Composition for treatment of estrogen-dependent cancer comprising a mettl-3 inhibitor and a topoisomerase-1 inhibitor

Abstract

The invention relates to methods and pharmaceutical composition for the treatment of estrogen-dependent cancers, particularly estrogen receptor-related cancers such as estrogen receptor-positive (ER+) cancers, like ER+ breast cancer (ER+BC). The invention relates to the combined use of an inhibitor of the methyltransferase-like protein 3 (METTL3) and an inhibitor of the nuclear DNA topoisomerase I (TOP1) for the treatment of estrogen-dependent cancers, particularly estrogen receptor-related cancers such as ER+ cancers. The inhibition of METTL3 increases the sensitivity of ER + breast cancer cells to Topoisomerase-1 inhibitor.

Description

[0001] COMPOSITION FOR TREATMENT OF ESTROGEN-DEPENDENT CANCER COMPRISING A METTL-3 INHIBITOR AND A TOPOISOMERASE-1 INHIBITOR

[0002] FIELD OF THE INVENTION

[0003] The invention relates to the field of medicine, in particular oncology. The invention relates to a combined treatment comprising a Topoisom erase- 1 (TOPI) inhibitor and an inhibitor increasing the sensitivity of the estrogen-dependent cancers to the TOPI inhibitor. The invention relates to the combination of inhibitors for the treatment of estrogen-dependent cancers, particularly estrogen receptor-related cancers, such as estrogen receptor-positive cancers.

[0004] BACKGROUND OF THE INVENTION

[0005] Estrogen is a steroid hormone that has critical roles in reproductive development, bone homeostasis, cardiovascular remodeling, and brain functions. The biological effects of estrogen are mostly mediated by its binding and activation of the estrogen receptors (ER), which are members of the nuclear receptor superfamily of transcription factors (Hua, H. et al., 2018; Damodaran, S. et al., 2021). However, estrogen receptor (ER) signaling also promotes tumorigenesis. Indeed, ER signaling plays a major role not only in breast cancer, but also in other cancers including ovarian cancer, endometrial cancer, uterine cancer, prostate cancer, and acute myeloid leukemia (AML) (Di Zazzo, E. et al., 2019; Clusan, L. et al, 2023; Langdon, S. P. et al, 2020; Roma, A. et a / ., 2020). These cancers are thus dependent of estrogen and related to the ER, particularly to ER-alpha (ERa) (Liu, Y et al., 2020). Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide, with more than 2 million new cases in 2020. Among the female breast cancer (BC) subtypes, estrogen receptor-positive (ER+) breast cancer (ER+BC) remains the most common and represents almost 70% of all cases of breast cancer in Western populations (Lukasiewicz, S. et al., 2021).

[0006] In the last decades, many efforts have been undertaken to improve diagnosis, prognosis and treatment of estrogen-receptor-positive cancers, particularly ER+ BC. Despite initial positive responses to hormonotherapy, like antiestrogens, between 40 and 50% of ER+ patients' tumors demonstrate resistance to standard-of-care therapies, and result in metastasis or relapse five or more years after diagnosis (Anurag, M. et al., 2018).

[0007] Hence, there is still a need to improve the treatment of cancers that are estrogen-dependent, like estrogen receptor-related cancer, in particular ER+ cancer, by inhibiting cancer cell growth and preventing resistance, relapse, and metastasis phenomenon, while having minimal effects on non-tumorigenic cells. SUMMARY OF THE INVENTION

[0008] For that purpose, the inventors first investigated the role of the methyltransferase-like 3 (METTL3), which exhibits catalytic activity and functions synergistically with METTL14 by forming a stable heterodimer, together with many auxiliary subunits, for promoting the RNA methylation, by catalyzing the transfer of a methyl group to the N6-adenosine of RNA, thanks to its co-factors the S-adenosyl methionine (SAM).

[0009] N6 methyl -adenosine (m6A) modification is one of the most conserved RNA modifications playing a critical role in regulating RNA transcription, translation, and metabolism (Fiorentino, F. etal., 2023). There is growing evidence that METTL3 / m6A is involved in tumorigenesis in several cancers, including BC (Achour, C. et al., 2023; Wang, H. et al., 2020). Therefore, several METTL3 inhibitors, nucleoside and non-nucleoside-based, have been developed. Among them, the small molecule STM2457 (N-[(6-{[(cyclohexylmethyl)amino] methyl Jimidazo, CAS: 2499663-01-1) represents a promising novel active METTL3 inhibitor. Recently, STM2457 has been studied for treating AML and was used to show the role of METTL3 in modulating BC- associated alternative splicing programs (Yankova, E. et al., 2021; Achour, C. et al., 2023). However, this small molecule has not yet been investigated as a treatment strategy for estrogendependent cancer, in particular ER-related cancer, and more particularly ER+ cancer.

[0010] In a second time, the inventors investigated the role of the nuclear DNA topoisomerase I (TOPI), an essential human enzyme implicated in DNA replication. Camptothecin (CPT) is a natural alkaloid compound known to target TOPI, damage DNA and promote cell death. Its carboxylate moiety was tested clinically in the mid-1970s and showed anticancer activity (Pommier, Y. 2006). Several CPT and non-CPT derivatives have been developed and some are currently used as a second- or third-line treatment for patients with endocrine-resistant BC. Recent study shows that breast tumors belonging to the triple-negative (TN) BC subtype, may benefit from treatment with CPT derivatives (Tesauro, C. et al., 2019).

[0011] In addition, STC-15 anti-METTL3 compound (C24H25N5O2; CAS: 2648257-56-9), a more potent and with better drug like properties than STM2457, was recently developed to be the first RNA methyltransferase inhibitor to enter clinical study. STC-15 (formerly named STM3480) has been shown to inhibit tumor growth through mechanisms involving anti-cancer immune responses such as changes in interferon signaling and synergy with T cell checkpoint blockade. This compound has demonstrated efficacy in leukemia models via mechanisms such as inhibition of leukemia stem cell function. STC-15 compound is also used to treat solid tumors.

[0012] The inventors discovered that inhibition of METTL3 using STM2457 increases the sensitivity of ER + BC cells to the TOPI inhibitor camptothecin. The inventors demonstrated that combining a METTL3 inhibitor with a TOPI inhibitor, induces a decrease of ER-alpha protein expression, and synergistically inhibits ER+ BC cell growth and progression, and increases their apoptosis, while having minimal inhibitory effects on non-tumorigenic breast epithelial cells. The inventors demonstrated that this drug combination approach provides a new treatment strategy for specifically targeting ER+ BC.

[0013] The drug combination experiments were performed in ER+BC MCF7 cell line, compared to non-tumorigenic breast epithelial MCF-10A cells. The results indicate that STM2457 combined with CPT can yield a high synergistic effect in MCF-7 cells (i.e., ER+ BC cells), and that the combination does not affect MCF-10A cells (i.e., non-tumorigenic breast epithelial cells).

[0014] Moreover, the inventors confirmed that the inhibition of METTL3, using STC-15 compound, increases the sensitivity of ER + BC cells to the TOPI inhibitor camptothecin and the ER-alpha protein expression downmodulation. In particular, the inventors demonstrated that combining STC-15 anti-METTL3 compound with a TOPI inhibitor camptothecin synergistically inhibits ER+ BC cell viability and increases their apoptosis. Likewise, the inventors demonstrated that combining STC-15 anti-METTL3 compound with another TOPI inhibitor, more specifically topotecan, synergistically inhibits ER+ BC cell viability and increases their apoptosis. The inventors confirmed that this anti-METTL3 / anti-TOPl drug combination approach provides a new treatment strategy for specifically targeting ER+ BC. The combination does not affect MCF-10A cells (i.e., non-tumorigenic breast epithelial cells).

[0015] There is no disclosure in the art of such a specific combination or its use for the treatment of estrogen-dependent cancer, in particular estrogen receptor-related cancer, and more particularly estrogen receptor-positive cancer.

[0016] The invention relates to methods and pharmaceutical compositions for the treatment of estrogen-dependent cancers, in particular estrogen receptor-related cancers, preferably estrogen receptor-positive cancers. In particular, the invention is defined by the claims.

[0017] The present invention relates to a pharmaceutical composition comprising a METTL3 (methyltransferase-like protein 3) inhibitor for use in the treatment of estrogen-dependent cancer in combination with at least one Topoisomerase- 1 inhibitor; a pharmaceutical composition comprising a Topoisomerase- 1 inhibitor for use in the treatment of estrogen-dependent cancer in combination with a METTL3 inhibitor; a pharmaceutical composition comprising a METTL3 inhibitor and at least one Topoisomerase- 1 inhibitor for use in the treatment of estrogen-dependent cancer; the use of a METTL3 inhibitor for the manufacture of a medicament for the treatment of estrogen-dependent cancer in combination with at least one Topoisomerase- 1 inhibitor;

[0018] - the use of a Topoisomerase- 1 inhibitor for the manufacture of a medicament for the treatment of estrogen-dependent cancer in combination with a METTL3 inhibitor;

[0019] - the use of a METTL3 inhibitor and at least one Topoisom erase- 1 inhibitor for the manufacture of a medicament for the treatment of estrogen-dependent cancer; and a method for treating an estrogen-dependent cancer a subject in need thereof, comprising o administering to said subject a therapeutically effective amount or a sub- therapeutic amount of a METTL3 inhibitor, and administering to said subject a therapeutically effective amount or a sub-therapeutic amount of a Topoisomerase- 1 inhibitor; or o administering to said subject a therapeutically effective amount of a pharmaceutical composition comprising a METTL3 inhibitor and a Topoisomerase- 1 inhibitor.

[0020] Optionally, the estrogen-dependent cancer is estrogen receptor-related cancer, in particular estrogen receptor-positive cancer (ER+ cancer), preferably selected among breast cancer, ovarian cancer, endometrial cancer, uterine cancer, prostate cancer, uterine leiomyoma or any other estrogen receptor-positive gynecologic cancer, prostate cancer, testis cancer, thyroid cancer, lung cancer or osteosarcoma, in particular ER+ breast cancer.

[0021] Optionally, the METTL3 inhibitor is a small organic molecule, in particular a nonnucleoside-based small organic molecule. In a specific aspect, the METTL3 inhibitor is a nonnucleoside-based small organic molecule selected among STM2457, STC-15, UZHla, UZH2, STM3006, and STM3675, or any combination thereof.

[0022] Optionally, the Topoisomerase- 1 inhibitor is a small organic molecule. In a specific aspect, the Topoisomerase- 1 inhibitor is a small organic molecule selected among camptothecin (CPT), topotecan, irinotecan, and belotecan, or any combination thereof.

[0023] In a very specific aspect, the METTL3 inhibitor is STM2457 or STC-15 and the Topoi som erase- 1 inhibitor is camptothecin or topotecan. Optionally, the METTL3 inhibitor is STM2457 or STC-15 and the Topoi som erase- 1 inhibitor is camptothecin. Optionally, the METTL3 inhibitor is STM2457 or STC-15 and the Topoi som erase- 1 inhibitor is topotecan. Optionally, the METTL3 inhibitor is STC-15 and the Topoi som erase- 1 inhibitor is topotecan. The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount or a sub-therapeutic amount of METTL3 inhibitor STM2457 or STC-15 and of Topoisomerase- 1 inhibitor camptothecin or topotecan, and a pharmaceutically acceptable excipient and this pharmaceutical composition for use as a drug. Optionally, the METTL3 inhibitor is STM2457 or STC-15 and the Topoisomerase- 1 inhibitor is camptothecin. Optionally, the METTL3 inhibitor is STM2457 or STC-15 and the Topoisom erase- 1 inhibitor is topotecan. Optionally, the METTL3 inhibitor is STC-15 and the Topoisomerase- 1 inhibitor is topotecan.

[0024] Optionally, the pharmaceutical composition is administered in combination with surgery, radiotherapy, chemotherapy, hormonotherapy and / or immunotherapy or the method further comprises surgery, radiotherapy, chemotherapy, hormonotherapy and / or immunotherapy.

[0025] DETAILED DESCRIPTION OF THE INVENTION

[0026] The inventors demonstrated that combining a METTL3 inhibitor with a TOPI inhibitor synergistically inhibits ER+ BC cell growth and progression, and increases their apoptosis, while having minimal inhibitory effects on non-tumorigenic breast epithelial cells. The inventors demonstrated that this drug combination approach provides a new treatment strategy for specifically targeting ER+ BC. The inventors demonstrated that STM2457 or STC-15 combined with CPT can yield a high synergistic effect on MCF-7 ER+ BC cells, and that the combination does not affect non-tumorigenic breast epithelial MCF-10A cells.

[0027] Accordingly, the invention relates to the treatment of cancer, in particular estrogendependent cancers, in particular estrogen receptor-related cancers, and preferably estrogen receptor-positive cancers.

[0028] Therapeutic method

[0029] In a first aspect, the invention relates to a METTL3 inhibitor or a pharmaceutical composition comprising a METTL3 inhibitor for use in the treatment of cancer in combination with at least one Topoisomerase- 1 inhibitor.

[0030] In a second aspect, the invention relates to a Topoisom erase- 1 inhibitor or a pharmaceutical composition comprising a Topoisom erase- 1 inhibitor for use in the treatment of cancer in combination with a METTL3 inhibitor.

[0031] In a third aspect, the invention relates to a pharmaceutical composition comprising a METTL3 inhibitor and a Topoisomerase- 1 inhibitor for use in the treatment of cancer. Optionally, the pharmaceutical composition does not comprise a membrane-associated tyrosine- and threonine-specific cdc2-inhibitory kinase (Mytl) inhibitor. In a fourth aspect, the invention relates to a product or kit comprising a METTL3 inhibitor and a Topoisom erase- 1 inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of cancer; or to a combined preparation comprising a METTL3 inhibitor and a Topoisom erase- 1 inhibitor for simultaneous, separate or sequential use in the treatment of cancer.

[0032] In a fifth aspect, the invention relates to the use of a pharmaceutical composition comprising a METTL3 inhibitor and a Topoisom erase- 1 inhibitor for the manufacture of a medicament for the treatment of cancer; or to the use of a pharmaceutical composition comprising a METTL3 inhibitor for the manufacture of a medicament for the treatment of cancer in combination with a Topoisomerase- 1 inhibitor; or to the use of a pharmaceutical composition comprising a Topoisom erase- 1 inhibitor for the manufacture of a medicament for the treatment of cancer in combination with a METTL3 inhibitor.

[0033] In a sixth aspect, the invention relates to a method for treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a METTL3 inhibitor and a Topoisom erase- 1 inhibitor; or comprising administering a therapeutically effective amount or a sub-therapeutic amount of a pharmaceutical composition comprising a METTL3 inhibitor and administering a therapeutically effective amount or a sub-therapeutic amount of a pharmaceutical composition comprising a Topoisom erase- 1 inhibitor. Optionally, the invention relates to a method for treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a METTL3 inhibitor and a sub-therapeutic amount of a pharmaceutical composition comprising a Topoisomerase- 1 inhibitor, thereby the combined treatment with the METTL3 inhibitor and TOPI inhibitor has a therapeutical effect.

[0034] Optionally, the METTL3 inhibitor and the Topoisomerase- 1 inhibitor are used so as to obtain a synergistic effect, in particular for inducing cell death of cancer cells.

[0035] By the term “synergistic” therapeutic effect is meant that the obtained therapeutic effect of the combination is more than the addition of the therapeutic effect of each partner alone (i.e. more than the effect of the METTL3 inhibitor as disclosed herein alone plus the effect of the TOPI inhibitor alone).

[0036] By the term “synergistically therapeutically effective amount” or “synergistic ratio” is meant that the therapeutic effect of the combination is more than the addition of the therapeutic effect of each partner alone (i.e. more than the therapeutic effect of the METTL3 inhibitor as disclosed herein alone plus the therapeutic effect of the TOPI inhibitor alone). In addition, the combined use of the METTL3 inhibitor and the Topoisomerase- 1 inhibitor is adapted for an effect (i.e., inducing cell death of cancer cells) specific to cancer cells in comparison to normal cells.

[0037] Optionally, the method for treating a cancer does not comprise administration of a membrane-associated tyrosine- and threonine-specific cdc2 -inhibitory kinase (Mytl) inhibitor.

[0038] Optionally, the treatment is used or to be used in combination with surgery, radiotherapy, chemotherapy, hormonotherapy and / or immunotherapy. Optionally, the cancer is a hormonal cancer. Optionally, the cancer is an estrogen-dependent cancer. Optionally, the estrogen receptor- related cancer is estrogen receptor-positive cancer (ER+ cancer).

[0039] As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to a mammal. Typically, a subject according to the invention refers to any subject, preferably human. In a particular embodiment, the term “subject” refers to a subject afflicted or at risk to be afflicted with cancer. In a particular embodiment, the term “subject” refers to a subject afflicted or at risk to be afflicted with hormonal cancer. In a particular embodiment, the term “subject” refers to a subject afflicted or at risk to be afflicted with estrogen-dependent cancer. In some embodiment, the term “subject” refers to a subject afflicted or at risk to be afflicted with estrogen receptor- related cancer, in particular estrogen receptor-positive cancer. In some embodiment, the term “subject” refers to a subject afflicted or at risk to be afflicted with breast cancer, ovarian cancer, endometrial cancer, uterine cancer, uterine leiomyoma, prostate cancer, testis cancer, thyroid cancer, lung cancer or osteosarcoma. In some embodiment, the term “subject” refers to a subject afflicted or at risk to be afflicted with breast cancer (reviewed in Lukasiewicz, S. et al., 2021; Di Zazzo, E. etal., 2019; Clusan, L. etal., 2023; Langdon, S. P. etal., 2020; Roma, A. etal., 2020).

[0040] As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular interval, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).

[0041] As used herein, the term “cancer” refers to any cancer that may affect any one of the following tissues or organs: breast; liver; kidney; heart, mediastinum, pleura; floor of mouth; lip; salivary glands; tongue; gums; oral cavity; palate; tonsil; larynx; trachea; bronchus, lung; pharynx, hypopharynx, oropharynx, nasopharynx; esophagus; digestive organs such as stomach, intrahepatic bile ducts, biliary tract, pancreas, small intestine, colon; rectum; urinary organs such as bladder, gallbladder, ureter; rectosigmoid junction; anus, anal canal; skin; bone; joints, articular cartilage of limbs; eye and adnexa; brain; peripheral nerves, autonomic nervous system; spinal cord, cranial nerves, meninges; and various parts of the central nervous system; connective, subcutaneous and other soft tissues; retroperitoneum, peritoneum; adrenal gland; thyroid gland; endocrine glands and related structures; female genital organs such as ovary, uterus, cervix uteri; corpus uteri, vagina, vulva; male genital organs such as penis, testis and prostate gland; hematopoietic and reticuloendothelial systems; blood; lymph nodes; thymus.

[0042] The term “cancer” according to the invention comprises leukemias, seminomas, melanomas, teratomas, lymphomas, non-Hodgkin lymphoma, neuroblastomas, gliomas, adenocaminoma, mesothelioma (including pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma and end stage mesothelioma), rectal cancer, endometrial cancer, thyroid cancer (including papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma and paraganglioma), skin cancer (including malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi’s sarcoma, keratoacanthoma, moles, dysplastic nevi, lipoma, angioma and dermatofibroma), nervous system cancer, brain cancer (including astrocytoma, medulloblastoma, glioma, lower grade glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, glioma or sarcoma), skull cancer (including osteoma, hemangioma, granuloma, xanthoma or osteitis deformans), meninges cancer (including meningioma, meningiosarcoma or gliomatosis), head and neck cancer (including head and neck squamous cell carcinoma and oral cancer (such as, e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer or pharynx cancer)), lymph node cancer, gastrointestinal cancer, liver cancer (including hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma and hemangioma), colon cancer, stomach or gastric cancer, esophageal cancer (including squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma or lymphoma), colorectal cancer, intestinal cancer, small bowel or small intestines cancer (such as, e.g., adenocarcinoma lymphoma, carcinoid tumors, Karposi’s sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma or fibroma), large bowel or large intestines cancer (such as, e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma or leiomyoma), pancreatic cancer (including ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors or vipoma), ear, nose and throat (ENT) cancer, breast cancer (including HER2-enriched breast cancer, luminal A breast cancer, luminal B breast cancer and triple negative breast cancer), cancer of the uterus (including endometrial cancer such as endometrial carcinomas, endometrial stromal sarcomas and malignant mixed Mullerian tumors, uterine sarcomas, leiomyosarcomas and gestational trophoblastic disease), ovarian cancer (including dysgerminoma, granulosa-theca cell tumors and Sertoli-Leydig cell tumors), cervical cancer, vaginal cancer (including squamous-cell vaginal carcinoma, vaginal adenocarcinoma, clear cell vaginal adenocarcinoma, vaginal germ cell tumors, vaginal sarcoma botryoides and vaginal melanoma), vulvar cancer (including squamous cell vulvar carcinoma, verrucous vulvar carcinoma, vulvar melanoma, basal cell vulvar carcinoma, Bartholin gland carcinoma, vulvar adenocarcinoma and erythroplasia of Queyrat), genitourinary tract cancer, kidney cancer (including clear renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, adenocarcinoma, Wilm’s tumor, nephroblastoma, lymphoma or leukemia), adrenal cancer, bladder cancer, urethra cancer (such as, e.g., squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), prostate cancer (such as, e.g., adenocarcinoma or sarcoma) and testis cancer (such as, e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors or lipoma), lung cancer (including small cell lung carcinoma (SCLC), non-small cell lung carcinoma (NSCLC) including squamous cell lung carcinoma, lung adenocarcinoma (LU AD), and large cell lung carcinoma, bronchogenic carcinoma, alveolar carcinoma, bronchiolar carcinoma, bronchial adenoma, lung sarcoma, chondromatous hamartoma and pleural mesothelioma), sarcomas (including Askin's tumor, sarcoma botryoides, chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma and soft tissue sarcomas), soft tissue sarcomas (including alveolar soft part sarcoma, angiosarcoma, cystosarcoma phyllodes, dermatofibrosarcoma protuberans, desmoid tumor, desmoplastic small round cell tumor, epithelioid sarcoma, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma, gastrointestinal stromal tumor (GIST), hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant peripheral nerve sheath tumor (MPNST), neurofibrosarcoma, plexiform fibrohistiocytic tumor, rhabdomyosarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma, cardiac cancer (including sarcoma such as, e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma or liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma and teratoma), bone cancer (including osteogenic sarcoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing’s sarcoma, malignant lymphoma and reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma and giant cell tumors), hematologic and lymphoid cancer, blood cancer (including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma and myelodysplasia syndrome), Hodgkin’s disease, non-Hodgkin’s lymphoma and hairy cell and lymphoid disorders, and the metastases thereof.

[0043] In one embodiment, the term “cancer” refers to breast cancer, ovarian cancer, endometrial cancer, uterine cancer, uterine leiomyoma, prostate cancer, testis cancer, thyroid cancer, lung cancer or osteosarcoma.

[0044] In one embodiment, the term “cancer” refers to breast cancer.

[0045] As used herein, the term, “hormonal cancer” or “hormone-dependent cancer” or “hormonesensitive cancer”, are interchangeable and refers to cancers whose growth is stimulated and / or activated by hormones. These cancers are sensitive to hormonal treatments, estrogen or progesterone, used to slow down or stop their development.

[0046] In one embodiment, the term “hormonal cancer” refers to hormonal breast cancer, hormonal ovarian cancer, hormonal endometrial cancer, hormonal uterine cancer, hormonal uterine leiomyoma, hormonal prostate cancer, hormonal testis cancer, hormonal thyroid cancer, hormonal lung cancer or hormonal osteosarcoma.

[0047] In one embodiment, the term “hormonal cancer” refers to hormonal breast cancer. As used herein, the term, “estrogen-dependent cancer”, refers to cancer that rely on estrogen to develop and grow. Their treatment can be based on estrogen synthesis inhibition and / or preventing or inhibiting estrogen binding to its receptor ERs (in particular ERa, ERP). Drugs inhibiting estrogen synthesis are well known in the art, like aromatase inhibitors such as anastrozole, letrozole, or exemestane. Drugs targeting ERa, for preventing or inhibiting estrogen binding, for instance by competition, are well known in the art too, such as anti-estrogens (for example fulvestrant) or selective estrogen receptor modulators (also called SERM, for example tamoxifen or toremifene).

[0048] In one embodiment, the term “estrogen-dependent cancer” refers to estrogen-dependent breast cancer, estrogen-dependent ovarian cancer, estrogen-dependent endometrial cancer, estrogen-dependent uterine cancer, estrogen-dependent uterine leiomyoma, estrogen-dependent prostate cancer, estrogen-dependent testis cancer, estrogen-dependent thyroid cancer, estrogendependent lung cancer or estrogen-dependent osteosarcoma.

[0049] In one embodiment, the term “estrogen-dependent cancer” refers to estrogen-dependent breast cancer (reviewed in Fernando, T. M. et al., 2023; Damodaran, S. et al., 2021).

[0050] As used herein, the terms “estrogen receptor” or “estrogen receptors” or “ER” or “ERs” are interchangeable, have their general meaning in the art and refer to ligand-dependent or ligandinducible transcription factors that regulate gene transcription through estrogen response elements (EREs), thereby facilitating the normal biological functions of estrogens. There are three types of ERs, classical alpha (ERa) and beta (ERP), as well as non-classical G protein-coupled estrogen receptor 1 (GPER1). The ER protein molecule consists of A / B, C, D, and E / F domains, from amino to carboxyl terminals. ERa and ERP are encoded by ESRI on chromosome 6 (6q25.1) and ESR2 on chromosome 14 (14q23.2), respectively. ERa appears to be the major mediator of the estrogen response. Several isoforms of ERa have been identified arising from alternative gene splicing, including ERa-46 and ERa-36. Several ERP splice isoforms have also been discovered, namely ERpi-5, but ERpi is the predominant isoform. ERa and ERP are intracellular ER whereas GPER1, encoded on chromosome 7 (7p22.3), is a typical G protein-coupled receptor comprising seven transmembrane a-helices, four extracellular segments, and four cytosolic segments. ERa and ERP lead to genomic estrogen pathway while GPER1 leads to non-genomic estrogen pathway. ERs regulate transcription through the recruitment of transcriptional coregulators that act as either coactivators or corepressors of genes. In one embodiment, ER means ERa and ERP and estrogen signaling occurs through binding of estrogen hormone to ERa and ERP (reviewed in Chen, P. et 2018; Damodaran, S. et al., 2021). As used herein, the terms, “estrogen receptor-related cancer” or “ER-related cancer”, are interchangeable and refer to cancer wherein cancer cells present estrogen receptors at their surface and rely on estrogen receptors signaling pathways to develop and grow. Their treatment can be based on preventing or inhibiting estrogen binding to its receptor (in particular ERa, ERP).

[0051] In one embodiment, the term “estrogen receptor-related cancer” refers to estrogen receptor- related breast cancer, estrogen receptor-related ovarian cancer, estrogen receptor-related endometrial cancer, estrogen receptor-related uterine cancer, estrogen receptor-related uterine leiomyoma, estrogen receptor-related prostate cancer, estrogen receptor-related testis cancer, estrogen receptor-related thyroid cancer, estrogen receptor-related lung cancer or estrogen receptor-related osteosarcoma.

[0052] In one embodiment, the term “estrogen receptor-related cancer” refers to estrogen receptor- related breast cancer.

[0053] As used herein, the terms “estrogen receptor-positive cancer” or “ER positive cancer” or “ER+ cancer” are interchangeable and refer to cancer that express estrogen receptor at a level detectable by immunohistochemistry. These cancers need estrogen to develop and grow, though estrogen binding to its ER.

[0054] In one embodiment, the term “estrogen receptor-positive cancer” refers to estrogen receptor-positive breast cancer, estrogen receptor-positive ovarian cancer, estrogen receptorpositive endometrial cancer, estrogen receptor-positive uterine cancer, estrogen receptor-positive uterine leiomyoma, estrogen receptor-positive prostate cancer, estrogen receptor-positive testis cancer, estrogen receptor-positive thyroid cancer, estrogen receptor-positive lung cancer or estrogen receptor-positive osteosarcoma.

[0055] On the opposite, the term “estrogen receptor-negative cancer” or “ER negative cancer” or ‘ER- cancer” are interchangeable and refer to cancer that does not contain estrogen receptor positive cells, i.e., cells that lack estrogen receptors, and does not depend on the presence of estrogen for ongoing proliferation.

[0056] In one embodiment, the term “estrogen receptor-positive cancer” refers to estrogen receptor-positive breast cancer.

[0057] As used herein, the terms "Methyltransferase-like protein 3” or “METTL3” are interchangeable, have their general meaning in the art and refer to the RNA methyltransferase that catalyzes the transfer of a methyl group to the N6-adenosine of RNA, to generate m6A RNA, by forming a heterodimer complex with the methyltransferase METTL14 and in the presence of its cofactor S-adenosyl methionine (SAM). METTL3 serves as the catalytically active subunit with a catalytic active pocket and possesses a co-factor pocket for the binding of SAM. METTL14 acts as a structural role for stabilization and RNA-binding of their complex (reviewed in Fiorentino, F. et al., 2023; Yankova, E. et al., 2021; Xu, P. et al., 2022).

[0058] As used herein, the term “METTL3 inhibitor” has its general meaning in the art and refers to any inhibitor selected from the group consisting of, but not limited to, compounds targeting the RNA methyltransferase METTL3, in a competitive manner (i.e., competitive inhibitors of SAM) or in a non-competitive manner (i.e., allosteric inhibitors). Typically, a METTL3 inhibitor is a small organic molecule (z.e., small molecule), a protein, a polypeptide, a peptide, an oligopeptide, an aptamer, an oligonucleotide (antisense oligonucleotides, siRNA, shRNA, DNA and RNA aptamers), or an antibody. METTL3 inhibitors are well-known in the art such as described in International Patents Publications No. W02020201773 and WO2022074391, or in papers Oerum, S. et al., 2019 and Fiorentino, F. et al., 2023 (the disclosure thereof being incorporated herein by reference), which describe further METTL3 inhibitors that are suitable for the treatment of cancer.

[0059] In one embodiment, the METTL3 inhibitor is a small organic molecule.

[0060] In one embodiment, the METTL3 inhibitor is a nucleoside, or a non-nucleoside based small organic molecule.

[0061] As used herein, the term “nucleoside-based small organic molecule” refers to small organic molecule which chemical structure is derived from nucleoside and / or is based on nucleoside’s saccharide part (deoxyribose), such as SAM analogues.

[0062] Several nucleosides based METTL3 inhibitors are known in the art, including but not limited to: Sinefungin (5'-Deoxy-5'-(l,4-diamino-4-carboxybutyl)adenosine, Adenosylomithine - CAS 58944-73-3) or bisusbtate SAM analogues as described in Oerum, S. et al., 2019.

[0063] As used herein, the term “non-nucleoside-based small organic molecule” refers to small organic molecule which chemical structure does not derived from nucleoside and / or does not present a saccharide part (deoxyribose).

[0064] Several non-nucleosides based METTL3 inhibitors are known in the art, including but not limited to: STM2457 (CAS No: 2499663-01-1), STC-15 (CAS No: 2648257-56-9; N-[(2- {[(cyclobutylmethyl)amino]methyl}-lH-indol-6-yl)methyl]-4-oxo-4H-pyrido[l,2-] pyrimidine- 2-carboxamide, formerly named STM3480), UZHla (CAS No. : 2813577-78-3), UZHlb (CAS No. : 2814392-17-9), UZH2 (CAS No. : 2756566-45-5), (), STM3006 (6-bromo-4-[l-({6-[(4,4- dimethylpiperidin-l-yl)methyl]imidazo[l,2-a]pyridin-2-yl}methyl)-lH-l,2,3-triazol-4-yl]-lH- indazole), STM3675 (N-[(2-{[({3-fluorobicyclo[l. l.l]pentan-l-yl}methyl)amino]methyl}-lH- indol-6-yl)methyl]-4-oxo-4H-pyrido[l,2-a]pyrimidine-2-carboxamide), STM1760 (4-oxo-N-(4- (2-oxopyrrolidin-l-yl)benzyl)-4H-chromene-2-carboxamide), STM2120 (CAS No. : 2762286-04- 2), Quercetin (CAS No: 117-39-5), Luteolin (CAS No: 491-70-3), Scutellarin (CAS No: 27740- 01-8), Eltrombopag (CAS No: 496775-61-2), CDIBA (CAS No: 479422-22-5) and CDIBA derivatives as described in Fiorentino, F. et al., 2023 (reviewed in Xu, P. et al., 2022; Caflisch, A. et al., 2021; Du, Y. et al., Fiorentino, F. et al., 2023, the disclosure thereof being incorporated herein by reference).

[0065] In some embodiment, the METTL3 inhibitor is a non-nucleoside based small organic molecule.

[0066] In one embodiment, the METTL3 inhibitor is a non-nucleoside based small organic molecule selected from, but not limited to: STM2457, STC-15 (formerly named STM3480), UZHla, UZH2, STM3006, and STM3675, or any combination thereof.

[0067] In some embodiment, the METTL3 inhibitor is a non-nucleoside based small organic molecule selected from, but not limited to: STM2457 or STC-15.

[0068] In one embodiment, the METTL3 inhibitor is used in combination with at least one, two, three or four Topoisomerase- 1 inhibitor(s).

[0069] As used herein, the term " Topoisomerase- 1” or “TOPI” are interchangeable, have their general meaning in the art and refer to type I nuclear DNA topoisomerase, an essential human enzyme responsible for relaxing DNA supercoiling generated by transcription, replication and chromatin remodeling. TOPI is particularly vulnerable to Topoisomerase- 1 inhibitors during its cleavage reaction (Pommier, Y. 2006).

[0070] As used herein, the term “Topoisomerase- 1 inhibitor” or “TOPI inhibitor” has its general meaning in the art and refers to any inhibitor consisting of, but not limited to, compounds targeting the TOPI enzyme by interacting with TOPI and / or DNA during TOPI activity, in a canonical (i.e., by fitting into the Toplcc pocket) or non-canonical mode of action. (Capranico, G. et al., 2010). Typically, a Topoisom erase- 1 inhibitor is a small organic molecule, a protein, a polypeptide, a peptide, an oligopeptide, an aptamer, an oligonucleotide (antisense oligonucleotides, siRNA, shRNA, DNA and RNA aptamers), or an antibody.

[0071] Topoisomerase- 1 inhibitors are well-known in the art such as camptothecin (CPT), camptothecin derivatives and non-camptothecin derivatives (reviewed in Pommier, Y. 2006; Verschraegen, C. et al., 2012 and Capranico, G. et al., 2010, the disclosure thereof being incorporated herein by reference).

[0072] In one embodiment, the Topoisom erase- 1 inhibitor is a small organic molecule.

[0073] In one embodiment, the Topoisomerase- 1 inhibitor is camptothecin (CPT), topotecan (Topo) or another camptothecin derivative.

[0074] Several camptothecin derivatives as Topoisom erase- 1 inhibitors are known in the art, including but not limited to: Topotecan (HYCAMTIN™), Irinotecan (CAMPTOSAR™), Belotecan (CAMTOBELL™), 7-Ethyl-10-hydroxycamptothecin (also called SN-38 or NK012, CAS 86639-52-3), pegylated prodrugs of SN-38 such as PLX-038 (CAS No 2365392-86-3), Aminocamptothecin (also called 9-AC or IDEC-132, CAS No: 91421-43-1), exatecan (CAS No 171335-80-1), Exatecan mesylate (also called DX-8591f or DEG 10, CAS No: 169869-90-3), Lurtotecan (also called GI-147211 or NX 211, CAS No: 149882-10-0), Gimatecan (also called ST-1481, CAS No: 292618-32-7), PEG-camptothecin (PROTHECAN™, Pegamotecan), Karenitecin (also called BNP-1350 or Cositecan, CAS No: 203923-89-1), Silatecan (also called DB-67, CAS No: 220913-32-6), homocamptothecin Diflomotecan (also called BN 80915, CAS No: 220997-97-7), S39625 (CAS No: 98187-86-1) (reviewed in Pommier, Y. 2006; Verschraegen, C. et al., 2012 and Capranico, G. et al., 2010, the disclosure thereof being incorporated herein by reference), deruxtecan (CAS No 1599440-13-7), govitecan (CAS No 1918106-06-5), tirumotecan, brengitecan (CAS No 2750623-07-3), adizutecan, samrotecan (CAS No 2495742-34-0), tocentecan, and sesutecan.

[0075] In one embodiment, the Topoisomerase- 1 inhibitor is a non-camptothecin derivative, such as indolocarbazoles, indenoisoquinolines, phenanthridines, dibenzo naphthyridines or aromathecins.

[0076] Several non-camptothecin derivatives as Topoisomerase- 1 inhibitors are known in the art, including, but not limited to: BMS 250749 (CAS No: 406913-72-2), NB-506 glucoronide (CAS No: 217187-87-6), Edotecarin (CAS No: 174402-32-5), LMP744 (also called NSC 706744 orMJ- III-65, CAS No: 308246-52-8), Indimitecan (also called LMP776 or NSC 725776, CAS No: 915360-05-3), Indotecan (also called LMP400 or NSC 724998, CAS No: 915303-09-2), Topovale (also called ARC-111, CAS No: 500214-53-9), Topopyrones, Calothrixins, Saintopin (CAS No: 131190-63-1), Coralyne (CAS No: 38989-38-7), 9-Aminoacridine (CAS No: 90-45-9), Bulgarein , Lamellarins, Batracylin (CAS No: 67199-66-0), dibenzo naphthyridines, aromathecins, Tafluposide (CAS No: 179067-42-6 ), bisBenzimide H 33258 (CAS No: 23491-45-4), Diospyrin (CAS No: 28164-57-0), Plukenetione A, P-Lapachone (CAS No: 4707-32-8), Thaspine (CAS No: 74578-01-1), or Erybraedin C (CAS No: 119269-74-8) (reviewed in Pommier, Y. 2006; Verschraegen, C. et al., 2012 and Capranico, G. et al., 2010, the disclosure thereof being incorporated herein by reference).

[0077] In one embodiment, the Topoisom erase- 1 inhibitor is camptothecin (CPT) or a camptothecin derivative.

[0078] In one embodiment, the Topoisom erase- 1 inhibitor is selected among: camptothecin (CPT), Topotecan (HYCAMTIN™), Irinotecan (CAMPTOSAR™) and Belotecan (CAMTOBELL™), or any combination thereof. In some embodiment, the Topoisomerase- 1 inhibitor is camptothecin (CPT).

[0079] In another embodiment, the Topoisom erase- 1 inhibitor is topotecan.

[0080] In one embodiment, a Topoisom erase- 1 inhibitor is coupled or covalently linked to an antibody; thus, the Topoisomerase- 1 inhibitor is an antibody drug conjugate (ADC) comprising an antibody moiety (targeting moiety) covalently conjugated to a Topoisomerase- 1 inhibitor as a payload. As used herein, the term "antibody" describes a type of immunoglobulin molecule and is used in its broadest sense. In particular, antibodies include immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an antigen binding domain. Unless specifically noted otherwise, the term "antibody" includes intact or full immunoglobulins and "antigen binding fragment" and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site, including glycosylation variants of antibodies. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass. Preferably, the antibody is or derives from an IgG. Alternatively, the antigen binding fragment can be non- exhaustively Fab, Fab', F(ab')2, Fv, single chain (scFv or scFab), diabodies, linear antibodies, or CrossMAb.

[0081] As used herein, the terms “antibody-drug conjugate” or ”ADC” are used interchangeably and refer to antibodies or antigen-binding fragments thereof, including antibody derivatives that bind to an antigen, in particular a tumor-associated antigen (TAA), and are conjugated to a drug such as a cytotoxic, cytostatic, and / or therapeutic agent, as described herein. In particular, the ADC is a conjugate Ab-TOP 1 inhibitor: in other words, the antibody is conjugated to a topoisomerase 1 inhibitor. For example, a topoisomerase 1 inhibitor can be covalently linked or conjugated to an anti -TAA antibody as described herein for targeted local delivery of the topoisomerase 1 inhibitor to tumors. The topoisomerase 1 inhibitor as described herein can therefore be an Ab-TOP 1 conjugate. Topoisomerase 1 inhibitors which may be conjugated to an antibody include, without being limited to: deruxtecan, govitecan, tirumotecan, brengitecan, exatecan, adizutecan, samrotecan, tocentecan, Pl 021 (Duality Biologies) and sesutecan. Topoisomerase 1 inhibitors which are ADCs are known in the art, including, but not limited to: trastuzumab deruxtecan (CAS No 1826843-81-5), sacituzumab govitecan (CAS No 1491917-83-9), sacituzumab tirumotecan (MK-2870) (CAS No 2768350-77-0), izalontamab brengitecan (CAS No 2760528-47-8), telisotuzumab adizutecan (CAS No 3064606-04-5), puxitatug samrotecan (CAS No 2760250-80- 2), tilatamig samrotecan (CAS No 2868265-77-2), precemtabart tocentecan (M9140) (CAS No 2873366-83-5), rinatabart sesutecan (GEN1184), ADCs targeting CD70 such as PR01160 / GEN1160 (ProfoundBio / Genmab), ADCs targeting EGFR and / or cMET such as GEN1286 (ProfoundBio / Genmab), ADCs targeting Claudin 18.2 such as IB 1343 (Innovent Biologies), ADCs targeting FRa such as AZD5335 (AstraZeneca), ADCs targeting CD123 such as AZD-9829 (AstraZeneca), ADCs targeting HER3 such as BNT 325 (BioNTech / Duality Biologies).

[0082] In an embodiment, the Topoisom erase- 1 inhibitor is a peptide-drug conjugate such as CBX-12 (Cybrexa Therapeutics).

[0083] Several combinations of METTL3 inhibitor, as previously described, with at least one Topoi som erase- 1 inhibitor, as previously described, can be used for the treatment of estrogendependent cancer, in particular estrogen receptor-related cancer.

[0084] Several combinations of METTL3 inhibitor, as previously described, with at least one Topoi som erase- 1 inhibitor, as previously described, can be used for the treatment of estrogen receptor-positive cancer, as described above, in particular ER+ breast cancer.

[0085] In one embodiment, the METTL3 inhibitor according to the invention is STM2457 and the TOPI inhibitor according to the invention is camptothecin (CPT).

[0086] In one embodiment, the METTL3 inhibitor according to the invention is STC-15 and the TOPI inhibitor according to the invention is camptothecin (CPT).

[0087] In one embodiment, the METTL3 inhibitor according to the invention is STC-15 and the TOPI inhibitor according to the invention is Topotecan.

[0088] In another aspect, the invention relates to a METTL3 inhibitor in combination with at least one TOPI inhibitor for use in a method for inducing cell death of estrogen receptor-positive cancer (ER+) cells.

[0089] Optionally, the METTL3 inhibitor in combination with at least one TOPI inhibitor for use as defined above is used without a Mytl inhibitor.

[0090] The METTL3 inhibitor and TOPI inhibitor are defined as previously described.

[0091] In a further aspect, the invention relates to a method for treating estrogen-dependent cancer, in particular estrogen receptor-related cancer, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a METTL3 inhibitor in combination with at least one TOPI inhibitor. Optionally, the method for treating estrogendependent cancer does not comprise administration of a Mytl inhibitor.

[0092] In one embodiment, the invention relates to a method for treating estrogen receptor-positive cancer (ER+ cancer) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a METTL3 inhibitor in combination with at least one TOPI inhibitor.

[0093] The METTL3 inhibitor and TOPI inhibitor are defined as previously described. In a one embodiment, the invention relates to a method for treating estrogen receptorpositive cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a non-nucleoside based small organic molecule as METTL3 inhibitor, in combination with at least one camptothecin (CPT), topotecan or camptothecin derivative as TOPI inhibitor.

[0094] In a particular embodiment, the METTL3 inhibitor is selected among STM2457 or STC- 15 and the TOPI inhibitor is camptothecin or topotecan. Optionally, the METTL3 inhibitor is STM2457 or STC-15 and the Topoisom erase- 1 inhibitor is camptothecin. Optionally, the METTL3 inhibitor is STM2457 or STC-15 and the Topoisom erase- 1 inhibitor is topotecan. Optionally, the METTL3 inhibitor is STC-15 and the TOPI inhibitor is topotecan.

[0095] Pharmaceutical composition

[0096] The compounds or combinations of the invention may be used or prepared in a pharmaceutical composition.

[0097] The invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the compounds or combinations of the invention and a pharmaceutical acceptable carrier and the use thereof.

[0098] By a "therapeutically effective amount" of the agent of the present invention as above described is meant a sufficient amount of the agent at a reasonable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the agents and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific agent employed; the specific composition employed, the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific agent employed; the duration of the treatment; drugs used in combination or coincidental with the specific agent employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the agent at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.001 to 2,000 mg per adult.

[0099] In the context of the invention, the ranges of values expressed by “from X to XX” or “between X and XX” comprise the upper and lower limits.

[0100] Typically, the composition contains from 0.01 to 1,000 mg, in particular from 1 to 200 mg of the METTL3 inhibitor of the present invention for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from 0.01 to 1,000 mg of the METTL3 inhibitor of the present invention, in particular from 0.5 to 500 mg, in particular from 1 to 200 mg of the METTL3 inhibitor of the present invention, in particular from 10 to 200 mg of the METTL3 inhibitor of the present invention, specifically from 30 to 100 mg.

[0101] An effective amount of the TOPI inhibitor is ordinarily supplied at a dosage level from 0.0001 to 4,000 mg / ml, especially from 0.001 to 2,000 mg / ml, especially from 0.01 to 1,500 mg / ml, especially from 0.1 to 1,000 mg / ml, especially from 0.1 to 500 mg / ml, especially from 1 to 100 mg / ml, especially from 1 to 50 mg / ml, especially from 1 to 10 mg / ml, especially from 1 to 5 mg / ml, especially from 1 to 2 mg / ml.

[0102] Methods for the safe and effective administration are known to those skilled in the art. In addition, administration of anti -cancer inhibitor is described in the standard literature.

[0103] In one embodiment, the pharmaceutical composition contains from 0.01 to 1,000 mg of the METTL3 inhibitor, in particular from 0.5 to 500 mg, in particular from 1 to 200 mg.

[0104] In one embodiment, the pharmaceutical composition contains an effective amount of the METTL3 inhibitor at a dosage level from 0.01 to 1,000 mg, in particular from 0.5 to 500 mg, in particular from 1 to 200 mg, in particular from 10 to 200 mg, in particular from 30 to 100 mg.

[0105] In one embodiment, the pharmaceutical composition contains an effective amount of the TOPI inhibitor at a dosage level from 0.0001 to 4,000 mg / ml, especially from 0.001 to 2,000 mg / ml, especially from 0.01 to 1,500 mg / ml, especially from 0.1 to 1,000 mg / ml, especially from 0.1 to 500 mg / ml, especially from 1 to 100 mg / ml, especially from 1 to 50 mg / ml, especially from 1 to 10 mg / ml, especially from 1 to 5 mg / ml, especially from 1 to 2 mg / ml.

[0106] In a particular embodiment, the pharmaceutical composition contains an effective amount of the METTL3 inhibitor at a dosage level from 0.5 to 100 pM, in particular from 0.5 to 40 pM, in particular from 1 to 30 pM, in particular from 1 to 20 pM, in particular from 1 to 10 pM.

[0107] In another particular embodiment, the pharmaceutical composition contains an effective amount of the METTL3 inhibitor at a dosage level from 1 to 40 pM, in particular from 10 to 40 pM, in particular from 20 to 40 pM.

[0108] In a particular embodiment, the pharmaceutical composition contains an effective amount of the TOPI inhibitor at a dosage level from 0.5 to 100 nM, in particular from 5 to 80 nM, in particular from 5 to 40 nM, in particular from 10 to 40 nM, in particular from 10 to 20 nM.

[0109] In another particular embodiment, the pharmaceutical composition contains an effective amount of the TOPI inhibitor at a dosage level from 5 to 20 nM or from 40 to 80 nM.

[0110] In a particular aspect, the TOPI inhibitor is used with a sub -therapeutic amount. In another particular aspect, the METTL3 inhibitor is used with a sub-therapeutic amount. In a very particular aspect, the TOPI inhibitor and the METTL3 inhibitor are both used with a sub-therapeutic amount. As used herein, the term “sub-therapeutic amount” or “sub -therapeutic dose” refers to a dosage which is less than that dosage which would produce a therapeutic result in the subject if administered in the absence of the other inhibitor. Indeed, the synergistic effect of the combination might allow for lowering the dose of a toxic inhibitor while keeping the therapeutic effect. It is particularly interesting for the TOPI inhibitors. More particularly, the amount can be for instance 90, 80, 70, 60, 50, 40, 30, 20 or 10 % of the conventional therapeutic dosage (in particular for the same indication and the same administration route). The conventional therapeutic dosages are those acknowledged by the drug approvals agencies (e.g., FDA or EMEA).

[0111] In one embodiment, the invention relates to a pharmaceutical composition or a kit comprising a therapeutically effective amount of a METTL3 inhibitor and at least one TOPI inhibitor, and a pharmaceutical acceptable carrier.

[0112] The METTL3 inhibitor and TOPI inhibitor are defined as previously described.

[0113] In one embodiment, the METTL3 inhibitor is selected among non-nucleoside based small molecule and the TOPI inhibitor is selected among camptothecin, topotecan or other camptothecin derivatives.

[0114] In a particular embodiment, the METTL3 inhibitor is STM2457 or STC-15 and the TOPI inhibitor is camptothecin. In another embodiment, the METTL3 inhibitor is STC-15 and the TOPI inhibitor is topotecan.

[0115] Optionally, the pharmaceutical composition does not comprise a Mytl inhibitor.

[0116] In one embodiment, the invention relates to a pharmaceutical composition or a kit comprising a therapeutically effective amount of the compounds or combinations of the invention, and a pharmaceutical acceptable carrier, for use as a drug, in a subject in need thereof.

[0117] In one embodiment, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a METTL3 inhibitor and at least one TOPI inhibitor, and a pharmaceutical acceptable carrier, for use as a drug, in a subject in need thereof.

[0118] The METTL3 inhibitor and TOPI inhibitor are defined as previously described.

[0119] In one embodiment, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a METTL3 inhibitor selected among non-nucleoside based small molecule and at least one TOPI inhibitor selected among camptothecin, topotecan or other camptothecin derivatives, and a pharmaceutical acceptable carrier, for use as a drug, in a subject in need thereof. In a particular embodiment, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of METTL3 inhibitor STM2457 or STC-15 and TOPI inhibitor camptothecin or topotecan, and a pharmaceutical acceptable carrier, for use as a drug, in a subject in need thereof.

[0120] In a particular embodiment, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of METTL3 inhibitor STM2457 or STC-15 and TOPI inhibitor camptothecin, and a pharmaceutical acceptable carrier, for use as a drug, in a subject in need thereof.

[0121] In a particular embodiment, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of METTL3 inhibitor STC-15 and TOPI inhibitor topotecan, and a pharmaceutical acceptable carrier, for use as a drug, in a subject in need thereof.

[0122] In one embodiment, the invention relates to a pharmaceutical composition comprising the compounds or combinations of the invention and a pharmaceutical acceptable carrier for use in the treatment of estrogen-dependent cancer, in particular estrogen receptor-related cancer, in a subject in need thereof.

[0123] Estrogen-dependent cancer, and in particular estrogen receptor-related cancer, are as described above.

[0124] In a particular embodiment, the estrogen receptor-related cancer is estrogen receptorpositive cancer, as described above, in particular ER+ breast cancer.

[0125] In one embodiment, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a METTL3 inhibitor and at least one TOPI inhibitor, and a pharmaceutical acceptable carrier, for use in the treatment of estrogen-dependent cancer, in particular estrogen receptor-related cancer, in a subject in need thereof.

[0126] In one embodiment, the METTL3 inhibitor is selected among non-nucleoside based small molecule and the TOPI inhibitor is selected among camptothecin, topotecan or other camptothecin derivatives.

[0127] In a particular embodiment, the METTL3 inhibitor is STM2457 or STC-15 and the TOPI inhibitor is camptothecin.

[0128] In a particular embodiment, the METTL3 inhibitor is STC-15 and the TOPI inhibitor is topotecan.

[0129] In one embodiment, the estrogen receptor-related cancer is estrogen receptor-positive cancer.

[0130] In one embodiment, the METTL3 inhibitor is selected among non-nucleoside based small molecule and the TOPI inhibitor is selected among camptothecin or camptothecin derivatives. In a particular embodiment, the METTL3 inhibitor is STM2457 or STC-15 and the TOPI inhibitor is camptothecin.

[0131] In a particular embodiment, the METTL3 inhibitor is STC-15 and the TOPI inhibitor is topotecan.

[0132] In one embodiment, the estrogen receptor-positive cancer is selected among breast cancer, ovarian cancer, endometrial cancer, uterine cancer, uterine leiomyoma, prostate cancer, testis cancer, thyroid cancer, lung cancer or osteosarcoma.

[0133] In a particular embodiment, the estrogen receptor-positive cancer is ER+ breast cancer.

[0134] According to the invention, the inhibitor of the present invention is administered to the subject in the form of a pharmaceutical composition. Typically, the inhibitor(s) of the present invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions. "Pharmaceutically" or "pharmaceutically acceptable" refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0135] In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal, and intranasal administration forms and rectal administration forms.

[0136] Typically, the pharmaceutical compositions contain vehicles, which are pharmaceutically acceptable for a formulation capable of being injected. These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. Solutions comprising inhibitors of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The inhibitor of the present invention can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal inhibitors, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic inhibitors, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of inhibitor delaying absorption, for example, aluminium monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active inhibitor s in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized inhibitors of the present inventions into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the inhibitor of the present invention plus any additional desired ingredient from a previously sterile-filtered solution thereof. The preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active inhibitor s to a small tumor area. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed. For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.

[0137] In a particular embodiment, the pharmaceutical composition according to the invention is administered intravenously or orally. Optionally, the pharmaceutical composition comprising the METTL3 inhibitor is to be administered orally. Optionally, the pharmaceutical composition comprising the TOPI inhibitor is to be administered intravenously or orally. Optionally, the pharmaceutical composition comprising the METTL3 inhibitor is to be administered orally and the pharmaceutical composition comprising the TOPI inhibitor is to be administered intravenously. Optionally, the pharmaceutical composition comprising the METTL3 inhibitor and the pharmaceutical composition comprising the TOPI inhibitor is to be administered orally. Optionally, the pharmaceutical composition comprising the METTL3 inhibitor and the TOPI inhibitor is to be administered orally.

[0138] In a particular embodiment, the pharmaceutical composition according to the invention is a gel, a capsule, a powder, or a sterile injectable solution.

[0139] By “therapeutic effect” it is meant an effect induced by an inhibitor or a pharmaceutical composition comprising such inhibitor, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder.

[0140] Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary inhibitors, such as, e.g., stabilizers, antioxidants, binders, dyes, emulsifiers, or flavoring substances.

[0141] Optionally, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient every week, every two weeks, every three weeks, every four weeks, every five weeks, or every six weeks. Optionally, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient every week or two to six weeks, especially every week or two to three weeks.

[0142] Optionally, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient at a rate of one, two, three, four, five, six, seven, or eight times per week.

[0143] Optionally, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient at a rate of eight times per week.

[0144] Optionally, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient every day, every two days, every three days, every four days, every five days, every six days, or every seven days.

[0145] Optionally, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient every day.

[0146] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient for a period of 1 to 12 months, or 1 to 8 months, or 2 to 6 months.

[0147] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient for a period of 1 month (z.e., 4 weeks).

[0148] In a particular embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered to the patient for a period of 3 days to 3 weeks, or 5 days to 3 weeks.

[0149] The adaptation of posology and administration route for a given patient are common practices well known from those skilled in the art.

[0150] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention may further be administered in addition to other anti-cancer therapy, for example: surgery, chemotherapy, radiotherapy, hormonotherapy, immunotherapy, targeted therapy, and / or therapeutic vaccines.

[0151] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered to the subject in combination with radiotherapy.

[0152] Suitable examples of radiation therapies include, but are not limited to external beam radiotherapy (such as superficial X-rays therapy, orthovoltage X-rays therapy, megavoltage X- rays therapy, radiosurgery, stereotactic radiation therapy, Fractionated stereotactic radiation therapy, cobalt therapy, electron therapy, fast neutron therapy, neutron-capture therapy, proton therapy, intensity modulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy (3D-CRT) and the like); brachytherapy; unsealed source radiotherapy; tomotherapy; and the like. Gamma rays are another form of photons used in radiotherapy. Gamma rays are produced spontaneously as certain elements (such as radium, uranium, and cobalt 60) release radiation as they decompose, or decay. In some embodiments, radiotherapy may be proton radiotherapy or proton minibeam radiation therapy. Proton radiotherapy is an ultra-precise form of radiotherapy that uses proton beams (Prezado Y, Jouvion G, Guardiola C, Gonzalez W, Juchaux M, Bergs J, Nauraye C, Labiod D, De Marzi L, Pouzoulet F, Patriarca A, Dendale R. Tumor Control in RG2 Glioma-Bearing Rats: A Comparison Between Proton Minibeam Therapy and Standard Proton Therapy. Int J Radiat Oncol Biol Phys. 2019 Jun l;104(2):266-271. doi: 10.1016 / j .ijrobp.2019.01.080; Prezado Y, Jouvion G, Patriarca A, Nauraye C, Guardiola C, Juchaux M, Lamirault C, Labiod D, Jourdain L, Sebrie C, Dendale R, Gonzalez W, Pouzoulet F. Proton minibeam radiation therapy widens the therapeutic index for high-grade gliomas. Sci Rep. 2018 Nov 7;8(1): 16479. doi: 10.1038 / s41598-018-34796-8). Radiotherapy may also be FLASH radiotherapy (FLASH-RT) or FLASH proton irradiation. FLASH radiotherapy involves the ultrafast delivery of radiation treatment at dose rates several orders of magnitude greater than those currently in routine clinical practice (ultra-high dose rate) (Favaudon V, Fouillade C, Vozenin MC. The radiotherapy FLASH to save healthy tissues. Med Sci (Paris) 2015; 31 : 121-123. DOI: 10.1051 / medsci / 20153102002); Patriarca A., Fouillade C. M., Martin F., Pouzoulet F., Nauraye C., et al., Experimental set-up for FLASH proton irradiation of small animals using a clinical system. Int J Radiat Oncol Biol Phys, 102 (2018), pp. 619-626. doi: 10.1016 / j.ijrobp.2018.06.403. Epub 2018 Jul 11).

[0153] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention may be used in combination with chemotherapy.

[0154] As used herein, the term “antitumor chemotherapy” or “chemotherapy” has its general meaning in the art and refers to a cancer therapeutic treatment using chemical or biochemical substances, in particular using one or several antineoplastic inhibitors or chemotherapeutic inhibitors. Chemotherapeutic inhibitor s include, but are not limited to alkylating inhibitor such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); bryostatin; cally statin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancrati statin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g. , calicheamicin, especially calicheamicin gammall and calicheamicin omegall ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo- 5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin and deoxy doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5- fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; methylhydrazine derivatives including N-methylhydrazine (MIH) and procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel and doxetaxel; gemcitabine; 6- thioguanine; mercaptopurine; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; difluoromethylomithine (DMFO); retinoids such as retinoic acid; capecitabine; anthracyclines, nitrosoureas, antimetabolites, epipodophylotoxins, enzymes such as L-asparaginase; anthracenediones; hormones and antagonists including adrenocorticosteroid antagonists such as prednisone and equivalents, dexamethasone and aminoglutethimide; progestin such as hydroxyprogesterone caproate, medroxyprogesterone acetate and megestrol acetate; estrogen such as diethylstilbestrol and ethinyl estradiol equivalents; antiestrogen such as tamoxifen; androgens including testosterone propionate and fluoxymesterone / equivalents; antiandrogens such as flutamide, gonadotropin-releasing hormone analogs and leuprolide; and non-steroidal antiandrogens such as flutamide; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0155] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered to the subject in combination with hormonotherapy. As used herein, the term “hormonotherapy” or “endocrine therapy” or “hormonal therapy” has its general meaning in the art and refers to cancer therapeutic treatment slowing or stopping the growth of hormonesensitive tumors by blocking the body’s ability to produce hormones or by interfering with effects of hormones on cancer cells.

[0156] Suitable examples of hormonotherapy include, but are not limited to aromatase inhibitors (such as anastrozole, letrozole, exemestane), gonadotropin-releasing hormone - GnRH agonists (also known as luteinizing hormone-releasing hormone - LHRH agonists), selective estrogen receptor modulators - SERMs (such as tamoxifen and toremifene) or antiestrogen drugs (such as fulvestrant).

[0157] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered to the subject in combination with immunotherapy.

[0158] As used herein, the term “immunotherapy” has its general meaning in the art and refers to cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells.

[0159] Immune checkpoint therapy such as checkpoint inhibitors include, but are not limited to programmed death- 1 (PD-1) inhibitors, programmed death ligand- 1 (PD-L1) inhibitors, programmed death ligand-2 (PD-L2) inhibitors, lymphocyte-activation gene 3 (LAG3) inhibitors, T-cell immunoglobulin and mucin-domain containing protein 3 (TIM-3) inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, B- and T-lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T-cell activation (VISTA) inhibitors, cytotoxic T- lymphocyte-associated protein 4 (CTLA4) inhibitors, Indoleamine 2,3-dioxygenase (IDO) inhibitors, killer immunoglobulin-like receptors (KIR) inhibitors, KIR2L3 inhibitors, KIR3DL2 inhibitors and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitors. In particular, checkpoint inhibitors include antibodies anti-PDl, anti-PD-Ll, anti-CTLA-4, anti- TIM-3, anti-LAG3. Immune checkpoint therapy also includes co-stimulatory antibodies delivering positive signals through immune-regulatory receptors including but not limited to ICOS, CD137, CD27, OX-40 and GITR.

[0160] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention may be used in combination with targeted therapy.

[0161] As used herein, the term “targeted therapy” refers to targeted therapy inhibitor s, drugs designed to interfere with specific molecules necessary for tumor growth and progression. For example, targeted therapy inhibitor s such as therapeutic monoclonal antibodies target specific antigens found on the cell surface, such as transmembrane receptors or extracellular growth factors. Small molecules can penetrate the cell membrane to interact with targets inside a cell. Small molecules are usually designed to interfere with the enzymatic activity of the target protein such as for example proteasome inhibitor, tyrosine kinase or cyclin-dependent kinase inhibitor, histone deacetylase inhibitor. Targeted therapy may also use cytokines. Examples of such targeted therapy include with no limitations: Ado-trastuzumab emtansine (HER2), Afatinib (EGFR (HER1 / ERBB1), HER2), Aldesleukin (Proleukin), alectinib (ALK), Alemtuzumab (CD52), axitinib (kit, PDGFRbeta, VEGFR1 / 2 / 3), Belimumab (BAFF), Belinostat (HD AC), Bevacizumab (VEGF ligand), Blinatumomab (CD19 / CD3), bortezomib (proteasome), Brentuximab vedotin (CD30), bosutinib (ABL), brigatinib (ALK), cabozantinib (FLT3, KIT, MET, RET, VEGFR2), Canakinumab (IL-1 beta), carfilzomib (proteasome), ceritinib (ALK), Cetuximab (EGFR), cofimetinib (MEK), Crizotinib (ALK, MET, ROS1), Dabrafenib (BRAF), Daratumumab (CD38), Dasatinib (ABL), Denosumab (RANKL), Dinutuximab (B4GALNT1 (GD2)), Elotuzumab (SLAMF7), Enasidenib (IDH2), Erlotinib (EGFR), Everolimus (mTOR), Gefitinib (EGFR), Ibritumomab tiuxetan (CD20), Sonidegib (Smoothened), Sipuleucel-T, Siltuximab (IL-6), Sorafenib (VEGFR, PDGFR, KIT, RAF),(Tocilizumab (IL-6R), Temsirolimus (mTOR), Tofacitinib (JAK3), Trametinib (MEK), Tositumomab (CD20), Trastuzumab (HER2), Vandetanib (EGFR), Vemurafenib (BRAF), Venetoclax (BCL2), Vismodegib (PTCH, Smoothened), Vorinostat (HDAC), Ziv-aflibercept (PIGF, VEGFA / B), Olaparib (PARP inhibitor).

[0162] In one embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered to the subject in combination with therapeutic vaccine. As used herein, the term “therapeutic vaccine” has its general meaning in the art and refers to vaccine expressing specific endogenous or exogenous antigens to mainly induce or boost cell-mediated immunity, via provoking cytotoxic T cells or elicit humoral immunity via activating B cells, to produce specific antibodies. Therapeutic vaccine aims also to reshape the host immunity for eradicating a disease and establishing lasting memory.

[0163] Suitable examples of therapeutic vaccines include, but are not limited to, molecular-based vaccines (peptide / protein, DNA and mRNA vaccines), vector-based vaccines (bacterial vector vaccines, viral vector vaccines and yeast-based vaccines) and cell-based vaccines (dendritic cell vaccines and genetically modified cell vaccines), as well as combinatorial approaches.

[0164] In a particular embodiment, the compound, combination and / or pharmaceutical composition of the invention is administered in combination with surgery, radiotherapy, chemotherapy, hormonotherapy and / or immunotherapy.

[0165] In one embodiment, said additional active compounds may be contained in the same composition or administrated separately.

[0166] In one embodiment, said additional active compounds is administered simultaneously, separately or sequentially.

[0167] The invention also provides kits comprising the combination and / or the pharmaceutical composition of the invention.

[0168] Kits containing the combination and / or the pharmaceutical composition of the invention find use in therapeutic methods.

[0169] The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention.

[0170] BRIEF DESCRIPTION OF THE FIGURES

[0171] Figure 1: Sensitivity of ER+ breast cancer MCF7 cells, non-tumor breast epithelial MCF10A cells, to STM2457 treatment for 72h. Error bars indicate standard deviation, *p<0.05, **p<0.01, and ***p<0.001 (unpaired student t-test).

[0172] Figure 2: MCF7 ER+ breast cancer cells sensitivity in the presence of CPT alone or in combination with 30 pM of STM2457 for 72h. Error bars indicate standard deviation, *p<0.05, **p<0.01, and ***p<0.001 (paired student t-test).

[0173] Figure 3: a, MCF7 (breast cancer cell line) and MCF10A (non-tumorigenic breast epithelial cell line) cells viability in the presence of CPT in combination with 30 pM of STM2457, for 72h. b, MCF7 (breast cancer cell line) and MCF10A (non-tumorigenic breast epithelial cell line) cells viability in the presence of CPT in combination with 10 pM of STM2457, 72h treatment. Error bars indicate standard deviation, *p<0.05, **p<0.01, and ***p<0.001 (unpaired student t- test). Figure 4: a, Effect on MCF7 breast cancer cells viability of STM2457 alone or in combination with CPT at indicated dosage (at 10 or lOOnM), and comparison with the expected result if the combination had an additive effect, instead of synergic effect, for respective concentrations (expected bliss curve), b, Effect on MCF7 breast cancer cells viability of STM2457 alone or in combination with CPT at indicated dosages.

[0174] Figure 5: Effect on MDA-MB-468 triple-negative breast cancer (TNBC) cells viability of STM2457 alone or in combination with CPT at indicated dosages.

[0175] Figure 6: Effect on MCF7 breast cancer cells viability of STC-15 alone or in combination with CPT at indicated dosages.

[0176] Figure 7: Effect on MCF7 breast cancer cells viability of STC-15 alone or in combination with Topotecan (Topo) at indicated dosages.

[0177] Figure 8: Protein expression levels analysis, by western blotting, of ER-alpha and Total- Parp, under CPT alone (lOnM and lOOnM) and in combination with STM2457 (lOpM) and STC- 15 (10 pM). Densitometric analysis was performed by ImageJ software. Actin was used as loading control within the same sample and expressed as fold change, compared to control.

[0178] Figure 9: Protein expression levels analysis, by western blotting, of ER-alpha and Total- Parp, under Topotecan alone (lOnM, lOOnM and lOOOnM) and in combination with STC-15 (10 pM). Densitometric analysis was performed by ImageJ software. Actin was used as a loading control within the same sample and expressed as fold change, compared to control (DMSO).

[0179] EXAMPLES

[0180] Materials and methods

[0181] MCF7 ER+ BC cells were obtained from ATCC (HTB-22) and cultured in DMEM Glutamax (GIBCO) supplemented with 10% fetal bovine serum in 5% CO2 at 37°C. MCF-10A non-tumorigenic breast epithelial cells were cultured in DMEM-F12 Glutamax (GIBCO) supplemented with 5% horse serum, human insulin (0.01 mg / ml), cholera toxin (100 ng / ml), hydrocortisone (500 ng / ml), EGF (20 ng / ml) in 5% CO2 at 37°C. MDA-MB-468 triple negative breast cancer (TNBC) cells were cultured in RPMI Glutamax (GIBCO) supplemented with 10% fetal bovine serum in 5% CO2 at 37°C.

[0182] 5000 MCF7, MCF-10A or MDA-MB-468 cells were seeded in 100 uL of their respective growth medium in 96-well plates. Assay plates were incubated in 5% CO2 at 37°C for 24 hours and treated with varying dosages of test compounds (STM2457 alone, STC-15 alone, CPT alone, topotecan alone, in combination) or DMSO (maximum 0.5%) for 72 hours. To assess cell viability, 100 uL CellTiter-Glo 3D (Promega) was added to each well and incubated for 10 minutes at room temperature according to the manufacturer’s instructions. Luminescence was measured using the CLARIOstar Plus (BMG Labtech) microplate reader. Each experiment was done in 3 biological replicates. The signal values of each well were subtracted from the signal of blank wells, then compound-treated wells were normalized to DMSO-treated wells.

[0183] Protein extracts from CPT alone or in combination with STM2457 or STC-15 were subjected to immunoblot analysis. Proteins of interest were detected using anti-ER-alpha (F10, SantaCruz), anti -beta- Actin (Sigma), anti -P ARP (46D11, Cell signaling) antibodies.

[0184] SynergyFinder Plus R package was used to assess synergy based on the Bliss independence model (Zheng, S. et al., 2022). Bootstrapping of 100 iterations, with all baseline correction, was used to calculate synergy scores with summary statistics. A drug combination pair is considered synergistic if its score is higher than 0, strongly synergistic if higher than 10, according to the Bliss model.

[0185] MCF7 cells are more sensitive to STM2457 than MCF-10A.

[0186] Results

[0187] MCF7 cells are more sensitive to STM2457 than MCF10A, particularly at 10 uM and 20 uM concentrations. This indicates that a certain concentration range of STM2457 can inhibit breast cancer cell growth without impacting non-turmeric breast cells (Fig. 1).

[0188] STM treatment increases TOPI inhibitor (CPT) sensitivity in MCF7 cells.

[0189] Results

[0190] ST2457 treatment increases TOPI inhibitor (CPT) sensitivity in MCF7 cells when combining with 30 uM of STM2457 (Fig. 2).

[0191] MCF7 cells are more sensitive to CPT+STM treatment than MCF10A.

[0192] Results

[0193] MCF7 cell line is more sensitive than MCF10A cell line to the drug combination of CPT and 30 uM or 10 uM of STM2457, indicating specificity in treating ER+ BC cells while minimizing toxicity to non-tumor cells (Fig. 3 A and 3B).

[0194] STM2457-CPT combination shows a strong synergic effect in ER+ breast cancer cells, but a poor synergic effect at high concentrations in TNBC cells.

[0195] Results

[0196] STM2457 - CPT combination synergistically inhibits ER+ breast cancer cell growth. This combination effect is not additive as the observed cell viability is lower compared to the expected Bliss cell viability curve, at 10 nM or 100 nM of CPT combined with increasing STM2457 dosage (Fig. 4A). STM2457 - CPT combinations at a wide range of concentrations (0.5 to 40 uM of STM2457, 5 to 100 nM of CPT) determine the precise synergic range in MCF7 cells (Fig. 4B) and determine whether there is synergic range in MBA-MB-468 cells, which are TNBC cells (Fig. 5).

[0197] A synergic effect is obtained for a concentration of CPT comprised between 10-40 nM and a concentration of STM2457 comprised between 1-10 pM, in particular for a concentration of CPT between 10-20 nM and a concentration of STM2457 between 1-5 pM according to the heatmap of Bliss Synergy Score and score values in breast cancer cells MCF7 (data not shown). On the other hand, higher concentrations of CPT and STM2457 are required to observe synergy in TNBC cells: a synergic effect is obtained for a concentration of CPT comprised between 20-100 nM and a concentration of STM2457 comprised between 5-40 pM, in particular for a concentration of CPT between 40-80 nM and a concentration of STM2457 between 10-40 pM according to the heatmap of Bliss Synergy Score in triple negative breast cancer cells (data not shown). Comparing to MCF7 cells, MDA-MB-468 cells are less sensitive to STM2457 alone or combined with CPT and require higher concentrations to achieve synergy (data not shown).

[0198] STC-15-CPT combination shows a synergic effect in ER+ breast cancer cells but not in non-tumorigenic breast cells.

[0199] Results

[0200] STC15 - CPT combinations at a wide range of concentrations (0.5 to 40 uM of STM2457, 5 to 100 nM of CPT) determine whether there is synergic range in MCF7 cells (Fig. 6). A strong synergic effect is obtained for a concentration of CPT comprised between 5-40 nM and a concentration of STC-15 comprised between 0.5-10 pM, in particular for a concentration of CPT comprised between 5-20 nM and a concentration of STC-15 comprised between 0.5-5 pM according to the heatmap of Bliss Synergy Score in breast cancer cells MCF7 (data not shown). STC15 - CPT combinations at a wide range of concentrations (0.5 to 40 uM of STC15, 5 to 100 nM of CPT) determine whether there is synergic range in MCF10A cells No synergistic effect is observed at the combination ranges, according to the heatmap of Bliss Synergy Score (data not shown).

[0201] STC-15-Topotecan combination shows a synergic effect in ER+ breast cancer cells

[0202] STC15 - Topotecan combinations at a wide range of concentrations (0.5 to 40 uM of STM2457, 62.5 to 2000 nM of Topo) determine whether there is synergic range in MCF7 cells (Fig. 7). A strong synergic effect is obtained for a concentration of Topo comprised between 250- 1000 nM and a concentration of STC-15 comprised between 0.5-1 pM, in particular for a concentration of Topo at 1000 nM and a concentration of STC-15 comprised between 0.5-20 pM according to the heatmap of Bliss Synergy Score in breast cancer cells MCF7 (data not shown). STM2457- or STC-15-CPT combination show a strong reduction of ER-alpha protein and higher apoptosis, compared to CPT alone.

[0203] Protein expression analysis from CPT alone (lOnM and lOOnM), or in combination with STM lOuM (lOpM) and STC-15 (lOpM), demonstrate that ER-alpha and Total-Parp are strongly downregulated in anti-METT-CPT combinations, compared to CPT alone (Figure 8). This confirms the higher apoptosis induced by anti-METTL3 and CPT combination.

[0204] Combination of STC-15 and Topotecan confirms ER-alpha decrease and higher apoptosis, compared to Topotecan alone.

[0205] Protein expression analysis from Topotecan alone (lOnM, lOOnM and lOOOnM), or in combination with STC-15 (lOpM), confirms the decrease of ER-alpha levels, and the Total-Parp downregulation, indicating higher apoptosis, in anti-METT-Topotecan combinations, compared to Topotecan alone (Figure 9).

[0206] REFERENCES:

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Claims

CLAIMS1. A pharmaceutical composition comprising a METTL3 (methyltransferase-like protein 3) inhibitor for use in the treatment of estrogen-dependent cancer in combination with at least one Topoisom erase- 1 inhibitor.

2. A pharmaceutical composition comprising a Topoisomerase- 1 inhibitor for use in the treatment of estrogen-dependent cancer in combination with a METTL3 inhibitor.

3. A pharmaceutical composition comprising a METTL3 inhibitor and at least one Topoisom erase- 1 inhibitor for use in the treatment of estrogen-dependent cancer.

4. The pharmaceutical composition for use according to any one of claims 1-3, wherein the estrogen-dependent cancer is estrogen receptor-related cancer, in particular estrogen receptor-positive cancer (ER+ cancer).

5. The pharmaceutical composition for use according to claim 4, wherein the estrogen receptor-positive cancer is selected among breast cancer, ovarian cancer, endometrial cancer, uterine cancer, prostate cancer, uterine leiomyoma or any other estrogen receptorpositive gynecologic cancer, prostate cancer, testis cancer, thyroid cancer, lung cancer or osteosarcoma, in particular ER+ breast cancer.

6. The pharmaceutical composition for use according to any one of claims 1 to 5, wherein the METTL3 inhibitor is a small organic molecule, in particular a non-nucleoside-based small organic molecule.

7. The pharmaceutical composition for use according to claim 6, wherein the METTL3 inhibitor is a non-nucleoside-based small organic molecule selected among STM2457, STC-15, UZHla, UZH2, STM3006, and STM3675, or any combination thereof.

8. The pharmaceutical composition for use according to any one of claims 1 to 7, wherein the Topoisom erase- 1 inhibitor is a small organic molecule, a peptide-drug conjugate or an antibody-drug conjugate (ADC).

9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the Topoisom erase- 1 inhibitor is selected among camptothecin (CPT), topotecan, irinotecan, belotecan, deruxtecan, govitecan, tirumotecan, brengitecan, adizutecan,samrotecan, tocentecan, rinatabart sesutecan, GEN1160, GEN1286, IBI343, ABBV-706, AZD-5335, AZD-9829, BNT-325, CBX-12, and PLX-038 or any combination thereof.

10. The pharmaceutical composition for use according to any one of claims 1 to 9, wherein the Topoisom erase- 1 inhibitor is an ADC selected among: trastuzumab deruxtecan, sacituzumab govitecan, sacituzumab tirumotecan (MK-2870), izalontamab brengitecan, telisotuzumab adizutecan, puxitatug samrotecan, tilatamig samrotecan, and precemtabart tocentecan.

11. The pharmaceutical composition for use according to any one of claims 1 to 10, wherein the METTL3 inhibitor is STM2457 or STC-15 and the Topoisom erase- 1 inhibitor is camptothecin or topotecan.

12. A pharmaceutical composition comprising a therapeutically effective amount of METTL3 inhibitor STM2457 or STC-15 and Topoisomerase- 1 inhibitor camptothecin or topotecan, and a pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12 for use as a drug.

14. The pharmaceutical composition for use according to claim 13 in the treatment of an estrogen-dependent cancer, in particular an estrogen receptor-related cancer, in particular estrogen receptor-positive cancer.

15. The pharmaceutical composition for use according to claim 14, wherein the estrogen receptor-positive cancer is selected among breast cancer, ovarian cancer, endometrial cancer, uterine cancer, uterine leiomyoma, prostate cancer, testis cancer, thyroid cancer, lung cancer or osteosarcoma, in particular breast cancer.

16. The pharmaceutical composition for use according to any one of claims 1 to 11 and 13 to 15, wherein the pharmaceutical composition is administered in combination with surgery, radiotherapy, chemotherapy, hormonotherapy and / or immunotherapy.

17. A method for treating an estrogen-dependent cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a METTL3 inhibitor and a Topoisomerase- 1 inhibitor.

18. A method for treating an estrogen-dependent cancer in a subject in need thereof, comprising administering a therapeutically effective amount or a sub-therapeutic amount of a pharmaceutical composition comprising a METTL3 inhibitor and administering a therapeutically effective amount or a sub-therapeutic amount of a pharmaceutical composition comprising a Topoisom erase- 1 inhibitor.

19. Use of a METTL3 inhibitor for the manufacture of a medicament for the treatment of estrogen-dependent cancer in combination with a Topoisom erase- 1 inhibitor.

20. Use of a Topoisomerase- 1 inhibitor for the manufacture of a medicament for the treatment of estrogen-dependent cancer in combination with a METTL3 inhibitor.

21. Use of a METTL3 inhibitor and at least one Topoisomerase- 1 inhibitor for the manufacture of a medicament for the treatment of estrogen-dependent cancer.

22. The method according to claim 17 or 18, or the use according to any of claims 19 to 21, wherein the cancer is defined as in claim 4 or 5, and / or the METTL3 inhibitor is defined as in claim 6 or 7, and / or the Topoisomerase- 1 inhibitor is defined as in any of claims 8 to 10.

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