Siva Kolluri

Our research efforts are directed toward discovering molecular targets that are selective for cancer, developing agents that are selectively toxic to cancer cells, and devising optimal combinations of therapeutic agents aimed at different molecular pathways for the prevention and treatment of cancer. We are currently focusing our efforts to (i) Develop small molecules to treat Bcl-2 overexpressing cancers and (ii) Therapeutic targeting of the Ah Receptor in cancer and autoimmune diseases.

Conversion of Bcl-2 from a protector to a killer in cancer cells: Bcl-2-family proteins are evolutionarily conserved regulators of cell death. The Bcl-2 family primarily acts on mitochondria to regulate cell death. Overexpression of Bcl-2 contributes to cancer development and tumor progression by blocking pro-cell death Bcl-2 family members. The overexpression of Bcl-2 correlates with poor survival and correlates with resistance of cancer cells to many chemotherapeutic drugs and radiation.

We discovered a novel pathway in which Bcl-2 is converted from a protector to a killer protein (Cell 116, 527-540, 2004; Cancer Cell, 14:285-98, 2008; Oncotarget, 9:26072-26085, 2018; Apoptosis, 24:1-2 & 24:529-537, 2019). The dramatic change in Bcl-2 function is brought about by orphan nuclear receptor Nur77 binding, which exposes a hidden ‘killer BH3 domain’ of Bcl-2. We reported the identification of a Nur77-derived Bcl-2-converting peptide with 9 amino acids (NuBCP-9) and its enantiomer, which induce apoptosis of cancer cells in vitro and in animals. The apoptotic effect of NuBCPs are not inhibited but rather potentiated by Bcl-2 expression. NuBCP-9 and its enantiomer bound to the Bcl-2 loop, which shares the characteristics of structurally adaptable regions with many cancer-associated and signaling proteins. This discovery enabled extremely exciting new research possibilities, providing a molecular basis for the design and development of novel cancer therapeutics.

Cancer protector into killer:

Cancer therapeutics based on BCL-2 functional conversion.

The major goal of our laboratory is to identify small molecules that convert Bcl-2 from a protector to a killer protein, establish their therapeutic efficacy in various cancer models and move these ‘first-in-class’ cancer therapeutics to the clinic and help cancer patients.

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