Phone (Office): 919 668 0410

Phone (Lab): 919 684 8633

Our laboratory research involves four areas of investigations, all of which ultimately converge on basic and fundamental mechanisms of apoptosis, or programmed cell death. Apoptosis is required for normal tissue development and cellular homeostasis. Deregulation of most growth-promoting factors trigger apoptosis in a “normal cell” and this fundamental characteristic is lost in cancer cells. Our lab has identified the dominant role of a class of anti-cell death proteins called Inhibitor of Apoptosis Proteins (IAP) in cancer cell survival and therapeutic resistance models. The IAPs function by directly inhibiting specific caspases, the key enzymes responsible for execution of cell death. Our lab and others have observed IAP overexpression in many cancer types and documented that cancer cells are fundamentally dependent on continued high levels of IAP expression.

 

 

Our lab has developed rapid screening systems to assess cell viability and apoptosis in cellular assays. Target genes are selected based on the elucidated molecular and biochemical mechanisms in cell culture, precison-cut-tissue-slices, and plasmid-based screening models. Manipulation of selected pathways is carried out by targeted inhibition using either genomics-based strategies (antisense, siRNA), small molecule inhibitors and/or antibodies. Unique combination protocols involving targeted gene inhibition with specific schedule-dependent treatment with cytotoxic agents have resulted in overcoming resistance and/or increased potency of chemotherapeutic agents in cellular and in vivo models of prostate, lung and breast cancer.  

Apoptosis dysregulation in inflammatory breast cancer: The lab [Aird, 2008] has made a seminal identification of a functional link between expression of one of the IAP proteins, XIAP, in conferring therapeutic resistance to epidermal growth factor receptor (ErbB2/HER2) targeting agents and chemotherapy in inflammatory breast cancer (IBC). IBC is an aggressive, highly invasive tumor, with the worst clinical outcome among breast cancers. Although ErbB2 is commonly overexpressed in the patient tumors, acquired resistance to anti-ErbB2 agents like Trastuzumab and Lapatinib are common leading to poor therapeutic options. Our findings are the first example of an anti-apoptotic gene being controlled at the translational level in IBC which would provide much needed survival factor to the cancer cell and protection from undergoing death under stressful situations caused by therapeutic agents themselves. We were able to reverse the resistance to Trastuzumab and Lapatinib by using specific XIAP inhibitors which sensitized the IBC cells to the anti-ErbB2 agents.

 

Genomics-based therapeutics: Translational research focus involves pre-clinical and clinical research toward development of oligonucleotides-based therapeutics [Devi, 2006] which have led to the ‘first-in-man’ cancer clinical trial [Devi 2005] using phosphorodiamidate morpholino-based oligomer (PMO) agents. We have identified the use of a specific PMO in inhibiting lung metastasis in a syngeneic murine lung cancer model [Sekhon, 2007] which is expected to be a clinically viable strategy to target metastasis in cancer therapeutics. The lab has expanded the clinical use of PMOs in a recently funded grant in 2007 (DOD BCRP IDEA) to develop genomics-based therapeutics which destroy or inhibit the function of a subset of T cells (T-regulatory/ Treg) that have immunosuppressive action to allow optimization of cancer immunotherapies and a resultant induction in efficacious anti-tumor responses [Morse, 2007].