Resistance to kinase inhibitors exemplifies the greatest hindrance to effective treatment of cancer patients. Recent studies have suggested that the onset of said resistance might not only be explained by a drug selection of pre-existing resistant sub-clones as it what was generally assumed, but may also arise de novo from a small population of drug-tolerant cells (DTC) that initially resists the treatment by entering a slow cycling state. Thus, targeting these DTC should be a new promising approach to hamper the emergence of secondary resistance to kinase inhibitors. The inventors now demonstrate that farnesyltransferase (but not geranylgeranyl transferase) inhibition can prevent the emergence of said resistance in different oncogenic contexts. In particular, the inventors determined invitro the efficacy of farnesyltransferase inhibitor (i.e. Tipifarnib) in combination with erlotinib in several EGFR-mutated cell lines. They showed that the combination efficiently eliminated all drug tolerant cells, and fully prevented the emergence of resistant clones. Interestingly, similar results were observed in other oncogenic models such as ALK-translocated lung cancer cells or BRAF-mutated melanoma cells. Thus the present invention relates to use of farnesyl transferase inhibitors for the treatment of cancers that have acquired resistance to kinase inhibitors.

Resistance to kinase inhibitors exemplifies the greatest hindrance to effective treatment of cancer patients. Recent studies have suggested that the onset of said resistance might not only be explained by a drug selection of pre-existing resistant sub-clones as it what was generally assumed, but may also arise de novo from a small population of drug-tolerant cells (DTC) that initially resists the treatment by entering a slow cycling state. Thus, targeting these DTC should be a new promising approach to hamper the emergence of secondary resistance to kinase inhibitors. The inventors now demonstrate that farnesyltransferase (but not geranylgeranyl transferase) inhibition can prevent the emergence of said resistance in different oncogenic contexts. In particular, the inventors determined invitro the efficacy of farnesyltransferase inhibitor (i.e. Tipifarnib) in combination with erlotinib in several EGFR-mutated cell lines. They showed that the combination efficiently eliminated all drug tolerant cells, and fully prevented the emergence of resistant clones. Interestingly, similar results were observed in other oncogenic models such as ALK-translocated lung cancer cells or BRAF-mutated melanoma cells. Thus the present invention relates to use of farnesyl transferase inhibitors for the treatment of cancers that have acquired resistance to kinase inhibitors.

The present disclosure relates to tunable biocircuit systems for the development of controlled and/or regulated therapeutic systems. In particular, regulatable biocircuits containing destabilizing domains (DD) derived from mutant human cGMP-specific phosphodiesterase type 5 (PDE5) are disclosed. Especially, the present disclosure provides an effector module. Such effector module may include (a) a stimulus response element (SRE), wherein the SRE is a DD, said DD comprising at least one mutation relative to cGMP-specific 3′,5′-cyclic phosphodiesterase (hPDE5; SEQ ID NO: 1) and (b) at least one payload, which is attached, appended or associated with said SRE. The SRE may be responsive to one or more stimuli.

The present disclosure relates to tunable biocircuit systems for the development of controlled and/or regulated therapeutic systems. In particular, regulatable biocircuits containing destabilizing domains (DD) derived from mutant human cGMP-specific phosphodiesterase type 5 (PDE5) are disclosed. Especially, the present disclosure provides an effector module. Such effector module may include (a) a stimulus response element (SRE), wherein the SRE is a DD, said DD comprising at least one mutation relative to cGMP-specific 3′,5′-cyclic phosphodiesterase (hPDE5; SEQ ID NO: 1) and (b) at least one payload, which is attached, appended or associated with said SRE. The SRE may be responsive to one or more stimuli.

The present disclosure relates, in general, to therapeutic combinations of acalabrutinib and capivasertib, and to corresponding methods of treatment, pharmaceutical compositions, and kits.

The present disclosure relates, in general, to therapeutic combinations of acalabrutinib and capivasertib, and to corresponding methods of treatment, pharmaceutical compositions, and kits.

The present disclosure relates, in general, to therapeutic combinations of acalabrutinib and capivasertib, and to corresponding methods of treatment, pharmaceutical compositions, and kits.

The present disclosure provides peripherally acting cannabidiol (CBD)-containing compositions and methods of using thereof for treating or enhancing female sexual function. In some embodiments, the compositions are provided in the form of a lotion, containing highly CBD-loaded liposomes, which is applied to female genitalia shortly prior to sexual activity.

The present disclosure provides peripherally acting cannabidiol (CBD)-containing compositions and methods of using thereof for treating or enhancing female sexual function. In some embodiments, the compositions are provided in the form of a lotion, containing highly CBD-loaded liposomes, which is applied to female genitalia shortly prior to sexual activity.

The present invention relates to novel compounds having the general formula: ##STR00001##
and pharmaceutical compositions thereof, and methods for inhibiting the activity of SHP2 phosphatase with the compounds and compositions of the invention. The present invention further relates to, but is not limited to, methods for suppressing tumor cell growth, ameliorating the pathogenesis of systemic lupus erythematosus, and the treatment of various other disorders, including Noonan syndrome, diabetes, neutropenia, neuroblastoma, melanoma, juvenile leukemia, juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia, acute myeloid leukemia, and other cancers associated with SHP2 deregulation with the compounds and compositions of the invention, alone or in combination with other treatments. Other cancers associated with SHP2 deregulation include HER2-positive breast cancer, triple-negative breast cancer, ductal carcinoma of the breast, invasive ductal carcinoma of the breast, non-small cell lung cancer, esophageal cancer, gastric cancer, squamous-cell carcinoma of the head and neck (SCCHN), and colon cancer.