Institute for Cancer Research

Evol Science LLC

Institut Curie

Institut De Genetique Et De Biologie Moleculaire Et Cellulaire

The Research Institute of Fox Chase Cancer Center

Institute for Cancer Research D/b/a the Research Institute of Fox Chase Cancer Center

Institut De Genetique Et De Biologie Moleculaire Et Cellularire

Vikram Bhattacharjee

Timothy J Yen

Alfonso Bellacosa

Rossella Tricarico

Pietro Mancuso

Lionel Larue

Tim Yen

Neil Beeharry

Mitchell Smith

Irwin Davidson

Andrew J Andrews

The invention provides compositions, kits, and methods for inducing growth arrest, differentiation, or senescence of cancer cells that express thymine DNA glycosylase, and treating the cancer accordingly. The methods comprise inhibiting expression or biologic activity of thymine DNA glycosylase in cancer cells. Inhibition of thymine DNA glycosylase in cancer cells may induce the cells to revert to a healthy, non-cancerous phenotype and/or may induce the cells to senesce. Cancer cells include melanoma, lung, prostate, pancreatic, ovarian, brain, colon, recto-sigmoid colon, and breast cancer cells.

Inhibition of thymine DNA glycosylase in the treatment of cancer

This application describes compounds, compositions, and combinations thereof that can be used to treat cancer, such as cancers with and without BRAF and/or KRAS mutations.

Combinations to treat cancer

This application describes compounds, compositions, and combinations thereof that can be used to treat cancer, such as cancers with and without BRAF and/or RAS mutations.

Methods for treating tumors comprise contacting tumor cells expressing the vitamin D receptor with a vitamin D receptor ligand that inhibits homologous recombination in the tumor cells, and contacting the tumor cells with an amount of a Poly(ADP) Ribose Polymerase 1 (PARP-1) inhibitor. Inhibiting homologous recombination produces a synergistic therapeutic effect between the vitamin D receptor ligand and PARP-1 inhibitor, and may overcome PARP-1 resistance in killing tumor cells.

Combined inhibition of the vitamin D receptor and poly(ADP) ribose polymerase (PARP) in the treatment of cancer

The invention provides methods for enhancing the cytotoxicity of DNA damage in cancer cells that express thymine DNA glycosylase, and treating tumors accordingly. The methods comprise inhibiting the expression or biologic activity of thymine DNA glycosylase, and inducing DNA damage in the cancer cells. DNA damage may be induced by administration of bendamustine or gemcitabine to the cancer cells.

Combination of DNA repair inhibition with bendamustine or gemcitabine in the treatment of cancer

Methods for treating tumors comprising cells expressing the vitamin D receptor are provided, and comprise inhibiting the expression or the biologic activity of the vitamin D receptor in the tumor cells, and/or inhibiting the expression or the biologic activity of a constituent of the vitamin D receptor signaling pathway in the tumor cells, and administering to the tumor cells an effective amount of gemcitabine.

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Philadelphia, PA, United States of America

Vikram Bhattacharjee