant BRAF mutant melanoma. However, this method does not prevent the development of resistance to BRAF/MEK inhibitors either. W02015161230A1 discloses a method of treating ca