The American Association for Cancer Research (AACR) Annual Meeting 2018 was held at the McCormick Place, Chicago, IL, from April 14-18. Faculty, Scientists and Entrepreneurs from Academia and Industry came together and discussed many aspects of cancer research.
Advances in the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 system and the application of synthetic lethality for drugging “undruggable” targets were of particular interest to me. CRISPR-Cas9 technologies are now utilized not only in modeling liver and colon cancers, but for the generation of chromosomal rearrangements and larger deletions. Using the CRISPR-Cas9 system and using two different guide-sequences in the human genome, researchers were able to delete a large part of a chromosome to mimic clinical situations at the genome-scale, such as synthetic lethality. The concept of synthetic lethality is based on the discovery that cell death can be caused by a combination of deficiencies in the expression of two or more genes, whereas deficiency in only one of these genes can increase viability. E-cadherin deficiency and inhibition of the tyrosine kinase ROS1 in breast cancer, and the combination of IGF1R and MEK inhibitors in Kras-mutant lung cancer are good examples of synthetic lethality in cancer therapy.
At a poster session, I presented work from one of my projects entitled “A small-molecule inhibitor of the β-catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo”. The poster represented the preclinical research work I had carried out in the field of anti-colon cancer drug discovery. My collaborators and I showed that a novel compound we synthesized, called HI-B1, is a direct inhibitor of β-catenin. HI-B1 preferentially caused apoptosis in cancer cells, where β-catenin is essential for survival. In addition, we also showed that HI-B1 could retard cancer growth in a colon cancer patient-derived xenograft (PDX) mouse model, with a high-level of β-catenin. Standing by my poster, I got invaluable questions from several people. Two important questions that stood out for me were, firstly, whether our research could provide information about setting up a criterion for β-catenin expression levels to determine when a Wnt/β-catenin inhibitor regimen would be beneficial and secondly, whether we could make even better inhibitors, as compared to HI-B1. To address the first question, I would need data from a larger number of PDX models, to find the threshold for b-catenin expression levels through immunohistochemistry analysis. As the expression levels of PD-1 and PD-L1 have been important indicators for PD-L1 inhibitor treatment in immunotherapy, setting up the criterion of b-catenin expression levels for Wnt/β-catenin inhibitors would be beneficial to the field. To address the second question about designing a better inhibitor, I am working closely with Dr. Reddy, the chemist who designed HI-B1.
Professor Zigang Dong, Executive Director of The Hormel Institute, organized a symposium at the AACR Annual Meeting 2018 and co-chaired with Dr. Shivendra V. Singh (University of Pittsburgh). The symposium included preclinical studies in cancer prevention: the effect of intermittent dosing of naproxen and aspirin in carcinogen-induced rat colon adenocarcinoma, the effect of celastrol on intestinal tumorigenesis in APC/min mice, the clinical evaluation of metformin for oral cancer precision prevention, association of sirtuins and diet in cancer development, the effect of biofilm-producing sulfate-reducing bacteria in colon cancer, the roles of PI3Kγ in pancreatic tumorigenesis, and the efficacy of intermittent dosing of erlotinib and/or naproxen in the prevention of chemically-induced urinary bladder cancer.
Professor Ann M. Bode, Associate Director of the Hormel Institute, and Jessica Swanson, Human Resources Manager, participated in the Cancer and Biomedical Research Career Fair at AACR 2018, representing The Hormel Institute, to recruit outstanding faculty and postdoctoral associates from around the world. This career fair provided an unparalleled opportunity to advertise the new facilities at the institute including a state of the art cryo-electron microscope suite, a computational biology and supercomputing center, immunology and translational research labs, mass spectrometry and space for a dermatology clinic.