20^th Euro-Global Summit on Cancer Therapy& Radiation Oncology August 28-29, 2017 Brussels, Belgium

Adhip P N Majumdar received his MS and PhD degrees from the University of London, England, and DSc (Doctor of Science) degree in Gastroenterology from the University of Aarhus, Denmark. He has been a Professor at Wayne State University since 1992. He also holds the post of Senior Research Career Scientist at the Detroit VA Medical Center. Over the past several years his work has been streamlined to uncover the biochemical and physiological pathways governing the growth of gastrointestinal (GI) tract. He has published 200 original scientific articles in peer-reviewed journals and a multitude of book chapters and review articles. He is particularly interested in elucidating the patho-physiology of age-related changes in the GI mucosa, specifically those that lead to malignancy. To this end, he has begun to investigate the role of pluripotent, self-renewing CSCs in the development and progression of GI malignancies. He has been continually funded by the VA and NIH and is considered one of the nation’s leading investigators in gastrointestinal aging and cancer.

Recent evidence supports the contention that epithelial cancers, including sporadic colorectal cancer (CRC), the incidence of which increases with aging, are diseases driven by self-renewing cancer stem cells (CSCs). One of the characteristics of CSCs is their resistance to 5-FU based chemotherapy, the mainstay of colon cancer therapeutic with significant toxicities, resulting in high disease recurrence underscoring the need for improved CSC-targeted non-toxic preventive or therapeutics for recurrent CRC Investigations were carried out to examine the role of CSCs in the development of CRC and also to develop preventive and/or therapeutic strategies using natural agents to combat this malignancy. Initially we found that curcumin, the major active ingredient of turmeric (Curcuma longa), used in South Asian cuisine, with no discernible toxicity synergizes with FOLFOX (5-FU + Oxaliplatin) and this combination which attenuates EGFR signaling causes a marked inhibition in inhibition of colon cancer cell growth. However, use of curcumin as a chemotherapeutic agent has come under intense scrutiny because of its poor bioavailability. Recently, it has been reported that curcumin complexed with essential turmeric oils (ETOcurcumin) exhibit 7-10 fold higher bioavailability than standard curcumin. We found ETO-curcumin to synergize with palm oil (Trocotrinol) and together they were found to be highly effective in inhibiting the growth FOLFOX-resistant colon cancer cells that are highly enriched in CSCs. The results suggest that the combination of ETO-curcimin and palm oil could be an effective preventive/therapeutic strategy for recurrent colon tumor that are highly enriched in CSCs. Likewise, we found eicosapentaenoic acid (EPA), one of the components of omega-3 polyunsaturated fatty acids to also synergize with FOLFOX and that the combination of EPA and FOLFOX to be highly effective in inhibiting the growth of FOLFOX-resistant colon cancer cells in vitro and in vivo in SCID mice xenograft model. PTEN–Akt axis and Wnt signaling pathway were found to play a pivotal role in regulating the growth inhibitory process. In conclusion, our results suggest that certain natural agents by themselves or together with the conventional 5-FU based chemotherapy could be effective in eliminating or inhibiting the proliferation of CSCs and thus could be utilized to prevent the recurrence of colorectal cancer.

Myron R Szewczuk, PhD is Professor of Immunology, Department of Biomedical and Molecular Sciences and Medicine, Queen’s University, Kingston, Ontario Canada since 36 years. He received his BSc in Chemistry (U. of Guelph), MSc in Biochemistry (Guelph), PhD in Immunochemistry (U. of Windsor) and Post doctoral Training with Gregory Siskind, MD in Cellular Immunology at Cornell University Medical College, NYC. His recent research focuses on the role of glycosylation in receptor activation with a focus on TOLL-like, nerve growth factor Trk, EGFR and insulin receptors. He has discovered a novel receptor signaling platform and its targeted translation in multistage tumorigenesis.

A novel organizational signaling platform linked to glycosylated receptor tyrosine kinases (RTK) (e.g., EGFR, TrkA, insulin) and TOLL-like (TLR) receptors is identified to regulate receptor activation process, all of which are known to play major roles in tumorigenesis. This signaling paradigm proposes that ligand binding to its receptor on the cell surface induces a conformational change of the receptor to initiate matrix metalloproteinase-9 (MMP-9) activation to induce neuraminidase-1 (Neu1). Activated Neu1 hydrolyzes α-2,3-sialyl residues linked to β-galactosides, which are distant from the ligand binding sites. These findings predict a prerequisite desialylation process by activated Neu1 enabling the removal of steric hindrance to receptor association. In addition, the relative levels of specific sialoglycan structures on the cell surface correlate with the ability of cancer cells to form avascular 3D multicellular tumor spheroids and in vivo xenograft tumors. Here, we have identified an innovative and promising entirely new targeted therapy for cancer. Mammalian neuraminidase-1 (Neu1) in complex with matrix metalloproteinase-9 and G-protein coupled receptor tethered to RTKs and TLRs is identified as a major target in the multistage tumorigenesis. Preclinical studies support an entirely new cancer targeted therapy unaffected by mutations of growth factor receptors, involved in tumor neovascularization, chemo resistance of tumors, immune-mediated tumorigenesis, and tissue invasion and metastasis.