Research Focus: Mechanisms of Apoptosis Dysregulation in Cancer; Genomics-based Targeting Strategies.
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. We 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.
1. We are studying specific signaling pathways and cross-talk mechanisms mediated by specific growth factor receptors (epidermal growth factor and insulin-like growth factor receptors) in regulating IAP expression and function in cancer models.
2. We are investigating the caspase-independent functions of IAP in modulating mitochondrial bioenergetics, redox control and metabolism.
3. We are investigating how anti-apoptotic proteins suppress response to immunotherapy and are developing genomics and small-molecule inhibitor-based targeted strategies for specific IAPs to overcome therapeutic resistance in cancer cells.
4. We are investigating environmental and epigenetic links in mechanisms of resistance to therapy-mediated apoptosis.
We have developed rapid high throughput cell based assays to assess cancer behavior and create model systems similar to what is seen in the patients. 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 such as antisense, siRNA; small molecule inhibitors and/or antibodies in both in vitro and in vivo cancer models.
The lab 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.
Translational research focus involves pre-clinical and clinical research toward development of oligonucleotides-based therapeutics which have led to the ‘first-in-man’ cancer clinical trial using phosphorodiamidate morpholino-based oligomer (PMO) agents. The lab has expanded the clinical use of PMOs 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