Inventors have shown that targeting DDR1 and DDR2 collagen receptors by Imatinib resensitizes melanoma tumors to BRAFV600E to targeted therapy and normalizes the fibrotic stromal reaction. These findings provide the rationale to combine Imatinib (or other DDR inhibitors) and MAPK-targeting agents to disrupt the influence of the matrix microenvironment in order to delay or prevent the emergence of therapy-resistant cells. They have shown that inhibition of DDR1 and DDR2 kinase activities by Imatinib suppressed the protection of melanoma cells against Vemurafenib (BRAFi) and Trametinib (MEKi) co-drugging and led to cell cycle arrest and cell death. Similar biochemical cell cycle and apoptotic events were promoted in presence of Nilotinib. They validated this anti-tumor activity of Imatinib combined with Vemurafenib in a pre-clinical xenograft model of melanoma and showed that targeting DDR1/2 signaling delays tumor relapse. Accordingly, the present invention relates to a method for treating melanoma in a subject in need thereof comprising a step of administering said subject with a therapeutically effective amount of: i) an inhibitor of BRAF, ii) an inhibitor of MEK, and iii) an inhibitor of DDR1/2.

Inventors have shown that targeting DDR1 and DDR2 collagen receptors by Imatinib resensitizes melanoma tumors to BRAFV600E to targeted therapy and normalizes the fibrotic stromal reaction. These findings provide the rationale to combine Imatinib (or other DDR inhibitors) and MAPK-targeting agents to disrupt the influence of the matrix microenvironment in order to delay or prevent the emergence of therapy-resistant cells. They have shown that inhibition of DDR1 and DDR2 kinase activities by Imatinib suppressed the protection of melanoma cells against Vemurafenib (BRAFi) and Trametinib (MEKi) co-drugging and led to cell cycle arrest and cell death. Similar biochemical cell cycle and apoptotic events were promoted in presence of Nilotinib. They validated this anti-tumor activity of Imatinib combined with Vemurafenib in a pre-clinical xenograft model of melanoma and showed that targeting DDR1/2 signaling delays tumor relapse. Accordingly, the present invention relates to a method for treating melanoma in a subject in need thereof comprising a step of administering said subject with a therapeutically effective amount of: i) an inhibitor of BRAF, ii) an inhibitor of MEK, and iii) an inhibitor of DDR1/2.

The invention discloses that ER-negative breast cancers can be converted into ER positive breast cancers, such as to a breast cancer of luminal-like phenotype by treatment with anti-PDGF-CC antibodies. ER-positive breast cancers, including luminal-like breast cancers can be treated with anti-estrogen treatment. On this basis the invention discloses that surprisingly, ER-negative breast cancers can be treated with anti-estrogen treatment, if the treatment is combined with treatment with anti-PDGF-CC antibodies. Said treatment may for example be an adjuvant treatment, for example a treatment aiming at reducing the risk of relapse of a breast cancer after removal of the primary tumor by surgery.

The invention discloses that ER-negative breast cancers can be converted into ER positive breast cancers, such as to a breast cancer of luminal-like phenotype by treatment with anti-PDGF-CC antibodies. ER-positive breast cancers, including luminal-like breast cancers can be treated with anti-estrogen treatment. On this basis the invention discloses that surprisingly, ER-negative breast cancers can be treated with anti-estrogen treatment, if the treatment is combined with treatment with anti-PDGF-CC antibodies. Said treatment may for example be an adjuvant treatment, for example a treatment aiming at reducing the risk of relapse of a breast cancer after removal of the primary tumor by surgery.

Embodiments of the invention provide methods of attenuating, e.g., inhibiting or reducing, cellular proliferation and migration, particularly endothelial cell proliferation and migration, including that associated with angiogenesis, as well as attenuating cancerous tumor growth and metastasis, using opioid antagonists, including, but not limited to, those that are peripherally restricted antagonists.

Embodiments of the invention provide methods of attenuating, e.g., inhibiting or reducing, cellular proliferation and migration, particularly endothelial cell proliferation and migration, including that associated with angiogenesis, as well as attenuating cancerous tumor growth and metastasis, using opioid antagonists, including, but not limited to, those that are peripherally restricted antagonists.

The present invention relates to agonists of the 5-HT.sub.2A serotonin receptors and their medical uses. In one aspect the invention relates to 5-HT.sub.2A agonists of formula (I). In second aspect, the invention relates to selective 5-HT.sub.2A agonists of formula (II). In another aspect, the invention relates to mixed 5-HT.sub.2A/5-HT.sub.2C agonists of formula (III). In yet another aspect, the invention relates to 5-HT.sub.2A agonists for use in the treatment of a depressive disorder, more particular a 5-HT.sub.2A agonist for the use in the treatment of treatment-resistant depression.

The present invention relates to agonists of the 5-HT.sub.2A serotonin receptors and their medical uses. In one aspect the invention relates to 5-HT.sub.2A agonists of formula (I). In second aspect, the invention relates to selective 5-HT.sub.2A agonists of formula (II). In another aspect, the invention relates to mixed 5-HT.sub.2A/5-HT.sub.2C agonists of formula (III). In yet another aspect, the invention relates to 5-HT.sub.2A agonists for use in the treatment of a depressive disorder, more particular a 5-HT.sub.2A agonist for the use in the treatment of treatment-resistant depression.

The invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof: ##STR00001##
The compounds, compositions, methods and kits of the invention are useful for the treatment of pain, itch, and neurogenic inflammation.

The present disclosure is directed to compositions and methods for the treatment of inflammation, particularly methods using compositions containing paroxetine or a pharmaceutically acceptable salt or derivative thereof.