Current research

Research in the laboratory is focused on the molecular mechanisms responsible for the resistance of the tumors in the digestive tract to the classic chemotherapeutic and to the more recent targeted drugs.

Our research is currently concentrated in two areas:

(1) Determine the role of Mitogen-Activated Protein Kinase (MAPK) Kinase Kinases (MAP3Ks) in the resistance of pancreatic cancer to the pro-apoptotic effect of chemotherapeutic agents.

(2) Identification of the molecular mechanisms responsible for the evasive resistance of pancreatic cancer to anti-angiogenic therapy.


1. TAK1 as a Therapeutic Target to Modulate Pancreatic Cancer Chemoresistance

Nuclear factor kB (NF-kB) and activator protein-1 (AP-1) are key transcriptional factors that orchestrate expression of many genes involved in inflammation, oncogenesis, and apoptosis. Studies performed by Dr. Paul Chiao demonstrated that NF-kB is constitutively active in almost all human pancreatic cancer cell lines and in at least 70% of primary human pancreatic tumors, and its activation can suppressproapoptotic signaling pathways through the expression of several antiapoptotic genes. The exact function of AP-1 in cellular responses to genotoxic stress could be associated with the concomitant activation of other pathways known to mediate survival, including NF-kB. Because the cytotoxicity of chemotherapeutic agents is attributed largely to apoptosis, the coactivation of NF-kB and AP-1 can synergistically and effectively suppress the apoptotic potential of chemotherapeutic agents, thus contributing a significant obstacle to effective treatment of cancer. However, direct targeting for cancer therapy of transcriptional factors such as NF-kB and AP-1 still faces enormous challenges.

We demonstrated that an autocrine stimulation of interleukin -1 alpha (IL-1α), primarily mediated through induction of AP-1 activity, accounted for the constitutive activation of NF-kB and thus for the metastatic behavior of pancreatic cancer. During immune and inflammatory responses, detailed investigation of IL-1– induced TNF receptor associated factor (TRAF)-6 signaling demonstrated activation of NF-kB through two parallel signaling pathways, depending on differential activation of two MAP3Ks, including the TGF-β–activated kinase 1 (TAK1; MAP3K7). TAK1 was originally identified as a MAP3K, which can be rapidly activated in response to TGF-β signal transduction. We demonstrated that targeting the kinase activity of the TGF-β type I/II receptors complex on pancreatic cancer cells or the cells of the liver microenvironment represents a novel therapeutic approach to potentiate the antitumor activity of gemcitabine and to inhibit pancreatic cancer metastasis, through the reversion of several steps of the metastatic cascade, and the modulation of the secondary site.

Thus, in a recent study we hypothesized that TAK1 might be responsible for the resistance of pancreatic cancer to the pro-apoptotic effect of chemotherapeutic agents by increasing the NF-kB and AP-1- mediated transcription of the antiapoptotic gene cIAP-2.


We demonstrated that silencing the expression or inhibiting the kinase activity of TAK1 lead to a proapoptotic phenotype in pancreatic cancer cells in vitro and in vivo, and in turn to their statistically significantly higher sensitivity to the antitumor activity of chemotherapeutic drugs.



2. Overcoming Pancreatic Cancer Resistance to Anti-Angiogenic agents by Inhibiting Tumor Microenvironment ProInflammatory signaling pathways in models of in vivo Acquired Resistance to anti-VEGF Treatment

The resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. There are currently no validated predictive biomarkers for selecting which cancer patients will benefit from antiangiogenic therapy. Also lacking are resistance biomarkers that can identify which escape pathways should be targeted after tumors develop resistance to anti-vascular endothelial growth factor (VEGF) treatment. Recent studies showed that anti-VEGF treatment can make tumor cells more aggressive and metastatic. However, the mechanisms and mediators of this are unidentified.

In order to directly identify the tumor cell-initiated mechanisms responsible for the resistance of pancreatic cancer to anti-VEGF treatment, we recently established and validated two murine models of human pancreatic cancer resistant to the VEGF-specific antibody bevacizumab in vivo. Rather then direct proangiogenic factors, we identified several proinflammatory factors that were expressed at higher levels in cells resistant to anti-VEGF treatment than in treatment-sensitive control cells, including IL-1α and IL-1β, several CXCR2 ligands, and TGF-β. These proinflammatory factors acted in a paracrine manner to stimulate the recruitment of CD11b+ proangiogenic myeloid cells in the tumor microenvironment. Also, we found that secreted factors overexpressed by anti-VEGF treatment-resistant pancreatic cancer cells acted in an autocrine manner to induce epithelial- to- mesenchymal transition (EMT) and were thus responsible for increased aggressiveness of bevacizumab-resistant pancreatic cancer.

We hypothesize that these proinflammatory factors represent alternative signaling pathways responsible for the resistance of pancreatic cancer to bevacizumab and for the metastatic phenotype elicited by VEGF-targeted drugs through the induction of EMT. Thus, single or combined targeting of these proinflammatory signaling pathways would reverse the evasive resistance of pancreatic cancer to anti-VEGF treatments.